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High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts.,The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels.,Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis.,Regional analyses and comparisons with 2013 data were conducted.,A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population).,MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist.,The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years.,Females are twice as likely to live with MS as males.,The global prevalence of MS has risen since 2013, but good surveillance data is not universal.,Action is needed by multiple stakeholders to close knowledge gaps.
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The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults.,Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need.,Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury.,Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction.,These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury.,During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses.,In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased.,Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation.,Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan.,The online version of this article (10.1007/s00401-018-1813-3) contains supplementary material, which is available to authorized users.
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Describe the unique functions of immunoglobulin G4 (IgG4) in IgG4-neurologic disorders (IgG4-ND) and explain why, in contrast to their IgG1-counterparts, they respond poorly to intravenous immune globulin (IVIg) but effectively to anti-B cell therapies.,The IgG4 structure and isotype switch, B cells and plasmablasts relevant to IgG4 production, and IgG4-induced disruption of the targeted antigens are reviewed and compared with IgG1-mediated autoimmune ND, where IVIg inhibits IgG1-triggered inflammatory effects.,The main IgG4-ND include muscle-specific kinase myasthenia; nodal/paranodal chronic inflammatory demyelinating polyradiculoneuropathy with antibodies to neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; antileucine-rich, glioma-inactivated-1 and contactin-associated protein-like 2 associated-limbic encephalitis, Morvan syndrome, or neuromyotonia; and anti-IgLON5 disorder.,The IgG4, because of its unique structural features in the hinge region, has noninflammatory properties being functionally monovalent and bispecific, unable to engage in cross-linking and internalization of the targeted antigen.,In contrast to IgG1 subclass which is bivalent and monospecific, IgG4 does not activate complement and cannot bind to inhibitory Fcγ receptor (FcγRIIb) to activate cellular and complement-mediated immune responses, the key functions inhibited by IVIg.,Because IVIg contains only 0.7%-2.6% IgG4, its idiotypes are of IgG1 subclass and cannot effectively neutralize IgG4 or sufficiently enhance IgG4 catabolism by saturating FcRn.,In contrast, rituximab, by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells, induces long-lasting clinical benefits.,Rituximab is the preferred treatment in IgG4-ND patients with severe disease by effectively targeting the production of pathogenic IgG-4 antibodies.,In contrast, IVIG is ineffective because it inhibits immunoinflammatory functions irrelevant to the mechanistic effects of IgG4 and contains IgG-1 idiotypes that cannot sufficiently neutralize or possibly catabolize IgG4.,Controlled studies with anti-CD19/20 monoclonals that also activate FcγRIIb may be more promising in treating IgG4-ND.
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Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG.,MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction.,The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass.,MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles.,MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life.,Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors.,Therefore, current treatment involves immunosuppression, primarily by corticosteroids.,In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions.,Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.
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Intrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS).,Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS.,We combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders.,MS patients were stratified according to cortical lesion (CL) load.,We identified 227 proteins differently expressed between the patients with high and low CL load.,These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively).,Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected.,By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load.,Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell‐related molecules, such as CXCL13, CXCL12, IL10, and BAFF.,Intrathecal dysregulation of iron homeostasis and coagulation pathway as well as B‐cell and monocyte activity are strictly correlated with cortical damage at early disease stages.
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Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial.,This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies.,Often, patients receive several first-line therapies, while more recent and in part more effective treatments are still being introduced only after these have failed.,However, with the availability of highly efficacious therapies, a novel treatment strategy has emerged, where the aim is to achieve no evidence of disease activity (NEDA).,Achieving NEDA necessitates regular monitoring of relapses, disability and functionality.,However, there is only a poor correlation between conventional magnetic resonance imaging measures like T2 hyperintense lesion burden and the level of clinical disability.,Hence, MRI-based measures of brain atrophy have emerged in recent years potentially reflecting the magnitude of MS-related neuroaxonal damage.,Currently available DMTs differ markedly in their effects on brain atrophy: some, such as fingolimod, have been shown to significantly slow brain volume loss, compared to placebo, whereas others have shown either no, inconsistent, or delayed effects.,In addition to regular monitoring, treatment optimization also requires early intervention with efficacious therapies, because accumulating evidence shows that effective intervention during a limited period early in the course of MS is critical for maintaining neurological function and preventing subsequent disability.,Together, the advent of new MS therapies and evolving management strategies offer exciting new opportunities to optimize treatment outcomes.
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Several inflammatory diseases have been associated with increased bone resorption and fracture rates and different studies supported the relation between inflammatory cytokines and osteoclast activity.,The main factor required for osteoclast activation is the stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL) expressed on osteoblasts.,In this context, interleukin- (IL-) 1β, one of the most powerful proinflammatory cytokines, is a strong stimulator of in vitro and in vivo bone resorption via upregulation of RANKL that stimulates the osteoclastogenesis.,The resulting effects lead to an imbalance in bone metabolism favouring bone resorption and osteoporosis.,In this paper, we review the available literature on the role of IL-1β in the pathogenesis of bone loss.,Furthermore, we analysed the role of IL-1β in bone resorption during rheumatic diseases and, when available, we reported the efficacy of anti-IL-1β therapy in this field.
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Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases.,Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage.,The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA).,For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA.,The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling.,Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity.,Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities.,Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect.,Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.
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The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso).,Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010-2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs.,Random-effects meta-analyses were performed on extracted data.,Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso.,In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007).,Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib.,Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001).,In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003).,In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk.,Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA.,In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.
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Anti-tumour necrosis factor (anti-TNF) therapy has been associated with reports of rapid severe progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD).,However, reports also exist of favourable responses to anti-TNF therapy in patients with ILD.,The aim of this study was to examine the influence of anti-TNF therapy on mortality in patients with pre-existing RA-ILD.,Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, 367 patients with pre-existing RA-ILD were identified (299 treated with anti-TNF therapy and 68 treated with traditional disease-modifying antirheumatic drugs (DMARDs)).,70/299 patients (23%) in the anti-TNF cohort died after a median follow-up of 3.8 years compared with 14/68 (21%) in the DMARD cohort after a median follow-up of 2.1 years.,The mortality was 68 deaths/1000 person years (pyrs) (95% CI 53 to 86) in the anti-TNF cohort and 92/1000 pyrs (95% CI 50 to 155) in the DMARD cohort, generating an age- and sex-adjusted mortality rate ratio (aMRR) of 1.26 (95% CI 0.69 to 2.31).,After further adjustment for potential confounders, the aMRR fell to 0.81 (95% CI 0.38 to 1.73) for the anti-TNF cohort compared with the DMARD cohort.,RA-ILD was the underlying cause of death in 15/70 (21%) and 1/14 (7%) patients in the anti-TNF and DMARD cohorts, respectively.,The mortality in patients with RA-ILD is not increased following treatment with anti-TNF therapy compared with traditional DMARDs.,The proportion of deaths attributable to RA-ILD is higher in patients treated with anti-TNF therapy, although reporting bias may exist.
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Intravenous belimumab plus standard of care (SoC) is approved in the USA and Europe for treatment of active, autoantibody-positive systemic lupus erythematosus (SLE).,This phase III, multicentre, randomised, double-blind, placebo-controlled study (BEL113750; NCT01345253) was conducted in 49 centres across China, Japan and South Korea (May 2011-September 2015).,Patients with SLE were randomised 2:1 to intravenous belimumab 10 mg/kg or placebo, plus SoC, every 4 weeks until Week 48.,The primary endpoint was the SLE Responder Index (SRI) 4 response rate at Week 52.,Secondary endpoints were the percentage of patients with ≥4 point reduction in Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), SRI7, time to first severe flare and number of days prednisone (or equivalent) dose ≤7.5 mg/day and/or reduced by 50% from baseline.,Safety was assessed.,The modified intent-to-treat population included 677 patients (belimumab n=451, placebo n=226).,At Week 52, the SRI4 response rate was higher with belimumab versus placebo (53.8% vs 40.1%; OR: 1.99 (95% CI: 1.40, 2.82; P=0.0001)).,The percentages of patients with a ≥4 point reduction in SELENA-SLEDAI and an SRI7 response were significantly greater for belimumab versus placebo.,Patients in the belimumab group had a 50% lower risk of experiencing a severe flare than those receiving placebo (P=0.0004).,In patients with baseline prednisone dose >7.5 mg/day, there was a significant reduction in steroid use favouring belimumab (P=0.0228).,The incidence of adverse events was similar between groups.,In patients with SLE from North East Asia, belimumab significantly improved disease activity, while reducing prednisone use, with no new safety issues.
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We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients.,The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually.,We assessed relative rates of transition using maximum likelihood estimation in a multistate model.,The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality.,We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry.,Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001).,Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage.,Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)).,Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)).,Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point).,Damage in SLE predicts future damage accrual and mortality.,We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
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To assess the safety and efficacy of RSLV‐132, an RNase Fc fusion protein, in a phase II randomized, double‐blind, placebo‐controlled clinical trial in patients with primary Sjögren’s syndrome (SS).,Thirty patients with primary SS were randomized to receive treatment with RSLV‐132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks.,Eight patients received placebo and 20 patients received RSLV‐132 at a dose of 10 mg/kg.,Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT‐F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST).,Patients randomized to receive RSLV‐132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT‐F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures.,This improvement was significantly correlated with increased expression of selected interferon‐inducible genes (Pearson’s correlations, each P < 0.05).,Administration of RSLV‐132 improved severe fatigue, as determined by 4 independent patient‐reported measures of fatigue, in patients with primary SS.
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Fatigue occurs frequently in patients with cancer, neurological diseases and chronic inflammatory diseases, but the biological mechanisms that lead to and regulate fatigue are largely unknown.,When the innate immune system is activated, heat shock proteins (HSPs) are produced to protect cells.,Some extracellular HSPs appear to recognize cellular targets in the brain, and we hypothesize that fatigue may be generated by specific HSPs signalling through neuronal or glial cells in the central nervous system.,From a cohort of patients with primary Sjögren’s syndrome, 20 patients with high and 20 patients with low fatigue were selected.,Fatigue was evaluated with a fatigue visual analogue scale.,Plasma concentrations of HSP32, HSP60, HSP72 and HSP90α were measured and analysed to determine if there were associations with the level of fatigue.,Plasma concentrations of HSP90α were significantly higher in patients with high fatigue compared with those with low fatigue, and there was a tendency to higher concentrations of HSP72 in patients with high fatigue compared with patients with low fatigue.,There were no differences in concentrations of HSP32 and HSP60 between the high- and low-fatigue groups.,Thus, extracellular HSPs, particularly HSP90α, may signal fatigue in chronic inflammation.,This supports the hypothesis that fatigue is generated by cellular defence mechanisms.
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To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis.,A panel of PTMPs was developed.,Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)-either a citrullinated, carbamylated or acetylated residue.,Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested.,Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis).,Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis.,The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups.,Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups.,We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies.
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A hallmark of rheumatoid arthritis (RA) is the development of autoantibodies targeting proteins that contain citrulline.,Anticitrullinated protein antibodies (ACPAs) are currently detected by the commercial cyclic citrullinated peptide (CCP) assay, which uses a mix of cyclised citrullinated peptides as an artificial mimic of the true antigen(s).,To increase the sensitivity of ACPA detection and dissect ACPA specificities, we developed a multiplex assay that profiles ACPAs by measuring their reactivity to the citrullinated peptides and proteins derived from RA joint tissue.,We created a bead-based, citrullinated antigen array to profile ACPAs.,This custom array contains 16 citrullinated peptides and proteins detected in RA synovial tissues.,We used the array to profile ACPAs in sera from a cohort of patients with RA and other non-inflammatory arthritides, as well as sera from an independent cohort of RA patients for whom data were available on carriage of HLA-DRB1 ‘shared epitope’ (SE) alleles and history of cigarette smoking.,Our multiplex assay showed that at least 10% of RA patients who tested negative in the commercial CCP assay possessed ACPAs.,Carriage of HLA-DRB1 SE alleles and a history of cigarette smoking were associated with an increase in ACPA reactivity-in anti-CCP+ RA and in a subset of anti-CCP− RA.,Our multiplex assay can identify ACPA-positive RA patients missed by the commercial CCP assay, thus enabling greater diagnostic sensitivity.,Further, our findings suggest that cigarette smoking and possession of HLA-DRB1 SE alleles contribute to the development of ACPAs in anti-CCP− RA.
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Growing evidences indicate that the alterations in gut microbiota are associated with the efficacy of glucocorticoids (GCs) in the treatment of systemic lupus erythematosus (SLE).,However, there is no evidence to prove whether gut microbiota directly mediates the effects of GCs.,Using the MRL/lpr mice, this study firstly addressed the effects of three doses of prednisone on gut microbiota.,Then, this study used fecal microbiota transplantation (FMT) to transfer the gut microbiota of prednisone-treated MRL/lpr mice into the blank MRL/lpr mice to reveal whether the gut microbiota regulated by prednisone had similar therapeutic efficiency and side effects as prednisone.,The effects of prednisone on gut microbiota were dose-dependent in the treatment of MRL/lpr mice.,After transplantation into MRL/lpr mice, prednisone-regulated gut microbiota could alleviate lupus, which might be due to decreasing Ruminococcus and Alistipes and retaining the abundance of Lactobacillus.,However, prednisone-regulated gut microbiota did not exhibit side effects as prednisone.,The reason might be that the pathogens upregulated by prednisone could not survive in the MRL/lpr mice as exogenous microbiota, such as Parasutterella, Parabacteroides, and Escherichia-Shigella.,These data demonstrated that the transplantation of gut microbiota may be an effective method to obtain the therapeutic effects of GCs and avoid the side effects of GCs.,The online version contains supplementary material available at 10.1186/s13075-021-02620-w.
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Oral microbial dysbiosis is known to increase susceptibility of an individual to develop rheumatoid arthritis (RA).,Individuals at-risk of RA may undergo different phases of disease progression.,In this study, we aim to investigate whether and whereby the oral microbiome communities alter prior to symptoms of RA.,Seventy-nine saliva samples were collected from 29 high-risk individuals, who were positive for anti-citrullinated protein antibodies (ACPA) and have no clinical arthritis, 27 RA patients and 23 healthy controls (HCs).,The salivary microbiome was examined using 16S ribosomal RNA gene sequencing.,Alpha and beta diversity analysis and the linear discriminant analysis were applied to examine the bacterial diversity, community structure and discriminatory taxa between three groups, respectively.,The correlation between salivary bacteria and autoantibodies were analyzed.,In the “pre-clinical” stages, salivary microbial diversity was significantly reduced comparing to RA patients and HCs.,In contrast to HCs, like RA patients, individuals at high-risk for RA showed a reduction in the abundance of genus Defluviitaleaceae_UCG-011 and the species Neisseria oralis, but an expansion of Prevotella_6.,Unexpectedly, the relative abundance of Porphyromonas gingivalis, reported as opportunistic pathogens for RA development, was significantly decreased in high-risk individuals.,Additionally, we identified four genera in the saliva from high-risk individuals positively correlated with serum ACPA titers, and the other two genera inversely displayed.,In summary, we observed a characteristic compositional change of salivary microbes in individuals at high-risk for RA, suggesting that oral microbiota dysbiosis occurs in the “pre-clinical” stage of RA and are correlated with systemic autoimmune features.
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To investigate the effects of leptin on different T‐cell populations, in order to gain more insight into the link between leptin and obesity.,Three hundred and nine RRMS patients and 322 controls participated in a cross‐sectional survey, to confirm whether excess weight/obesity in adolescence or early adulthood increased the risk of MS.,Serum leptin levels were determined by ELISA.,MBP83-102, and MOG63-87 peptide‐specific T cells lines were expanded from peripheral blood mononuclear cells.,Leptin receptor expression was measured by RT‐PCR and flow cytometry.,Bcl‐2, p‐STAT3, pERK1/2, and p27kip1 expression were assayed using ELISA, and apoptosis induction was determined by Annexin V detection.,Cytokines were assessed by ELISPOT and ELISA, and regulatory T cells (Tregs) by flow cytometry.,Logistic regression analysis, showed excess weight at age 15, and obesity at 20 years of age increased MS risk (OR = 2.16, P = 0.01 and OR = 3.9, P = 0.01).,Leptin levels correlated with BMI in both groups.,The addition of Leptin increased autoreactive T‐cell proliferation, reduced apoptosis induction, and promoted proinflammatory cytokine secretion.,Obese patients produced more proinflammatory cytokines compared to overweight/normal/underweight subjects.,Inverse correlation was found between leptin levels and circulating Treg cells (r = −0.97, P < 0.0001).,Leptin inhibited Treg proliferation.,Effects of leptin on CD4+CD25− effector T cells were mediated by increased STAT3 and ERK1/2 phosphorylation, and down modulation of the cell cycle inhibitor P27kip1.,In contrast, leptin effects on Tregs resulted from decreased phosphorylation of ERK1/2 and upregulation of p27kip1.,Leptin promotes autoreactive T‐cell proliferation and proinflammatory cytokine secretion, but inhibits Treg‐cell proliferation.
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To determine the levels of brain‐derived neurotrophic factor (BDNF) in the serum of patients suffering from multiple sclerosis (MS) to evaluate the potential of serum BDNF as a biomarker for MS.,Using a recently validated enzyme‐linked immunoassay (ELISA) we measured BDNF in patients with MS (pwMS), diagnosed according to the 2001 McDonald criteria and aged between 18 and 70 years, participating in a long‐term cohort study with annual clinical visits, including blood sampling, neuropsychological testing, and brain magnetic resonance imaging (MRI).,The results were compared with an age‐ and sex‐matched cohort of healthy controls (HC).,Correlations between BDNF levels and a range of clinical and magnetic resonance imaging variables were assessed using an adjusted linear model.,In total, 259 pwMS and 259 HC were included, with a mean age of 44.42 ± 11.06 and 44.31 ± 11.26 years respectively.,Eleven had a clinically isolated syndrome (CIS), 178 relapsing remitting MS (RRMS), 56 secondary progressive MS (SPMS), and 14 primary progressive MS (PPMS).,Compared with controls, mean BDNF levels were lower by 8 % (p˂0.001) in pwMS.,The level of BDNF in patients with SPMS was lower than in RRMS (p = 0.004).,We conclude that while the use of comparatively large cohorts enables the detection of a significant difference in BDNF levels between pwMS and HC, the difference is small and unlikely to usefully inform decision‐making processes at an individual patient level.
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Cellular injury in AQP4-IgG seropositive neuromyelitis spectrum disorder (herein called NMO) involves AQP4-IgG binding to astrocytes, resulting in astrocyte injury by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mechanisms.,The rapid disease progression, severe tissue damage, and abundant leukocyte infiltration seen in some NMO patients suggest a more direct mechanism for demyelination and neurologic deficit than secondary injury from astrocyte loss.,Here, we report evidence for an ‘ADCC bystander mechanism’ in NMO involving injury to nearby cells by leukocytes following their activation by AQP4-bound AQP4-IgG on astrocytes.,In model cocultures containing AQP4-expressing and null CHO cells, AQP4-IgG and complement killed bystander null cells to ~ 100 μm away from AQP4-expressing cells; AQP4-IgG and NK cells produced bystander killing to ~ 300 μm, with perforin deposition seen on injured null cells.,Bystander cytotoxicity was also seen with neutrophil-mediated ADCC and in astrocyte-neuron cocultures.,Mechanistic studies, including real-time imaging, suggested that leukocytes activated by an AQP4-dependent ADCC mechanism injure bystander cells by direct targeted exocytosis on neighboring cells and not by diffusion of soluble granule contents.,In support of this conclusion, ADCC bystander injury was preferentially reduced by an RGDS peptide that inhibits integrin adhesion.,Evidence for ADCC bystander injury to oligodendrocytes and neurons was also found in mice following intracerebral injection of AQP4-IgG and NK cells, which was inhibited by RGDS peptide.,These results establish a novel cellular pathogenesis mechanism in AQP4-IgG seropositive NMO and provide evidence that inflammatory mechanisms can cause widespread tissue damage in NMO independently of the secondary effects from astrocyte loss.,The online version of this article (10.1186/s40478-019-0766-7) contains supplementary material, which is available to authorized users.
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Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord.,However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases.,Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method.,NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE.,Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG.,Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %.,These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology.,In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage.,In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO.,In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models.,Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages.,(350/350),The online version of this article (doi:10.1186/s40478-015-0259-2) contains supplementary material, which is available to authorized users.
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Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA).,Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation.,To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles.,Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs.,Differentially marked genes are enriched for immunological and unexpected pathways, with “Huntington’s Disease Signaling” identified as particularly prominent.,We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix.,This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets.,Fibroblast-like synoviocytes (FLS) in the intimal layer of the synovium can become invasive and destroy cartilage in patients with rheumatoid arthritis (RA).,Here the authors integrate a variety of epigenomic data to map the epigenome of FLS in RA and identify potential therapeutic targets.
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As there are pharmacological differences between males and females, and glucocorticoid (GC) treatment is associated with increased cardiovascular mortality rate in rheumatoid arthritis (RA) patients, it is important to study serum polar lipid profiles of male and female patients in response to GC therapy.,Gender differences may require an adjustment to the treatment strategy for a selection of patients.,Serum samples from 281 RA patients were analysed using a targeted lipidomics platform.,The differences in GC use and gender on polar lipid profiles were cross sectionally examined by multiple linear regressions, while correcting for confounding factors.,Differences in polar lipids between GC users and non-GC users in females and males were merely restricted to lysophospholipids (lysophosphatidylcholines and lysophosphatidylethanolamines).,Lysophospholipids in female patients treated with GCs were significantly higher than female patients not treated with GCs (p = 6.0 E−6), whereas no significant difference was observed in male GC users versus non-users (p = 0.397).,The lysophospholipid profiles in response to GCs were significantly different between male and female RA patients, which may have implications for the cardiovascular risk of GC treatment.,The online version of this article (doi:10.1007/s10787-016-0284-1) contains supplementary material, which is available to authorized users.
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To analyze characteristics of clinical practice guidelines (CPGs) for the management of rheumatoid arthritis (RA) developed in Latin American (LA) countries and to describe the knowledge, use, and barriers for their implementation perceived among LA rheumatologists, a comprehensive literature search including Medline, PubMed, Cochrane Library, LILACS and Scielo was performed.,The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was applied for evaluation.,A survey was sent to PANLAR members containing questions related to knowledge about guidelines, application of the recommendations, and difficulties in implementing CPGs.,Eight guidelines were identified.,Most guidelines were evidence based (62 %), but in only 37 % a systematic literature search was done.,None of the guidelines included patients’ views and preferences, and only few of them stated an updating procedure.,Funding body independence and disclosure of conflicts of interest were rarely reported.,The survey was answered by 214 rheumatologists from all Latin American countries.,Most rheumatologist reported knowledge and use of clinical guidelines, mainly international ones.,In general, rheumatologist felt that guidelines apply to only a minority of patients seen in daily clinical practice.,Limited access expensive drugs, suggested by the guidelines, was the most frequent barrier to guidelines implementation that was reported.,A good number of guidelines on the treatment of rheumatoid arthritis have been developed in Latin America.,Most of them are lacking some of the components recognized for high-quality clinical guidelines development.,In spite that most rheumatologist know and apply guidelines, access to drugs is still a very important barrier to their implementation in Latin America.
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Early rheumatoid arthritis (RA) patients may show rapid radiographic progression (RRP) despite rapid initiation of synthetic disease-modifying anti-rheumatic drugs (DMARDs).,The present study aimed to develop a matrix to predict risk of RRP despite early DMARD initiation in real life settings.,The ESPOIR cohort included 813 patients from the community with early arthritis for < 6 months; 370 patients had early RA and had received methotrexate or leflunomide during the first year of follow-up.,RRP was defined as an increase in the van der Heijde-modified Sharp score (vSHS) ≥ 5 points at 1 year.,Determinants of RRP were examined first by bivariate analysis, then multivariate stepwise logistic regression analysis.,A visual matrix model was then developed to predict RRP in terms of patient baseline characteristics.,We analyzed data for 370 patients.,The mean Disease Activity Score in 28 joints was 5.4 ± 1.2, 18.1% of patients had typical RA erosion on radiographs and 86.4% satisfied the 2010 criteria of the American College of Rheumatology/European League Against Rheumatism.,During the first year, mean change in vSHS was 1.6 ± 5.5, and 41 patients (11.1%) showed RRP.,A multivariate logistic regression model enabled the development of a matrix predicting RRP in terms of baseline swollen joint count, C-reactive protein level, anti-citrullinated peptide antibodies status, and erosions seen on radiography for patients with early RA who received DMARDs.,The ESPOIR matrix may be a useful clinical practice tool to identify patients with early RA at high risk of RRP despite early DMARD initiation.
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This ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE).,Patients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy.,Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52).,Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and ‘30 alternative’ definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global).,Safety and pharmacokinetics were assessed.,Study not powered for statistical testing.,Ninety-three patients were randomised (belimumab, n=53; placebo, n=40).,At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)).,PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)).,Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo).,Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL.,The belimumab intravenous pharmacokinetics and benefit-risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate.,NCT01649765.
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We undertook this US multicenter continuation study (GlaxoSmithKline study BEL112233; ClinicalTrials.gov identifier: NCT00724867) to assess long‐term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) who completed the Study of Belimumab in Subjects with SLE 76‐week trial (ClinicalTrials.gov identifier: NCT00410384).,Patients continued to receive the same belimumab dose plus standard therapy; patients previously receiving placebo received 10 mg/kg belimumab.,The primary outcome measure was long‐term safety of belimumab (frequency of adverse events [AEs] and damage assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI], evaluated every 48 weeks [1 study year]).,Other assessments included the SLE Responder Index (SRI), flare rates (using the modified SLE Flare Index [SFI]), prednisone use, and B cell levels.,Of 268 patients, 140 completed the study and 128 withdrew.,The mean ± SD score on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) at baseline was 7.8 ± 3.86.,The mean ± SD SDI score increased by 0.4 ± 0.68 from its value at baseline (1.2 ± 1.51).,The overall incidence of treatment‐related and serious AEs remained stable or declined through study year 7.,An SRI response was achieved by 41.9% and 75.6% of patients at the study year 1 and study year 7 midpoints, respectively.,At the study year 7 midpoint, relative to baseline, 78.2% had achieved a ≥4‐point reduction in the SELENA-SLEDAI score, 98.4% had no new British Isles Lupus Assessment Group (BILAG) A organ domain score and no more than 1 new BILAG B organ domain score, 93.7% had no worsening in the physician's global assessment of disease activity, 20.6% had experienced ≥1 severe SFI flare, the mean decrease in prednisone dose was 31.4%, and the median change in CD20+ B cell numbers was −83.2%.,These long‐term exposure results confirm the previously observed safety and efficacy profiles of belimumab in patients with SLE.
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To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG).,In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo.,In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99).,Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score.,Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety.,Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]).,Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean −1.8 vs −1.2, difference −0.7, 95% upper confidence limit [UCL] 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean −1.8 vs −0.4, difference −1.4, 95% UCL −0.4), and MGC (LS mean −3.1 vs −1.2, difference −1.8, 95% UCL 0.4) scores.,Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2.,The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%).,Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated.,Phase 3 evaluation is ongoing (NCT03971422).,This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score.
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To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment.,Cross-sectional study.,We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration.,All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry.,Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite.,Maximum dose and duration of dose ≥20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records.,Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry.,We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income.,In addition, 49.0% of the patients reported feeling reduced social positivity.,Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids.,Early achievement of the treatment target was a major inhibiting factor.,Patients with MG often experience unemployment, unwilling job transfers and a decrease in income.,In addition, many patients report feeling reduced social positivity.,To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.
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Research in recent years has largely explored the immunomodulatory effects of mesenchymal stem cells (MSCs) and their secretory products, called “secretome,” in the treatment of neuroinflammatory diseases.,Here, we examined whether such immunosuppressive effects might be elicited due to inflammasome inactivation.,To this end, we treated experimental autoimmune encephalomyelitis (EAE) mice model of multiple sclerosis (MS) with the conditioned medium or purified exosomes/microvesicles (EMVs) obtained from relapsing-remitting-MS patients human periodontal ligament stem cells (hPDLSCs) and investigated the regulation of NALP3 inflammasome.,We noticed enhanced expression of NALP3, Cleaved Caspase 1, interleukin (IL)-1β, and IL-18 in EAE mouse spinal cord.,Conversely, hPDLSCs-conditioned medium and EMVs significantly blocked NALP3 inflammasome activation and provided protection from EAE.,Reduction in NALP3, Cleaved Caspase 1, IL-1β, and IL-18 level was noticed in conditioned medium and EMVs-treated EAE mice.,Pro-inflammatory Toll-like receptor (TLR)-4 and nuclear factor (NF)-κB were elevated in EAE, while hPDLSCs-conditioned medium and EMVs treatment reduced their expression and increased IκB-α expression.,Characterization of hPDLSCs-conditioned medium showed substantial level of anti-inflammatory IL-10, transforming growth factor (TGF)-β, and stromal cell-derived factor 1α (SDF-1α).,We propose that the immunosuppressive role of hPDLSCs-derived conditioned medium and EMVs in EAE mice may partly attribute to the presence of soluble immunomodulatory factors, NALP3 inflammasome inactivation, and NF-κB reduction.
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The mechanism of leukocyte transendothelial migration (TEM) across the highly restrictive blood-brain barrier (BBB) remains enigmatic, with paracellular TEM thought to require leukocytes to somehow navigate the obstructive endothelial tight junctions (TJs).,Transient interactions between TJ proteins on the respective leukocyte and endothelial surfaces have been proposed as one mechanism for TEM.,Given the expanding role of extracellular vesicles (EVs) in intercellular communication, we investigated whether EVs derived from brain microvascular endothelial cells (BMEC) of the BBB may play a role in transferring a major TJ protein, claudin-5 (CLN-5), to leukocytes as a possible basis for such a mechanism during neuroinflammation.,High-resolution 3D confocal imaging was used to highlight CLN-5 immunoreactivity in the central nervous system (CNS) and on leukocytes of mice with the neuroinflammatory condition experimental autoimmune encephalomyelitis (EAE).,Both Western blotting of circulating leukocytes from wild-type mice and fluorescence imaging of leukocyte-associated eGFP-CLN-5 in the blood and CNS of endothelial-targeted, Tie-2-eGFP-CLN-5 transgenic mice were used to confirm the presence of CLN-5 protein on these cells.,EVs were isolated from TNF-α-stimulated BMEC cultures and blood plasma of Tie-2-eGFP-CLN-5 mice with EAE and evaluated for CLN-5 protein by Western blotting and fluorescence-activated cell sorting (FACS), respectively.,Confocal imaging and FACS were used to detect binding of endothelial-derived EVs from these two sources to leukocytes in vitro.,Serial electron microscopy (serial EM) and 3D contour-based surface reconstruction were employed to view EV-like structures at the leukocyte:BBB interface in situ in inflamed CNS microvessels.,A subpopulation of leukocytes immunoreactive for CLN-5 on their surface was seen to infiltrate the CNS of mice with EAE and reside in close apposition to inflamed vessels.,Confocal imaging of immunostained samples and Western blotting established the presence of CLN-5+ leukocytes in blood as well, implying these cells are present prior to TEM.,Moreover, imaging of inflamed CNS vessels and the associated perivascular cell infiltrates from Tie-2-eGFP-CLN-5 mice with EAE revealed leukocytes bearing the eGFP label, further supporting the hypothesis CLN-5 is transferred from endothelial cells to circulating leukocytes in vivo.,Western blotting of BMEC-derived EVs, corresponding in size to both exosomes and microvesicles, and FACS analysis of plasma-derived EVs from Tie-2-eGFP-CLN-5 mice with EAE validated expression of CLN-5 by EVs of endothelial origin.,Confocal imaging and FACS further revealed both PKH-67-labeled EVs from cultured BMECs and eGFP-CLN-5+ EVs from plasma of Tie-2-eGFP-CLN-5 mice with EAE can bind to leukocytes.,Lastly, serial EM and 3D contour-based surface reconstruction revealed a close association of EV-like structures between the marginating leukocytes and BMECs in situ during EAE.,During neuroinflammation, CLN-5+ leukocytes appear in the CNS, and both CLN-5+ leukocytes and CLN-5+ EVs are detected in the blood.,As endothelial cells transfer CLN-5+ to leukocytes in vivo, and EVs released from BMEC bind to leukocytes in vitro, EVs may serve as the vehicles to transfer CLN-5 protein at sites of leukocyte:endothelial contact along the BBB.,This action may be a prelude to facilitate TEM through the formation of temporary TJ protein bridges between these two cell types.,The online version of this article (doi:10.1186/s12974-016-0755-8) contains supplementary material, which is available to authorized users.
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T cell Ig and mucin domain (Tim) protein family members were identified to be important regulators of the immune response.,As their name indicates, Tim proteins were originally considered a T cell-specific markers, and they mainly regulate the responses of T helper cells.,However, accumulating evidence indicates that Tims are also expressed on antigen-presenting cells (APCs), such as monocytes, macrophages, dendritic cells (DCs) and B cells, and even plays various roles in natural killer cells (NKs) and mast cells.,In recent years, the expression and function of Tims on different cells and the identification of new ligands for the Tim family have suggested that the Tim family plays a crucial role in immune regulation.,In addition, the relationship between Tim family gene polymorphisms and susceptibility to several autoimmune diseases has expanded our knowledge of the role of Tim proteins in immune regulation.,In this review, we discuss how the Tim family affects immunomodulatory function and the potential role of the Tim family in typical autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D).,A deeper understanding of the immunoregulatory mechanism of the Tim family might provide new insights into the clinical diagnosis and treatment of autoimmune diseases.
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The aim of our study was to determine whether there is a correlation between transcription factors expression and Th17/Treg ratio, cytokine profile in the RA phenotype as well as to identify transcription factors that could be a potential biomarker for RA.,The study was conducted on 45 patients with RA, 27 patients with OA and 46 healthy controls (HCs).,Th17 and Treg frequency was determined by flow cytometry (15 patients with RA/OA and 15 subjects of HC).,Gene expression was estimated by qPCR, and the serum cytokine levels were determined by ELISA.,The percentage of Treg (CD4+CD25highCD127-) cells in RA patients was lower than in OA patients or HCs.,Proportions of Th17 (CD4+CCR6+CXCR3-) cells were higher in RA and OA in comparison to HCs.,STAT5 showed a very high expression in the blood of RA patients compared to healthy subjects.,The expression of STAT5 and HELIOS was not detected in Th17 cells.,A positive correlation between SMAD3 and STAT3 in RA patients was observed.,Negative correlations between HIF-1A and SMAD2 in RA Treg cells and DAS-28 score were observed.,The range of serum of IL-17 and IL-21 were higher in RA patients than in OA patients.,Concentrations of serum IL-2 and IFN-γ were higher in RA and OA patients than in healthy subjects.,Based on the ROC analysis, the diagnostic potential of the combination of HIF1A, SMAD3 and STAT3, was determined at AUC 0.95 for distinguishing RA patients from HCs.,For distinguishing RA patients from OA patients the diagnostic potential of the combination of SMAD2, SMAD3, SMAD4 and STAT3, was determined at AUC 0.95.,Based on our study, we conclude that SMAD3 and STAT3 could be potential diagnostic biomarkers for RA.
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To report a unique case and literature review of post COVID-19 associated transverse myelitis and dysautonomia with abnormal MRI and CSF findings.,Coronavirus disease have been reported to be associated with several neurological manifestations such as stroke, Guillain-Barré syndrome, meningoencephalitis amongst others.,There are only few reported cases of transverse myelitis with the novel coronavirus (n-CoV-2) and only one reported case identifying dysautonomia in COVID-19 patient.,Here, we identify a COVID-19 patient diagnosed with acute transverse myelitis in addition to dysautonomia following with complete resolution of symptoms.,A retrospective chart review of a patient diagnosed with post SARS-CoV-2 infection acute transverse myelitis and dysautonomia, and a review of literature of all the reported cases of transverse myelitis and COVID-19, from December 1st, 2019 till December 25th, 2020, was performed.,To our knowledge, this is the first reported case of transverse myelitis and dysautonomia in a patient with SARS-CoV-2 infection, who responded to intravenous methyl prednisone and bromocriptine.,Follow-up imaging of the spine showed complete resolution of the lesion.,Further studies would be recommended to identify the underlying correlation between COVID-19 and transverse myelitis.
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Varicella zoster virus (VZV) infection has been implicated in multiple sclerosis (MS), but direct causal involvement has been disputed.,Nevertheless, knowledge of VZV exposure is important, given the risk of serious complications of first exposure while undergoing immunosuppressive treatment, in particular with fingolimod.,We distributed questionnaires to MS clinic patients, requesting information about history of chickenpox, sibling/household/occupational exposure, history of zoster (shingles), and disease-modifying treatment.,A random, proportionally representative sample of 51 patients that included patients with positive, negative, and unknown chickenpox history were selected for determination of VZV IgG by ELISA.,Of 1206 distributed questionnaires, 605 were returned (50% response rate).,Of these, 86% reported history of chickenpox, 5.6% gave negative history, and 8.5% did not know.,Of 594 who answered the zoster question, 78% gave a negative response, 4% did not know, and 104 (17%) answered yes.,Of these, 83 reported 1 episode; 12 had 2; 5 had 3; and 1 each reported 5, 6, and 15 episodes.,Of 51 patients tested for VZV IgG (44 “yes,” 4 “no,” and 3 “I don’t know” answers to the question of whether they had chickenpox), 48 were seropositive; the 3 seronegative all had reported having had chickenpox.,The high rate of MS patients reporting prior chickenpox infection is comparable with previous reports.,A substantial proportion of MS patients, estimated to be higher than an age-matched general population, report single or multiple episodes of zoster.,These data are useful for consideration of immunosuppressive treatments and/or VZV and zoster vaccination.
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Rheumatoid arthritis (RA), a kind of autoimmune disorder, is featured by many physical symptoms and proliferation of fibroblast-like synoviocytes (FLSs).,The relevance of long non-coding RNAs (lncRNAs) in the progression of RA has been probed.,Hence, the goal of this report was to investigate the action of plasmacytoma variant translocation 1 (PVT1), a lncRNA, in FLSs and the basic mechanism.,Initially, RA rats were developed to evaluate the expression of PVT1, microRNA-543 (miR-543), and signal peptide-CUB-EGF-like containing protein 2 (SCUBE2) in synovial tissues.,Enhancement or loss of PVT1 or miR-543 was achieved to explore their effects on proliferation, cell cycle, and apoptosis of FLSs.,The interaction between PVT1 and miR-543 and between miR-543 and its putative target SCUBE2 was examined to elucidate the correlations.,Finally, the protein expression of proliferation- and apoptosis-associated genes were assessed by western blot assays.,PVT1 was overexpressed in synovial tissues from RA patients through microarray expression profiles.,The PVT1 and SCUBE2 expression was boosted, and miR-543 was reduced in synovial tissues of rats with RA.,PVT1 specifically bound to miR-543, and miR-543 negatively regulated SCUBE2 expression.,Overexpression of PVT1 or silencing of miR-543 enhanced SCUBE2 expression, thereby promoting proliferation and interleukin-1β (IL-1β) secretion, while inhibiting apoptosis rate of FLSs.,Conversely, si-SCUBE2 reversed the role of miR-543 inhibitor.,The key findings support that PVT1 knockdown has the potency to hinder RA progression by inhibiting SCUBE2 expression to sponge miR-543.
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The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation.,MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases.,Here, we explored the mechanisms of microRNAs in RA.,We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor.,Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC.,This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13.,In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs.,Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs.,Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.
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Aging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure.,Lymph nodes, which filter the lymph to identify and fight infections, play a central role in this process.,However, careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking.,We combined single-cell RNA sequencing (scRNA-seq) with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes (CDLNs) of both young and old mice with or without experimental autoimmune uveitis (EAU).,We found extensive and complicated changes in the cellular constituents of CDLNs during aging.,When confronted with autoimmune challenges, old mice developed milder EAU compared to young mice.,Within this EAU process, we highlighted that the pathogenicity of T helper 17 cells (Th17) was dampened, as shown by reduced GM-CSF secretion in old mice.,The mitigated secretion of GM-CSF contributed to alleviation of IL-23 secretion by antigen-presenting cells (APCs) and may, in turn, weaken APCs’ effects on facilitating the pathogenicity of Th17 cells.,Meanwhile, our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs.,Overall, aging altered immune cell responses, especially through toning down Th17 cells, counteracting EAU challenge in old mice.,The online version contains supplementary material available at 10.1007/s13238-021-00882-3.
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Non-infectious uveitis is an inflammatory disorder of the eye that accounts for severe visual loss without evident infectious agents.,While T cells are supposed to dominate the induction of inflammation in non-infectious uveitis, the role of B cells in the pathogenesis of this disease is obscure.,Therefore, this review aimed to discuss diverse B-cell participation in different non-infectious uveitides and their roles in the pathogenesis of this disease as well as the mechanism of action of rituximab.,Increasing evidence from experimental models and human non-infectious uveitis has suggested the participation of B cells in non-infectious uveitis.,The participation levels vary in different uveitides.,Furthermore, B cells play multiple roles in the pathogenic mechanisms.,B cells produce autoantibodies, regulate T cell responses via antibody-independent functions, and constitute ectopic lymphoid structures.,Regulatory B cells perform pivotal anti-inflammatory functions in non-infectious uveitis.,Rituximab may work by depleting pro-inflammatory B cells and restoring the quantity and function of regulatory B cells in this disease.,Identifying the levels of B-cell participation and the associated roles is beneficial for optimizing therapy.,Diversified experimental model choices and emerging tools and/or methods are conducive for future studies on this topic.
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We report COVID-19 presentation, course and outcomes in teriflunomide-treated MS patients in Argentina.,Methods: descriptive, retrospective, multicentre, study that included MS patients receiving teriflunomide who developed COVID-19, with clinical follow-up at reference MS centres, also listed in a nationwide registry.,Results: Eighteen MS patients on teriflunomide treatment, from eight MS centres developed COVID-19.,The mean age was 41,2 years and 72% of them were female; 94% had diagnosis of relapsing-remitting MS and 6% presented a radiologically isolated syndrome.,Median EDSS was 2 (range 0-5.5).,The average time on teriflunomide therapy was 3 years.,COVID-19 diagnosis was confirmed with nasal swab in 61%.,None required hospitalization and they completely recovered from the acute-phase within 7-14 days.,All the patients continued their teriflunomide therapy during COVID-19 course.,No MS relapses occurred during or after COVID-19 course.,Conclusion: Our report adds to the evidence that COVID-19 is mild in patients receiving teriflunomide therapy and that continuing with teriflunomide therapy during Sars-CoV-2 infection is safe and advisable for MS patients.
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The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown.,To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells.,A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine.,The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry.,Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories.,Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia.,CD3+ T cell depletion was modest.,The mRNA expression of metabolism genes varied between lymphocyte subsets.,A high ratio of deoxycytidine kinase to group I cytosolic 5′ nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells.,Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine.,These may offer a new target, possibly with potential biomarker activity, for future drug development.,The online version of this article (10.1007/s00415-018-8830-y) contains supplementary material, which is available to authorized users.
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The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown.,Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic.,To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS).,All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study.,Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects.,528 pwMS and 627 healthy subjects were included.,Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS.,We found a significant correlation between time since the last rituximab dose and the development of humoral immunity.,Revaccination in two seronegative patients induced a weak antibody response.,Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients.,Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations.
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In this consensus statement, we provide updated recommendations on multiple sclerosis (MS) management during the COVID-19 crisis and the post-pandemic period applicable to neurology services around the world.,Statements/recommendations were generated based on available literature and the experience of 13 MS expert panelists using a modified Delphi approach online.,The statements/recommendations give advice regarding implementation of telemedicine; use of disease-modifying therapies and management of MS relapses; management of people with MS at highest risk from COVID-19; management of radiological monitoring; use of remote pharmacovigilance; impact on MS research; implications for lowest income settings, and other key issues.
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Single-cell RNA sequencing (scRNA-seq) technology can analyze the transcriptome expression level of cells with high-throughput from the single cell level, fully show the heterogeneity of cells, and provide a new way for the study of multicellular biological heterogeneity.,Synovitis is the pathological basis of rheumatoid arthritis (RA).,Synovial fibroblasts (SFs) and synovial macrophages are the core target cells of RA, which results in the destruction of articular cartilage, as well as bone.,Recent scRNA-seq technology has made breakthroughs in the differentiation and development of two types of synovial cells, identification of subsets, functional analysis, and new therapeutic targets, which will bring remarkable changes in RA treatment.
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Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs.,JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response.,The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence.,A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected.,The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed.,Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time.,Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy.,Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use.
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The COVID‐19 pandemic has brought challenges for healthcare management of patients with multiple sclerosis (MS).,Concerns regarding vulnerability to infections and disease‐modifying therapies (DMTs) and their complications have been raised.,Recent published guidelines on the use of DMTs in relation to COVID‐19 in MS patients have been diverse between countries with lack of evidence‐based facts.,In Sweden, there exists a particular interest in anti‐CD20 therapy as a possible risk factor for severe COVID‐19 due to the large number of rituximab‐treated patients off‐label in the country.,Rapid responses from the Swedish MS Association (SMSS) and the Swedish MS registry (SMSreg) have resulted in national guidelines on DMT use for MS patients and implementation of a COVID‐19 module in the SMSreg.,Recently updated guidelines also included recommendations on COVID‐19 vaccination with regard to the different DMTs.,Social distancing policies forced implementation of telemedicine consultation to replace in‐person consultations as part of regular MS health care.,Patient‐reported outcome measures (PROMs) in SMSreg have been useful in this respect.,This paper reports our experiences on the progress of national MS health care during the COVID‐19 pandemic, in addition to offering an overview of the present scientific context.
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•Prolonged lockdown and business closure determined disruption of lifestyle, social isolation, and loss on personal incomes.,•In our cohort of relapsing remitting multiple sclerosis patients the return to work was associated with the presence of psychiatric concerns that were higher in patients who have started /switched disease modifying therapies in the last 12 months or in those with higher levels of disability.,•Multiple sclerosis patients, already burdened in physical and psychological terms, may be more vulnerable to the concerns and neuropsychiatric consequences related to COVID-19.,Prolonged lockdown and business closure determined disruption of lifestyle, social isolation, and loss on personal incomes.,In our cohort of relapsing remitting multiple sclerosis patients the return to work was associated with the presence of psychiatric concerns that were higher in patients who have started /switched disease modifying therapies in the last 12 months or in those with higher levels of disability.,Multiple sclerosis patients, already burdened in physical and psychological terms, may be more vulnerable to the concerns and neuropsychiatric consequences related to COVID-19.,The prolonged lockdown related to COVID-19 pandemic determined disruption of lifestyle and social isolation.,To assess the mental health status of Relapsing-Remitting Multiple Sclerosis (RRMS) patients regularly followed at the MS center of Catania (Italy) and returning to work after the easing of lockdown during COVID-19 pandemic.,Then, to identify any variables associated to psychological distress.,RRMS patients returning to work during the COVID-19 pandemic were invited to answer a telephonic interview consisting of the administration of the Short-Screening-Scale for DSM IV (SSS-DSM-IV), the Depression, Anxiety, Stress Scale- 21 (DASS-21) and the Insomnia Severity Index (ISI).,Other information was extracted from electronic medical records.,Valid and complete interviews were obtained from 432 patients (response rate 64.3%).,Out of them, 277 (64.1%) were female, mean age 40.4 (SD 12.4) years.,One-hundred thirty-seven (31.7%) RRMS patients received a score ≥4 at the SSS-DSM-IV, indicating clinically significant PTSD-like symptoms.,About DASS-21, moderate-to-severe anxiety was reported by 210 RRMS patients (48.6%), moderate-to-severe depression, and moderate-to-severe stress were respectively reported by 95 (22%) and 220 (50.9%) RRMS patients.,Insomnia was reported by 128 patients (29.6%).,Factors associated with major severity of symptoms were: marital status, previous diagnosis of mood disorders, switching/starting Disease-Modifying Therapies in the last 12 months, and a higher level of disability measured with Expanded Disability Status Scale (for all, p<.05).,Our findings highlight the need to provide psychological support to MS patients facing the delicate phase of returning to work and to normal activities.
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The CNS vasculature tightly regulates the passage of circulating molecules and leukocytes into the CNS.,In the neuroinflammatory disease multiple sclerosis (MS), these regulatory mechanisms fail, and autoreactive T cells invade the CNS via blood vessels, leading to neurological deficits depending on where the lesions are located.,The region-specific mechanisms directing the development of such lesions are not well understood.,In this study, we investigated whether pericytes regulate CNS endothelial cell permissiveness toward leukocyte trafficking into the brain parenchyma.,By using a pericyte-deficient mouse model, we show that intrinsic changes in the brain vasculature due to absence of pericytes facilitate the neuroinflammatory cascade and can influence the localization of the neuroinflammatory lesions.,Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood-brain barrier (BBB) and astrocytic end-feet.,Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive.,Using adult pericyte-deficient mice (Pdgfbret/ret), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation.,The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage.,Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain.,Additionally, administration of anti-VCAM-1 and anti-ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation.,Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain.,These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.
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Disruption of the BBB is critical to initiation and perpetuation of disease in Multiple Sclerosis (MS).,We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury.,We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration.,Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte end-feet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation.,Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment, and also leads to OPC secretion of Wif1, that interferes with Wnt ligand function on endothelial tight junction integrity.,Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB.
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To investigate the long‐term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody‐positive SLE.,The study was designed as a multicenter, open‐label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double‐blind study.,Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose.,Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16‐week intervals) and glucocorticoid use (assessed at 4‐week intervals).,Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study.,Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient‐years, median number of infusions 115.5 [range 7-155]).,The percentage of patients with AEs each year remained stable or decreased.,Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable.,The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12.,The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline.,This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials.,Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study.,For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long‐term disease control.
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We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients.,The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually.,We assessed relative rates of transition using maximum likelihood estimation in a multistate model.,The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality.,We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry.,Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001).,Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage.,Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)).,Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)).,Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point).,Damage in SLE predicts future damage accrual and mortality.,We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
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This study describes the development and feasibility evaluation of a physical activity intervention for children with type 1 diabetes called ‘Steps to Active Kids with Diabetes’ (STAK-D).,It aims to explore the feasibility and acceptability of the intervention and study design.,Thirteen children aged 9-11 years and their parents were recruited from one paediatric diabetes clinic.,A process evaluation was conducted alongside a two-arm randomised feasibility trial, including assessment of rate of recruitment, adherence, retention, data completion and burden, implementation fidelity and adverse events.,Qualitative interviews with children (n = 9), parents (n = 8), healthcare professionals (n = 3) and STAK-D volunteers (n = 8) explored intervention acceptability.,Interviews were analysed thematically.,Rate of recruitment was 25%, with 77% retention at 3-month follow-up.,Study burden was low, data completion was high and the intervention was delivered as per protocol.,No serious adverse event was reported.,Engagement with intervention materials was generally good, but attendance at group activity sessions was low due to logistical barriers.,Interview analysis identified preferred methods of recruitment, motivations for recruitment, barriers and facilitators to adherence, the experience of data collection, experience of the STAK-D programme and its perceived benefits.,STAK-D was feasible and acceptable to children, their parents and healthcare professionals, but group sessions may present logistical issues.,Recruitment and retention may be improved with a clinic-wide approach to recruitment.,This trial was registered on ClinicalTrials.gov: NCT02144337 (16/01/2014).,The online version of this article (10.1186/s12887-018-1036-8) contains supplementary material, which is available to authorized users.
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To synthesize evidence from randomized and non-randomized studies of physical activity interventions in children and young people with Type 1 diabetes so as to explore clinically relevant health outcomes and inform the promotion of physical activity.,We conducted a search of CINAHL Plus, the Cochrane Library, EMBASE, MEDLINE, PsycINFO, SCOPUS, SportDiscus and Web of Science between October and December 2012.,Eligible articles included subjects aged ≤18 years with Type 1 diabetes and a physical activity intervention that was more than a one-off activity session.,Physiological, psychological, behavioural or social outcomes were those of interest.,A total of 26 articles (10 randomized and 16 non-randomized studies), published in the period 1964-2012, were reviewed.,Although there was heterogeneity in study design, methods and reporting, 23 articles reported at least one significant beneficial health outcome at follow-up.,Meta-analyses of these studies showed potential benefits of physical activity on HbA1c (11 studies, 345 participants, standardized mean difference -0.52, 95% CI -0.97 to -0.07; P = 0.02), BMI (four studies, 195 participants, standardized mean difference -0.41, 95% CI -0.70 to -0.12; P = 0.006) and triglycerides (five studies, 206 participants, standardized mean difference -0.70, 95% CI -1.25 to -0.14; P = 0.01).,The largest effect size was for total cholesterol (five studies, 206 participants, standardized mean difference -0.91, 95% CI -1.66 to -0.17; P = 0.02).,Physical activity is important for diabetes management and has the potential to delay cardiovascular disease, but there is a lack of studies that are underpinned by psychological behaviour change theory, promoting sustained physical activity and exploring psychological outcomes.,There remains a lack of knowledge of how to promote physical activity in people with Type 1 diabetes.
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Synovial fibroblasts (SF) undergo phenotypic changes in rheumatoid arthritis (RA) that contribute to inflammatory joint destruction.,This study was undertaken to evaluate the clinical and functional significance of ectopic podoplanin (gp38) expression by RA SF.,Expression of gp38 and its CLEC2 receptor was analyzed by immunohistochemistry in synovial arthroscopic biopsies from RA patients and normal and osteoarthritic controls.,Correlation between gp38 expression and RA clinicopathological variables was analyzed.,In patients rebiopsied after anti-TNF-α therapy, changes in gp38 expression were determined.,Platelet-SF coculture and gp38 silencing in SF were used to analyze the functional contribution of gp38 to SF migratory and invasive properties, and to SF platelet crosstalk.,gp38 was abundantly but variably expressed in RA, and it was undetectable in normal synovial tissues.,Among clinicopathologigal RA variables, significantly increased gp38 expression was only found in patients with lymphoid neogenesis (LN), and RF or ACPA autoantibodies.,Cultured synovial but not dermal fibroblasts showed strong constitutive gp38 expression that was further induced by TNF-α.,In RA patients, anti-TNF-α therapy significantly reduced synovial gp38 expression.,In RA synovium, CLEC2 receptor expression was only observed in platelets. gp38 silencing in cultured SF did not modify their migratory and invasive properties but reduced the expression of IL-6 and IL-8 genes induced by SF-platelet interaction.,In RA, synovial expression of gp38 is strongly associated to LN and it is reduced after anti-TNF-α therapy.,Interaction between gp38 and CLEC2 platelet receptor is feasible in RA synovium in vivo and can specifically contribute to gene expression by SF.
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Mast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease.,Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator.,Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well.,We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients.,Synovial samples of anticitrullinated protein antibody-positive (ACPA+) and ACPA-negative (ACPA-) RA and osteoarthritis (OA) patients were stained for IL-17 in combination with CD117 (mast cells), CD3 (T cells) and CD68 (macrophages).,Concentrations of IL-17 in synovial fluid were determined by ELISA.,The number of IL-17+ cells in synovium was comparable in all groups.,Although the vast majority of IL-17+ cells are mast cells, no difference in the percentage of IL-17+ mast cells was observed.,Nonetheless, levels of IL-17 in synovial fluid were increased in ACPA+ RA patients compared to ACPA- RA and OA patients.,The synovial mast cell is the main IL-17+ cell in all three arthritis groups analyzed.,These data are relevant for studies aimed at blocking IL-17 in the treatment of arthritis.
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Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution.,The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification.,Machine learning can identify groups with similar features using multidimensional data.,Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies.,We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation.,Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led.,People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate.,People with the lesion-led MS subtype show positive treatment response in selected clinical trials.,Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials.,Multiple sclerosis is a heterogeneous progressive disease.,Here, the authors use an unsupervised machine learning algorithm to determine multiple sclerosis subtypes, progression, and response to potential therapeutic treatments based on neuroimaging data.
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Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing.,Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research.,A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis.,Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation.,Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS.,Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.
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SB2 is a biosimilar to the reference infliximab (INF).,Similar efficacy, safety and immunogenicity between SB2 and INF up to 30 weeks were previously reported.,This report investigates such clinical similarity up to 54 weeks, including structural joint damage.,In this phase III, double-blind, parallel-group, multicentre study, patients with moderate to severe RA despite MTX were randomized (1:1) to receive 3 mg/kg of either SB2 or INF at 0, 2, 6 and every 8 weeks thereafter.,Dose escalation by 1.5 mg/kg up to a maximum dose of 7.5 mg/kg was allowed after week 30.,Efficacy, safety and immunogenicity were measured at each visit up to week 54.,Radiographic damage evaluated by modified total Sharp score was measured at baseline and week 54.,A total of 584 patients were randomized to receive SB2 (n = 291) or INF (n = 293).,The rate of radiographic progression was comparable between SB2 and INF (mean modified total Sharp score difference: SB2, 0.38; INF, 0.37) at 1 year.,ACR responses, 28-joint DAS, Clinical Disease Activity Index and Simplified Disease Activity Index were comparable between SB2 and INF up to week 54.,The incidence of treatment-emergent adverse events and anti-drug antibodies were comparable between treatment groups.,Such comparable trends of efficacy, safety and immunogenicity were consistent from baseline up to 54 weeks.,The pattern of dose increment was also comparable between SB2 and INF.,SB2 maintained similar efficacy, safety and immunogenicity with INF up to 54 weeks in patients with moderate to severe RA.,Radiographic progression was comparable at 1 year.,ClinicalTrials.gov (http://clinicaltrials.gov; NCT01936181) and EudraCT (https://www.clinicaltrialsregister.eu; 2012-005733-37)
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To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).,In this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX.,PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient’s Global Assessment of Disease Activity (PtGA), patient’s assessment of pain and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain.,The primary study endpoint was at week 12.,Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables.,Compared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12.,Improvements were maintained for measures assessed to week 52.,Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05).,Baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life.,Improvement was maintained to the end of the study (week 52).,NCT01710358.
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Type 1 diabetes (T1D) is an autoimmune disease, which is characterized by the destruction of islet β cells in the pancreas triggered by genetic and environmental factors.,In past decades, extensive familial and genome‐wide association studies have revealed more than 50 risk loci in the genome.,However, genetic susceptibility cannot explain the increased incidence of T1D worldwide, which is very likely attributed by the growing impact of environmental factors, especially gut microbiome.,Recently, the role of gut microbiome in the pathogenesis of T1D has been uncovered by the increasing evidence from both human subjects and animal models, strongly indicating that gut microbiome might be a pivotal hub of T1D‐triggering factors, especially environmental factors.,In this review, we summarize the current aetiological and mechanism studies of gut microbiome in T1D.,A better understanding of the role of gut microbiome in T1D may provide us with powerful prognostic and therapeutic tools in the near future.
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To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies.,Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes.,Venous blood and rectal swabs were collected every 3-6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes.,Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5′ noncoding region, detecting essentially all enterovirus serotypes.,Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years.,The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95-25.3] after adjusting for number of autoantibodies).,Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups.,Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes.,No evidence for viral persistence was found.,This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood.
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In our present single-center pilot study, umbilical cord (UC)-derived mesenchymal stem cells (MSCs) had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE).,The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation (MSCT) in patients with active and refractory SLE.,Forty patients with active SLE were recruited from four clinical centers in China.,Allogeneic UC MSCs were infused intravenously on days 0 and 7.,The primary endpoints were safety profiles.,The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse.,Clinical indices, including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) score and renal functional indices, were also taken into account.,The overall survival rate was 92.5% (37 of 40 patients).,UC-MSCT was well tolerated, and no transplantation-related adverse events were observed.,Thirteen and eleven patients achieved MCR (13 of 40, 32.5%) and PCR (11 of 40, 27.5%), respectively, during 12 months of follow up.,Three and four patients experienced disease relapse at 9 months (12.5%) and 12 months (16.7%) of follow-up, respectively, after a prior clinical response.,SLEDAI scores significantly decreased at 3, 6, 9 and 12 months follow-up.,Total BILAG scores markedly decreased at 3 months and continued to decrease at subsequent follow-up visits.,BILAG scores for renal, hematopoietic and cutaneous systems significantly improved.,Among those patients with lupus nephritis, 24-hour proteinuria declined after transplantation, with statistically differences at 9 and 12 months.,Serum creatinine and urea nitrogen decreased to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in seven relapse cases.,In addition, serum levels of albumin and complement 3 increased after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations.,Serum antinuclear antibody and anti-double-stranded DNA antibody decreased after MSCT, with statistically significant differences at 3-month follow-up examinations.,UC-MSCT results in satisfactory clinical response in SLE patients.,However, in our present study, several patients experienced disease relapse after 6 months, indicating the necessity to repeat MSCT after 6 months.,ClinicalTrials.gov identifier: NCT01741857.,Registered 26 September 2012.
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The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles.,However, the optimum frequency of the MSCs transplantation (MSCT) is unknown.,This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation.,Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT.,Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events.,SLE disease activity index (SLEDAI) and serologic features were evaluated.,Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup.,This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients.
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What factors are associated with the occurrence of hyperglycemic crises (diabetic ketoacidosis and hyperglycemic hyperosmolar state) among adults with diabetes?,In this cohort study of 816 538 adults with diabetes in the US (20 156 adults with type 1 diabetes and 796 382 with type 2 diabetes), younger age, low income, Black race/ethnicity, high hemoglobin A1c level, prior hyperglycemic crises, severe hypoglycemia, depression, neuropathy, and nephropathy were associated with increased risk of hyperglycemic crises in both groups.,The findings suggest that multidisciplinary interventions focusing on groups at high risk of hyperglycemic crises are needed to decrease the incidence and impact of these potentially preventable complications of diabetes.,Hyperglycemic crises (ie, diabetic ketoacidosis [DKA] and hyperglycemic hyperosmolar state [HHS]) are life-threatening acute complications of diabetes.,Efforts to prevent these events at the population level have been hindered by scarce granular data and difficulty in identifying individuals at highest risk.,To assess sociodemographic, clinical, and treatment-related factors associated with hyperglycemic crises in adults with type 1 or type 2 diabetes in the US from 2014 to 2020.,This retrospective cohort study analyzed administrative claims and laboratory results for adults (aged ≥18 years) with type 1 or type 2 diabetes from the OptumLabs Data Warehouse from January 1, 2014, through December 31, 2020.,Rates of emergency department or hospital visits with a primary diagnosis of DKA or HHS (adjusted for age, sex, race/ethnicity, and region, and for year when calculating annualized rates) were calculated separately for patients with type 1 diabetes and type 2 diabetes.,The associations of sociodemographic factors (age, sex, race/ethnicity, region, and income), clinical factors (comorbidities), and treatment factors (glucose-lowering medications, hemoglobin A1c) with DKA or HHS in patients with type 1 or type 2 diabetes were assessed using negative binomial regression.,Among 20 156 adults with type 1 diabetes (mean [SD] age, 46.6 [16.5] years; 51.2% male; 72.6% White race/ethnicity) and 796 382 with type 2 diabetes (mean [SD] age, 65.6 [11.8] years; 50.3% female; 54.4% White race/ethnicity), adjusted rates of hyperglycemic crises were 52.69 per 1000 person-years (95% CI, 48.26-57.12 per 1000 person-years) for type 1 diabetes and 4.04 per 1000 person-years (95% CI, 3.88-4.21 per 1000 person-years) for type 2 diabetes.,In both groups, factors associated with the greatest hyperglycemic crisis risk were low income (≥$200 000 vs <$40 000: type 1 diabetes incidence risk ratio [IRR], 0.61 [95% CI, 0.46-0.81]; type 2 diabetes IRR, 0.69 [95% CI, 0.56-0.86]), Black race/ethnicity (vs White race/ethnicity: type 1 diabetes IRR, 1.33 [95% CI, 1.01-1.74]; type 2 diabetes IRR, 1.18 [95% CI, 1.09-1.27]), high hemoglobin A1c level (≥10% vs 6.5%-6.9%: type 1 diabetes IRR, 7.81 [95% CI, 5.78-10.54]; type 2 diabetes IRR, 7.06 [95% CI, 6.26-7.96]), history of hyperglycemic crises (type 1 diabetes IRR, 7.88 [95% CI, 6.06-9.99]; type 2 diabetes IRR, 17.51 [95% CI, 15.07-20.34]), severe hypoglycemia (type 1 diabetes IRR, 2.77 [95% CI, 2.15-3.56]; type 2 diabetes IRR, 4.18 [95% CI, 3.58-4.87]), depression (type 1 diabetes IRR, 1.62 [95% CI, 1.37-1.92]; type 2 diabetes IRR, 1.46 [95% CI, 1.34-1.59]), neuropathy (type 1 diabetes IRR, 1.64 [95% CI, 1.39-1.93]; type 2 diabetes IRR, 1.25 [95% CI, 1.17-1.34]), and nephropathy (type 1 diabetes IRR, 1.22 [95% CI, 1.01-1.48]; type 2 diabetes IRR, 1.23 [95% CI, 1.14-1.33]).,Age had a U-shaped association with hyperglycemic crisis risk in patients with type 1 diabetes (compared with patients aged 18-44 years: 45-64 years IRR, 0.72 [95% CI, 0.59-0.87]; 65-74 years IRR, 0.62 [95% CI, 0.47-0.80]; ≥75 years IRR, 0.96 [95% CI, 0.66-1.38]).,In type 2 diabetes, risk of hyperglycemic crises decreased progressively with age (45-64 years IRR, 0.57 [95% CI, 0.51-0.63]; 65-74 years IRR, 0.44 [95% CI, .39-0.49]; ≥75 years IRR, 0.41 [95% CI, 0.36-0.47]).,In patients with type 2 diabetes, higher risk was associated with sodium-glucose cotransporter 2 inhibitor therapy (IRR, 1.30; 95% CI, 1.14-1.49) and insulin dependency (compared with regimens with bolus insulin: regimens with basal insulin only, IRR, 0.69 [95% CI, 0.63-0.75]; and without any insulin, IRR, 0.36 [95% CI, 0.33-0.40]).,In this cohort study, younger age, Black race/ethnicity, low income, and poor glycemic control were associated with an increased risk of hyperglycemic crises.,The findings suggest that multidisciplinary interventions focusing on groups at high risk for hyperglycemic crises are needed to prevent these dangerous events.,This cohort study uses administrative claims and laboratory results from a nationwide database to assess the sociodemographic, clinical, and treatment-related factors associated with diabetic ketoacidosis and hyperglycemic hyperosmolar states among adults with type 1 or type 2 diabetes in the US from 2014 to 2020.
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Are there socioeconomic disparities in functional status among individuals with rheumatoid arthritis seen in rheumatology practices?,In this national cohort of 83 965 individuals with rheumatoid arthritis, functional status was statistically significantly worse across each successively lower quintile of socioeconomic status (SES).,In addition, the probability of functional decline over the study period was statistically significantly higher in individuals with low SES (18.9% in the lowest SES quintile) compared with individuals with high SES (14.1% in the highest SES quintile).,These findings suggest that disparate health outcomes exist among individuals with rheumatoid arthritis seen in rheumatology practices.,This cohort study examines the association between socioeconomic status and functional status among patients with rheumatoid arthritis and evaluates the association between socioeconomic status and functional declines over time in patients who received at least some rheumatology care.,Little is known about the association of poverty with functional status (FS) in patients with rheumatoid arthritis (RA) who use rheumatology care.,To examine the association between socioeconomic status (SES) and FS among patients with RA and to evaluate the association between SES and functional declines over time in patients who received at least some rheumatology care.,This cohort study used data from the American College of Rheumatology’s Rheumatology Informatics System for Effectiveness (RISE) registry between January 1, 2016, and December 31, 2018.,Analyses included all adult patients with a confirmed RA diagnosis (ie, had ≥2 encounters associated with RA International Classification of Diseases codes ≥30 days apart) and at least 1 FS score documented between 2016 and 2018 seen at participating rheumatology practices.,Data analysis was conducted from April to December 2020.,The Area Deprivation Index (ADI), a zip code-based indicator of neighborhood poverty, was used as a proxy for SES.,ADI scores were categorized into quintiles.,FS measures included Multidimensional Health Assessment Questionnaire (MDHAQ), Health Assessment Questionnaire Disability index, and Health Assessment Questionnaire-II.,Cross-sectionally, mean FS scores were compared across ADI quintiles.,Longitudinally, among patients with at least 2 FS scores, multilevel multivariate regression computed the probability of functional decline, defined as a change greater than the minimum clinically important difference, across ADI quintiles.,In a subgroup analysis, whether disease activity mediated the association between SES and functional decline was examined.,Of the 83 965 patients included in the study, 66 649 (77%) were women, and 60 037 (72%) were non-Hispanic White.,Mean (SD) age was 63.4 (13.7) years.,MDHAQ was the most reported FS measure (56 928 patients [67.8%]).,For all measures, mean (SD) FS score was worse at lower SES levels (eg, for MDHAQ quintile 1: 1.79 [1.87]; quintile 5: 2.43 [2.17]).,In longitudinal analyses, the probability of functional decline was 14.1% (95% CI, 12.5%-15.7%) in the highest SES quintile and 18.9% (95% CI, 17.1%-20.7%) in the lowest SES quintile.,The association between SES and functional decline was partially mediated (7%; 95% CI, 4%-22%) by disease activity.,In this cohort study of patients with RA, worse FS and faster declines in functioning over time were observed in patients with lower SES.,These findings provide a framework for monitoring disparities in RA and for generating evidence to spur action toward achieving health equity.
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Clinical manifestations of COVID-19 are known to be variable with growing evidence of nervous system involvement.,In this case report, we describe the symptoms of a patient infected with SARS-CoV-2 whose clinical course was complicated with Guillain-Barré syndrome (GBS).,We present a case of a 58-year-old woman who was initially diagnosed with COVID-19 pneumonia due to symptoms of fever and cough.,Two weeks later, after the resolution of upper respiratory tract symptoms, she developed symmetric ascending quadriparesis and paresthesias.,The diagnosis of GBS was made through cerebrospinal fluid analysis and she was successfully treated with intravenous immunoglobulin administration.
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•A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,•SARS-CoV-2 has also been shown to affect the peripheral nervous system.,•Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,•Some GBS have led to hypothesize a possible parainfectious pathogenesis.,A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,SARS-CoV-2 has also been shown to affect the peripheral nervous system.,Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,Some GBS have led to hypothesize a possible parainfectious pathogenesis.,In recent months, the new beta-coronavirus has caused a pandemic with symptoms affecting mainly the respiratory system.,It is established that the virus may play a neurotropic role and in recent months several cases of Guillain-Barré-Strohl syndrome (GBS) have been reported in patients infected with COVID-19.,We report the case of a 54-year-old patient with acute demyelinating polyneuropathy during infection by SARS-CoV-2 who progressed clinically to require assisted ventilation.,After several weeks of specific symptomatic treatment, the patient had a favorable outcome.,In conclusion, despite being a rare complication, we think it is important to consider the possibility of diffuse involvement of the peripheral nervous system in patients with COVID-19 to adjust clinical monitoring and treatment in these cases.
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In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens.,Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response.,We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc).,A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics).,The log-transform of the antibody levels was analyzed by multivariable linear regression.,780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies.,At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients.,Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001).,The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days).,In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines.,As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod.,Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS.,FISM[2021/Special-Multi/001]; Italian Ministry of Health‘Progetto Z844A 5 × 1000′.
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This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis (PwMS).,We retrospectively collected data of PwMS with suspected or confirmed COVID‐19.,All the patients had complete follow‐up to death or recovery.,Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death.,We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models.,Sensitivity analyses were run to confirm the results.,Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy.,Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.,After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID‐19.,Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001).,Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.,This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action.,However, some specific elements of risk emerged.,These will need to be considered while the COVID‐19 pandemic persists.,ANN NEUROL 2021;89:780-789
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Despite significant breakthroughs in understanding of immunological and physiological features of autoimmune diseases, there is currently no specific therapeutic option with prolonged remission.,Cell-based therapy using engineered-T cells has attracted tremendous attention as a practical treatment for autoimmune diseases.,Genetically modified-T cells armed with chimeric antigen receptors (CARs) attack autoreactive immune cells such as B cells or antibody-secreting plasma cells.,CARs can further guide the effector and regulatory T cells (Tregs) to the autoimmune milieu to traffic, proliferate, and exert suppressive functions.,The genetically modified-T cells with artificial receptors are a promising option to suppress autoimmune manifestation and autoinflammatory events.,Interestingly, CAR-T cells are modified to a new chimeric auto-antibody receptor T (CAAR-T) cell.,This cell, with its specific-antigen, recognizes and binds to the target autoantibodies expressing autoreactive cells and, subsequently, destroy them.,Preclinical studies of CAR-T cells demonstrated satisfactory outcomes against autoimmune diseases.,However, the lack of target autoantigens remains one of the pivotal problems in the field of CAR-T cells.,CAR-based therapy has to pass several hurdles, including stability, durability, trafficking, safety, effectiveness, manufacturing, and persistence, to enter clinical use.,The primary goal of this review was to shed light on CAR-T immunotherapy, CAAR-T cell therapy, and CAR-Treg cell therapy in patients with immune system diseases.
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The humanized monoclonal antibody eculizumab (Soliris®) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody-positive adults with generalized myasthenia gravis (gMG) in the USA, refractory gMG in the EU, or gMG with symptoms that are difficult to control with high-dose IVIg therapy or PLEX in Japan.,It is the first complement inhibitor to be approved for use in these patients.,In the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis (change from baseline in MG-activities of daily living (ADL) score assessed by worst-rank ANCOVA) was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as well as other secondary outcomes supported the efficacy of eculizumab.,Overall, patients receiving eculizumab experienced significant improvements in the ADL, muscle strength and health-related quality of life (HR-QOL) parameters relative to patients receiving placebo.,Moreover, an ongoing extension of REGAIN showed that treatment benefits with eculizumab were sustained during continued therapy for at least 52 weeks.,Eculizumab was generally well tolerated in these studies, with a tolerability profile similar to that reported previously in other indications.,Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG.
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C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes.,Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to the different treatment requirements of Type 1 and Type 2 diabetes.,This article reviews the use of C-peptide measurement in the clinical management of patients with diabetes, including the interpretation and choice of C-peptide test and its use to assist diabetes classification and choice of treatment.,We provide recommendations for where C-peptide should be used, choice of test and interpretation of results.,With the rising incidence of Type 2 diabetes in younger patients, the discovery of monogenic diabetes and development of new therapies aimed at preserving insulin secretion, the direct measurement of insulin secretion may be increasingly important.,Advances in assays have made C-peptide measurement both more reliable and inexpensive.,In addition, recent work has demonstrated that C-peptide is more stable in blood than previously suggested or can be reliably measured on a spot urine sample (urine C-peptide:creatinine ratio), facilitating measurement in routine clinical practice.,The key current clinical role of C-peptide is to assist classification and management of insulin-treated patients.,Utility is greatest after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes.,Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of Type 1 diabetes management strategies regardless of apparent aetiology.
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Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non-insulin requiring, e.g., with latent autoimmune diabetes (LADA).,We aimed to characterize adult-onset autoimmune diabetes.,We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30-70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).,Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone.,More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs.,13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes.,Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs.,39.7%) (P < 0.02 for each).,Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3).,Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes.,Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum.,At diagnosis, patients with adult-onset autoimmune diabetes are usually non-insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner.,Only with screening for autoantibodies, especially GADA, can they be identified with certainty.
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T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE).,CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking.,Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease.,To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis.,Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity.,ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN.,CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures.,Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.
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To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.,In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up.,Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events.,Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients.,Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome.,The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%).,Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker.,The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis.,Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome.,NCT00204022.
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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries.,One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis).,We investigated environmental factors in early childhood associated with MS.,A case-control study was performed of 245 MS patients and 296 population-based controls in Berlin.,The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene.,Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS.,Mean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female.,The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS.,The hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.
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New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis.,The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan.,These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.,Ann Neurol 2011
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B lymphocytes have a central role in autoimmune diseases, which are often defined by specific autoantibody patterns and feature a loss of B cell tolerance.,A prototypic disease associated with B cell hyperactivity is systemic lupus erythematosus (SLE).,In patients with SLE, the loss of B cell tolerance to autoantigens is controlled in a cell-intrinsic manner by Toll-like receptors (TLRs), which sense nucleic acids in endosomes.,TLR7 drives the extrafollicular B cell response and the germinal centre reaction that are involved in autoantibody production and disease pathogenesis.,Surprisingly, TLR9 seems to protect against SLE, even though it is required for the production of autoantibodies recognizing double-stranded DNA-associated antigens, which are abundant in SLE and are a hallmark of this disease.,The protective function of TLR9 is at least partly mediated by its capacity to limit the stimulatory activity of TLR7.,The roles of TLR7 and TLR9 in the effector function of B cells in lupus-like disease and in patients with SLE, and the unique features of TLR signalling in B cells, suggest that targeting TLR signalling in SLE might be therapeutically beneficial.,Loss of B cell tolerance to autoantigens in systemic lupus erythematosus (SLE) is driven by TLR7, whereas TLR9 appears to protect against SLE by limiting the stimulatory activity of TLR7.,The unique features of Toll-like receptor signalling in B cells implicate it as a therapeutic target in SLE.,Intrinsic TLR7 and TLR9 signalling in B cells plays an important role in the development and pathogenesis of systemic lupus erythematosus (SLE).,In patients with SLE, effector plasma cells are generated via the extrafollicular response and via the formation of spontaneous germinal centres.TLR7 plays key roles in the extrafollicular response and the response mediated by germinal centres.Some plasma cells produce IL-10 and can have protective roles in lupus-like disease.,Intrinsic TLR7 and TLR9 signalling in B cells plays an important role in the development and pathogenesis of systemic lupus erythematosus (SLE).,In patients with SLE, effector plasma cells are generated via the extrafollicular response and via the formation of spontaneous germinal centres.,TLR7 plays key roles in the extrafollicular response and the response mediated by germinal centres.,Some plasma cells produce IL-10 and can have protective roles in lupus-like disease.
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The causes of increased cardiovascular risk in systemic lupus erythematosus (SLE) are not understood thoroughly, although presence of traditional cardiovascular risk factors and disease-specific agents were also proposed.,In this study, we investigated the quantitative changes in the lipid profile, as well as qualitative characteristics of high-density lipoprotein (HDL) and markers of inflammation and disease activity in SLE patients.,Lipoprotein levels were determined in 51 SLE patients and 49 healthy controls, matched in age and gender.,HDL antioxidant capacity was determined spectrophotometrically with a cell-free method of hemin-induced low-density lipoprotein (LDL) oxidation.,Polyacrylamide gel-electrophoresis was used for HDL subfraction analysis.,Human paraoxonase-1 (PON1) activity, apolipoprotein A1 (ApoA1) and oxidized LDL concentrations, as well as interleukin-6, high-sensitivity C-reactive protein, serum amyloid A and monocyte chemotactic protein-1 levels were determined.,HDL-cholesterol and ApoA1 concentrations decreased significantly in SLE subjects.,Also, PON1 arylesterase activity (125.65 ± 26.87 vs.,148.35 ± 39.34 U/L, p = 0.001) and total HDL antioxidant capacity (165.82 ± 58.28 % vs.,217.71 ± 54.36 %, p < 0.001) were significantly reduced in patients compared to controls.,Additionally, all HDL subfraction concentrations were significantly decreased in patients, while the levels of the examined inflammatory markers were significantly elevated in SLE subjects.,The latter correlated positively with disease activity, and negatively with HDL concentration and total HDL antioxidant capacity, respectively.,PON1 arylesterase activity and erythrocyte sedimentation rate were independent predictors of total HDL antioxidant capacity.,Induced by the systemic inflammation, altered composition and antioxidant activity may diminish the anti-atherogenic effect of HDL and therefore may contribute to the increased cardiovascular risk of SLE patients.
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Recent metabolomics studies of Rheumatoid Arthritis (RA) reported few metabolites that were associated with the disease, either due to small cohort sizes or limited coverage of metabolic pathways.,Our objective is to identify metabolites associated with RA and its cofounders using a new untargeted metabolomics platform.,Moreover, to investigate the pathomechanism of RA by identifying correlations between RA-associated metabolites.,132 RA patients and 104 controls were analyzed for 927 metabolites.,Metabolites were tested for association with RA using linear regression.,OPLS-DA was used to discriminate RA patients from controls.,Gaussian Graphical Models (GGMs) were used to identify correlated metabolites. 32 metabolites are identified as significantly (Bonferroni) associated with RA, including the previously reported metabolites as DHEAS, cortisol and androstenedione and extending that to a larger set of metabolites in the steroid pathway.,RA classification using metabolic profiles shows a sensitivity of 91% and specificity of 88%.,Steroid levels show variation among the RA patients according to the corticosteroid treatment; lowest in those taking the treatment at the time of the study, higher in those who never took the treatment, and highest in those who took it in the past.,Finally, the GGM reflects metabolite relations from the steroidogenesis pathway.
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Arthritis patients often take fish oil supplements to alleviate symptoms, but limited evidence exists regarding their efficacy.,The objective was to evaluate whether marine oil supplements reduce pain and/or improve other clinical outcomes in patients with arthritis.,Six databases were searched systematically (24 February 2015).,We included randomized trials of oral supplements of all marine oils compared with a control in arthritis patients.,The internal validity was assessed using the Cochrane Risk of Bias tool and heterogeneity was explored using restricted maximum of likelihood (REML)-based meta-regression analysis.,Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to rate the overall quality of the evidence.,Forty-two trials were included; 30 trials reported complete data on pain.,The standardized mean difference (SMD) suggested a favorable effect (−0.24; 95% confidence interval, CI, −0.42 to −0.07; heterogeneity, I2 = 63%.,A significant effect was found in patients with rheumatoid arthritis (22 trials; −0.21; 95% CI, −0.42 to −0.004) and other or mixed diagnoses (3 trials; −0.63; 95% CI, −1.20 to −0.06), but not in osteoarthritis patients (5 trials; −0.17; 95% CI, −0.57-0.24).,The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality, but of moderate quality in rheumatoid arthritis patients.
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Although hydroxychloroquine (HCQ) is a mainstay of treatment for patients with systemic lupus erythematosus (SLE), ocular toxicity can result from accumulated exposure.,As the longevity of patients with SLE improves, data are needed to balance the risk of ocular toxicity and the risk of disease flare, especially in older patients with quiescent disease.,Accordingly, this study was initiated to examine the safety of HCQ withdrawal in older SLE patients.,Data were obtained by retrospective chart review at three major lupus centers in New York City.,Twenty-six patients who discontinued HCQ and thirty-two patients on HCQ matched for gender, race/ethnicity, and age were included in this study.,The primary outcome was the occurrence of a lupus flare classified by the revised version of the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare composite index, within 1 year of HCQ withdrawal or matched time of continuation.,Five patients (19.2%) in the HCQ withdrawal group compared to five (15.6%) in the HCQ continuation group experienced a flare of any severity (odds ratio [OR] = 1.28; 95% CI 0.31, 5.30; p = 0.73).,There were no severe flares in either group.,The results were similar after adjusting for length of SLE, number of American College of Rheumatology criteria, low complement levels, and SELENA-SLEDAI score, and in a propensity score analysis (OR = 1.18; 95% CI 0.23, 6.16; p = 0.84).,The analysis of time to any flare revealed a non-significant earlier time to flare in the HCQ withdrawal group (log-rank p = 0.67).,Most flares were in the cutaneous and musculoskeletal systems, but one patient in the continuation group developed pericarditis.,The most common reason for HCQ withdrawal was retinal toxicity (42.3%), followed by patient’s preference (34.6%), other confirmed or suspected adverse effects (15.4%), ophthalmologist recommendation for macular degeneration (3.8%), and rheumatologist recommendation for quiescent SLE (3.8%).,In this retrospective study of older stable patients with SLE on long-term HCQ, withdrawal did not significantly increase the risk of flares.
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Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes.,Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein I antibodies (aβ2-GPIs), and lupus anti-coagulant (LA), is well-established.,However, the ontogeny of these pathogenic aPLs remains less clear.,While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS).,Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS.,Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between β2-GPI molecule and infection-relevant structures.,In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.
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Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension.,Such targets have not been defined for rheumatoid arthritis (RA).,To develop recommendations for achieving optimal therapeutic outcomes in RA.,A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure.,Levels of evidence, strength of recommendations and levels of agreement were derived.,The treat-to-target activity resulted in 10 recommendations.,The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease.,Regular follow-up (every 1-3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended.,Follow-up examinations ought to employ composite measures of disease activity which include joint counts.,Additional items provide further details for particular aspects of the disease.,Levels of agreement were very high for many of these recommendations (≥9/10).,The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
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Early treatment of rheumatoid arthritis (RA) has been shown to retard the development of joint damage for a period of up to 5 years.,The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs (DMARDs) or a single DMARD.,A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone (FIN-RACo), or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone (SINGLE).,After 2 years, the drug-treatment strategy became unrestricted, but still targeted remission.,The radiographs of hands and feet were analyzed by using the Larsen score at baseline, 2, 5, and 11 years, and the radiographs of large joints, at 11 years.,Sixty-five patients in the FIN-RACo and 65 in the SINGLE group had radiographs of hands and feet available at baseline and at 11 years.,The mean change from baseline to 11 years in Larsen score was 17 (95% CI, 12 to 26) in the FIN-RACo group and 27 (95% CI, 22 to 33) in the SINGLE group (P = 0.037).,In total, 87% (95% CI, 74 to 94) and 72% (95% CI, 58 to 84) of the patients in the FIN-RACo and the SINGLE treatment arms, respectively, had no erosive changes in large joints at 11 years.,Targeting to remission with tight clinical controls results in low radiologic progression in most RA patients.,Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy.,Current Controlled Trials ISRCTN18445519.
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The SEARCH for Diabetes in Youth Study prospectively identified youth aged <20 years with physician-diagnosed diabetes.,Annual type 1 diabetes (T1D) incidence per 100,000 person-years (95% CI) overall, by age-group, and by sex were calculated for at-risk non-Hispanic white (NHW) youth from 2002 through 2009.,Joinpoint and Poisson regression models were used to test for temporal trends.,The age- and sex-adjusted incidence of T1D increased from 24.4/100,000 (95% CI 23.9-24.8) in 2002 to 27.4/100,000 (26.9-27.9) in 2009 (P for trend = 0.0008).,The relative annual increase in T1D incidence was 2.72% (1.18-4.28) per year; 2.84% (1.12-4.58) per year for males and 2.57% (0.68-4.51) per year for females.,After adjustment for sex, significant increases were found for youth aged 5-9 years (P = 0.0023), 10-14 years (P = 0.0008), and 15-19 years (P = 0.004) but not among 0-4-year-olds (P = 0.1862).,Mean age at diagnosis did not change.,The SEARCH study demonstrated a significant increase in the incidence of T1D among NHW youth from 2002 through 2009 overall and in all but the youngest age-group.,Continued surveillance of T1D in U.S. youth to identify future trends in T1D incidence and to plan for health care delivery is warranted.
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We studied ten individuals from eight families showing features consistent with the immuno-osseus dysplasia spondyloenchondrodysplasia (SPENCD).,Of particular note was the diverse spectrum of autoimmune phenotypes observed in these patients, including systemic lupus erythematosus (SLE), Sjögren's syndrome, haemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease, and vitiligo.,Haplotype data indicated the disease gene to be on chromosome 19p13 and linkage analysis yielded a combined multipoint lod score of 3.6.,Sequencing of the ACP5 gene, encoding tartrate resistant acid phosphatase (TRAP), identified biallelic mutations in each of the patients studied, and in vivo testing confirmed a loss of expressed protein.,All eight patients assayed demonstrated elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature.,Our findings reveal a previously unrecognised link between TRAP activity and interferon metabolism, and highlight the importance of type I interferon in the genesis of autoimmunity.
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The classification of seronegative arthritides can be challenging.,Our aim was to examine the incidence of SpA diagnosis among patients initially diagnosed as seronegative RA.,Using nationwide Finnish registers from social insurance institutions, we identified all adult patients who were diagnosed with incident seronegative RA [International Classification of Diseases (ICD)-10 code M06] from 1 January 2000 to 31 December 2014.,The patients whose diagnoses subsequently changed to the ICD-10 codes of SpA (M07, M45, M46, K50 and K51) were identified in the national care register, until 31 December 2016.,A total of 9784 adult seronegative RA patients were identified.,Of these, 564 patients had their diagnosis subsequently changed to SpA: 275 (48.7%) patients with PsA, 245 (43.4%) patients with axial SpA and 44 (7.8%) patients with diagnoses related to IBD.,The cumulative incidence of SpA diagnoses in 15 years was 10.4% (95% CI 8.9, 12.1) and 8.1% (95% CI 7.1, 9.3) in men and women, respectively.,This study calls for vigilance in seronegative RA patients, especially those with more atypical presentations, since the diagnosis could change.,The possibility of SpA diagnosis should be considered and specifically looked for, as this could impact on management and response to treatment.
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Non-adherence to disease-modifying antirheumatic drugs (DMARDs) is suspected to relate to health care costs.,In this study we investigated this relation in the first year of treatment.,In a multi-center cohort study with a one year follow up, non-adherence was continuously measured using electronic monitored medication jars.,Non-adherence was defined as the number of days with a negative difference between expected and observed opening of the container.,Cost measurement focused on hospital costs in the first year: consultations, emergency room visits, hospitalization, medical procedures, imaging modalities, medication costs, and laboratory tests.,Cost volumes were registered from patient medical files.,We applied multivariate regression analyses for the association between non-adherence and costs, and other variables (age, sex, center, baseline disease activity, diagnosis, socioeconomic status, anxiety and depression) and costs.,Of the 275 invited patients, 206 were willing to participate.,74.2% had rheumatoid arthritis, 20.9% had psoriatic arthritis and 4.9% undifferentiated arthritis.,23.7% of the patients were more than 20% non-adherent over the follow-up period.,Mean costs are € 2117.25 (SD € 3020.32).,Non-adherence was positively related to costs in addition to baseline anxiety.,Non-adherence is associated with health care costs in the first year of treatment for arthritis.,This suggests that improving adherence is not only associated with better outcome, but also with savings.
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Fibroblast-like synoviocytes (FLSs) are key effector cells in the pathogenesis of rheumatoid arthritis (RA) and display a unique aggressive tumor-like phenotype with remarkable hyperplasia, increased cell migration and invasion.,How FLSs undergo these changes in RA remains unknown.,We previously reported a novel function of transcription factor SOX5 in RA-FLSs that promote cell migration and invasion.,In this study, we found that miR-15a/16 directly targets the SOX5 3’UTR and suppresses SOX5 expression.,Moreover, miR-15a/16 is significantly down-regulated in RA-FLSs, which negatively correlates with SOX5 expression.,Transfection with miR-15a/16 mimics in RA-FLSs inhibits cell migration, invasion, IL-1β and TNFα expression.,Overexpression SOX5 in RA-FLSs decreases miR-15a/16 expression and rescues miR-15a/16-mediated inhibitory effect.,Furthermore, RA patients with the lower baseline serum miR-15a/16 level present poor response of 3 months disease-modifying antirheumatic drugs (DMARDs) therapy.,Collectively, this study reveals that miR-15a/16/SOX5 axis functions as a key driver of RA-FLSs invasion, migration and inflammatory response in a mutual negative feedback loop and correlates with DMARDs treatment response in RA.
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Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial inflammation.,Fibroblast-like synoviocytes (FLS) serve a vital role in the initiation and perpetuation of the immune response in patients with RA.,The present study aimed to investigate the potential role of microRNA (miR)-34a-3p in the pathogenesis of RA.,FLS were collected from patients with RA and osteoarthritis (OA).,The miR-34a-3p mimics and inhibitor vectors were constructed and transfected into RAFLS using Lipofectamine® 2000.,Cell proliferation was determined by Cell Counting kit-8 assay and cell cycle progression was analyzed by flow cytometry.,In addition, the expression levels of cell cycle control genes, matrix metalloproteinase (MMP)-1 and MMP-9, and pro-inflammatory cytokines were detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis.,The potential targets of miR-34a-3p were predicted by TargetScan and MiRWalk; the target genes were further verified using a luciferase reporter assay.,The expression levels of miR-34a-3p were generally lower in RAFLS compared with in OAFLS. miR-34a-3p overexpression significantly inhibited the proliferation of FLS (P<0.01) by suppressing the expression levels of cyclin-dependent kinase 2, cell division cycle 25A and cyclin D1 (P<0.01), and arresting FLS cell cycle progression at the G1 phase.,Furthermore, the expression levels of MMP-1 and 9 were markedly decreased, as were the mRNA and protein expression levels of pro-inflammatory cytokines (tumor necrosis factor α and interleukin 6; P<0.01).,Murine double minute 4 (MDM4) was predicted and verified as a potential target gene of miR-34a-3p; the 547-554 nt position of the MDM4 3′-untranslated region harbored one potential binding site for miR-204-3p.,The results of the present study indicated that miR-34a-3p may be considered a promising therapeutic target for RA through inhibiting FLS proliferation and suppressing the production of pro-inflammatory cytokines and MMPs.
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Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur.,Autoimmune diseases (ADs) are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage.,Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today.,Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable.,Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies.,However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown.,Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy.,In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases-systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.
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Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN).,Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN.,Dysregulation of B cell transcription factors, cytokines and B cell-T cell interaction can result in aberrant B cell maturation and autoantibody production.,These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients.,Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications.,While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells.,Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation.,Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell-T cell interaction.,These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients.,Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire.,Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN.,Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.
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Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown.,This is in part because of the difficulty in the functional translation of genotype into disease‐relevant mechanisms.,Building on our recent work showing the association of clinical disease course with post‐mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue.,To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions.,Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A).,Three SNPs linked to MS pathology‐associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4).,In addition, rs2234978/FAS T‐allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation.,Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.
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Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies.,The assessment of antibody assays needs to reflect their clinical utility.,We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).,Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).,Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD).,On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays.,The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.,The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres.,Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way.,The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.
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The pathogenesis of systemic lupus erythematosus (SLE) is influenced by both genetic factors and epigenetic modifications; the latter is a result of exposure to various environmental factors.,Epigenetic modifications affect gene expression and alter cellular functions without modifying the genomic sequences.,CpG-DNA methylation, histone modifications, and miRNAs are the main epigenetic factors of gene regulation.,In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur in CD4+ T-cells.,Moreover, histone acetylation and deacetylation inhibitors reverse the expression of multiple genes involved in SLE, indicating histone modification in SLE.,Autoreactive T-cells and B-cells have been shown to alter the patterns of epigenetic changes in SLE patients.,Understanding the molecular mechanisms involved in the pathogenesis of SLE is critical for the introduction of effective, target-directed and tolerated therapies.,In this review, we summarize the recent findings that highlight the importance of epigenetic modifications and their mechanisms in SLE.
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Epigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE).,Here, we report a 2-step study of discovery followed by replication to identify DNA methylation alterations associated with SLE in a Chinese population.,Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls.,We identified 36 CpG sites with differential loss of DNA methylation and 8 CpG sites with differential gain of DNA methylation, representing 25 genes and 7 genes, respectively.,Surprisingly, 42% of the hypomethylated CpG sites were located in CpG shores, which indicated the functional importance of the loss of DNA methylation.,Microarray results were replicated in another cohort of 100 SLE patients and 100 healthy controls by performing bisulfite pyrosequencing of four hypomethylated genes, MX1, IFI44L, NLRC5 and PLSCR1.,In addition, loss of DNA methylation in these genes was associated with an increase in mRNA expression.,Gene ontology analysis revealed that the hypomethylated genes identified in the microarray study were overrepresented in the type I interferon pathway, which has long been implicated in the pathogenesis of SLE.,Our epigenetic findings further support the importance of the type I interferon pathway in SLE pathogenesis.,Moreover, we showed that the DNA methylation signatures of SLE can be defined in unfractionated white blood cells.
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To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).,After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse).,Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement).,Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients.,Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity.,Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation.,Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab.,Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization.,For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered.,The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE.,Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively).,Recommendations on the timing of oncologic searches are provided.,These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules.,A similar recommendation could be applicable to adult patients.
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Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis.,A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis.,The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls.,Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism.,This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.
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Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals.,However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy.,Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity.,TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 μg/ml; TOF1, 1.1 μM; TOF2, 0.12 µM; MTX, 10 μM.,Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents.,Although the BioMAP activity profile for TCZ + MTX was not significantly different from that for TCZ alone, profiles for ADA + MTX and TOF1 + MTX or TOF2 + MTX had a greater number of statistically significant different activities (P < 0.01) than did agents profiled individually.,These data support the comparable efficacy of TCZ as monotherapy and as combination therapy and suggest that TOF, like ADA, may be more beneficial in combination with MTX.,Taking an orthogonal approach to directly compare monotherapy and combination therapies indicates that MTX contributes to the efficacy of some, but not all, RA therapies and can be affected by factors additional to reduced immunogenicity.,The online version of this article (10.1186/s12967-018-1532-5) contains supplementary material, which is available to authorized users.
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To examine the effectiveness of tocilizumab (TCZ) with and without synthetic disease-modifying antirheumatic drugs (sDMARDs) in a large observational study.,Patients with rheumatoid arthritis treated with TCZ who had a baseline visit and information on concomitant sDMARDs were included.,According to baseline data, patients were considered as taking TCZ as monotherapy or combination with sDMARDs.,Main study outcomes were the change of Clinical Disease Activity Index (CDAI) and TCZ retention.,The prescription of TCZ as monotherapy was analysed using logistic regression.,CDAI change was analysed with a mixed-effects model for longitudinal data.,TCZ retention was analysed with a stratified extended Cox model.,Multiple-adjusted analysis suggests that prescription of TCZ as monotherapy varied according to age, corticosteroid use, country of the registry and year of treatment initiation.,The change of disease activity assessed by CDAI as well as the likelihood to be in remission were not significantly different whether TCZ was used as monotherapy or in combination with sDMARDs in a covariate-adjusted analysis.,Estimates for unadjusted median TCZ retention were 2.3 years (95% CI 1.8 to 2.7) for monotherapy and 3.7 years (lower 95% CI limit 3.1, upper limit not estimable) for combination therapies.,In a covariate-adjusted analysis, TCZ retention was also reduced when used as monotherapy, with an increasing difference between mono and combination therapy over time after 1.5 years (p=0.002).,TCZ with or without concomitant sDMARDs resulted in comparable clinical response as assessed by CDAI change, but TCZ retention was shorter under monotherapy of TCZ.
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A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).,To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.,Retrospective multicenter study.,The sex ratio was 1:2.8 (m:f).,Median age at onset was 31 years (range 6-70).,The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae.,Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %.,Perioptic enhancement was present in several patients.,Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %).,Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %.,Fourty-one percent had a history of simultaneous ON and myelitis.,Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one).,CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %.,Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal.,Full recovery was achieved by plasma exchange in some cases, including after IVMP failure.,Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids.,Methotrexate was effective in 5/6 patients.,Interferon-beta was associated with ongoing or increasing disease activity.,Rituximab and ofatumumab were effective in some patients.,However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion.,Coexisting autoimmunity was rare (9 %).,Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %.,Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.,Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD.,The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.
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Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity.,Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004.,In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings.,Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases.,Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD).,In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup.,It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns.,Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage.,Therapy of NMO should be initiated early.,Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients.,Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments.,Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.
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This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes.,Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet).,Participants were grouped according to history of DKA severity (none/mild or moderate/severe).,Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months.,In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry.,The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group.,When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores and cognitive performance on the Detectability and Commission subtests of the Conners’ Continuous Performance Test II and the Dot Locations subtest of the Children’s Memory Scale.,A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth.,Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.
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The purpose of this cross-sectional study was to determine the rates of diabetes device use (insulin pump and continuous glucose monitor (CGM)) and association with glycemic control in youth with type 1 diabetes in a large, diverse pediatric center.,Demographic and clinical data were obtained from 1992 patients who met the eligibility criteria (age < 26 years, diabetes duration ≥ 1 year, and ≥1 clinic visit in the preceding 12 months).,Statistical analyses assessed the likelihood of device use based on demographic characteristics and the association between device use and glycemic control based on most recent hemoglobin A1c (HbA1c).,Mean age was 13.8 ± 4.2 years, 50.7% were female, diabetes duration was 6.2 ± 4 years, and mean HbA1c was 8.7 ± 1.8%.,Overall, 38.2% of patients were on pump therapy and 18.5% were on CGM.,Patients who were non-Hispanic (NH) white, privately insured, and with primary English-speaking parent(s) had higher rates of insulin pump use, as well as CGM use (P < 0.001 for both).,Female patients had higher rates of pump use only (P < 0.01).,Private health insurance, NH white race/ethnicity, and CGM use were each associated with lower HbA1c (P = 0.03, <0.001, and <0.008, resp.).,At a large, diverse, pediatric diabetes center, disparities in diabetes device use were present across sex, race/ethnicity, health insurance coverage, and primary language of parent(s).,CGM use was associated with lower HbA1c.,Quality improvement efforts are underway to ensure improved access, education, and clinical programs for advanced diabetes devices for T1D patients.
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For more than a year now, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the coronavirus disease (COVID-19) pandemic with high mortality and detrimental effects on society, economy, and individual lives.,Great hopes are being placed on vaccination as one of the most potent escape strategies from the pandemic and multiple vaccines are already in clinical use.,However, there is still a lot of insecurity about the safety and efficacy of vaccines in patients with autoimmune diseases like multiple sclerosis (MS), especially under treatment with immunomodulatory or immunosuppressive drugs.,We propose strategic approaches to SARS-CoV-2 vaccination management in MS patients and encourage fellow physicians to measure the immune response in their patients.,Notably, both humoral and cellular responses should be considered since the immunological equivalent for protection from SARS-CoV-2 after infection or vaccination still remains undefined and will most likely involve antiviral cellular immunity.,It is important to gain insights into the vaccine response of immunocompromised patients in order to be able to deduce sensible strategies for vaccination in the future.
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Here, we provide an extensive overview of all reported COVID-19 cases in multiple sclerosis (MS) patients in the Netherlands between 27 February and 9 June 2020, gathered by the Dutch MS Taskforce of the Netherlands Society of Neurology.,A total of 86 MS patients were reported, 43 of whom tested positive for COVID-19.,Of 43 patients who tested positive, 22 patients were hospitalized.,Three intensive care unit (ICU) admissions and four deaths were reported.,Our findings show no apparent difference in disease-modifying treatment (DMT) use and COVID-19 disease course in Dutch MS patients.,In addition, a clear link between low lymphocyte count and severe disease was not observed.
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Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints.,We investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints.,CD14+ cells from BM and peripheral blood (PB) of patients with RA and osteoarthritis (OA) were profiled with GeneChip microarrays.,Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilisation.,Cytometric profiling determined monocyte subsets of CD14++CD16−, CD14++CD16+ and CD14+CD16+ cells in BM, PB and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum.,Investigation of genes differentially expressed between RA and OA monocytes with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+monocytes in RA-PB.,Patterns associated with tumor necrosis factor/lipopolysaccharide (TNF/LPS) stimulation were weak and more pronounced in RA-PB than RA-BM.,Cytometric phenotyping of cells in BM, blood and SF disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+monocytes in RA-PB.,Monocyte activation in SF was characterised by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P.,Patterns of less mature and less differentiated RA-BM and RA-PB monocytes suggest increased turnover with accelerated monocytopoiesis, BM egress and migration into inflamed joints.,Predominant activation in the joint indicates the action of local and primary stimuli, which may also promote adaptive immune triggering through monocytes, potentially leading to new diagnostic and therapeutic strategies.
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Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens.,Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression.,Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear.,Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells.,In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood.,Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation.,To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli.,CD16 expression on CD14+ monocytes was clearly induced by TGF-β, although co-treatment with IL-1β, TNF-α, or IL-6 did not result in any additive effects.,In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified.,Furthermore, treatment of monocytes with IFN-γ resulted in the induction of CD80 and HLA-DR expression even in the presence of TGF-β.,An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells.,Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA.
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This meta-analysis was performed to evaluate the efficacy and safety of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) in children with type 1 diabetes.,A literature search was conducted on databases including PubMed and Embase up to June 2017.,The pooled weighted mean difference or risk ratio as well as 95% confidence intervals were calculated using RevMan 5.3 software.,Eight studies involving 310 children with type 1 diabetes were included.,Results showed that HbA1c (%) was significantly lower (p=0.007) after CSII compared with MDI in children with type 1 diabetes.,In addition, there was no significant difference between groups in HbA1c (%) change, total daily insulin doses, change of total daily insulin doses and incidence of ketoacidosis and severe hypoglycemia.,However, subgroup analyses indicated that age, treatment duration and study design were influenced the efficacy of CSII and MDI in children with type 1 diabetes.,CSII is associated with lower HbA1c levels in children with type 1 diabetes but appears to have no effect on insulin requirement or incidence of ketoacidosis and severe hypoglycemia.
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We recently reported the scalable in vitro production of functional stem cell-derived β-cells (SC-β cells).,Here we extend this approach to generate the first SC-β cells from type 1 diabetic patients (T1D). β-cells are destroyed during T1D disease progression, making it difficult to extensively study them in the past.,These T1D SC-β cells express β-cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice and respond to anti-diabetic drugs.,Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of β-cell stress.,Using these assays, we find no major differences in T1D SC-β cells compared with SC-β cells derived from non-diabetic patients.,These results show that T1D SC-β cells could potentially be used for the treatment of diabetes, drug screening and the study of β-cell biology.,Pancreatic β cells can be generated from pluripotent stem cells.,Here, the authors show that human induced pluripotent stem cells from patients with type 1 diabetes can be differentiated into β-like cells that have no detectable differences compared with cells from non-diabetic individuals.
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Ceramide and sphingosine display a unique profile during brain development, indicating their critical role in myelinogenesis.,Employing advanced technology such as gas chromatography-mass spectrometry, high performance liquid chromatography, and immunocytochemistry, along with cell culture and molecular biology, we have found an accumulation of sphingosine in brain tissues of patients with multiple sclerosis (MS) and in the spinal cord of rats induced with experimental autoimmune encephalomyelitis.,The elevated sphingosine leads to oligodendrocyte death and fosters demyelination.,Ceramide elevation by serine palmitoyltransferse (SPT) activation was the primary source of the sphingosine elevation as myriocin, an inhibitor of SPT, prevented sphingosine elevation and protected oligodendrocytes.,Supporting this view, fingolimod, a drug used for MS therapy, reduced ceramide generation, thus offering partial protection to oligodendrocytes.,Sphingolipid synthesis and degradation in normal development is regulated by a series of microRNAs (miRNAs), and hence, accumulation of sphingosine in MS may be prevented by employing miRNA technology.,This review will discuss the current knowledge of ceramide and sphingosine metabolism (synthesis and breakdown), and how their biosynthesis can be regulated by miRNA, which can be used as a therapeutic approach for MS.
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To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis.,We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes.,At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both).,Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01).,High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: −0.78% [−1.02 to −0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605).,Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments).,Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value.,Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.
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Toll-like receptors (TLRs) are a large family of pattern recognition receptors.,TLR signals are involved in the pathogenesis of systemic lupus erythematosus.,Mouse and human B cells constitutively express most TLRs.,Many B cell subpopulations are highly responsive to certain TLR ligation, including B-1 B cells, transitional B cells, marginal zone B cells, germinal center B cell and memory B cells.,The B cell-intrinsic TLR signals play critical roles during lupus process.,In this review, roles of B cell-intrinsic TLR2, 4, 7, 8 and 9 signals are discussed during lupus pathogenesis in both mouse model and patients.,Moreover, mechanisms underlying TLR ligation-triggered B cell activation and signaling pathways are highlighted.
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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease resulting in loss of self-tolerance with multiple organs, such as the kidney, skin, joints, and the central nervous system (CNS), being targeted.,Numerous immunosuppressant therapies are currently being used for the treatment of SLE, but their clinical utility is somewhat variable because of the clinical heterogeneity.,Melanocortins are a family of peptides derived from the common precursor protein pro-opiomelanocortin.,These multifunctional peptides activate five subtypes of melanocortin receptors expressed on immune, skin, muscle, bone, and kidney cells and cells within the CNS.,Melanocortin peptides have demonstrated a variety of biologic actions including immunomodulation, melanogenesis, and renoprotection.,This review aims to introduce the melanocortin system and explore the mechanisms by which they may be beneficial in diseases such as SLE.
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A family of eleven proteins comprises the Janus kinases (JAK) and signal transducers and activators of transcription (STAT) signaling pathway, which enables transduction of signal from cytokine receptor to the nucleus and activation of transcription of target genes.,Irregular functioning of the cascade may contribute to pathogenesis of autoimmune diseases; however, there are no reports concerning autoimmune bullous diseases yet to be published.,The aim of this study was to evaluate the expression of proteins constituting the JAK/STAT signaling pathway in skin lesions and perilesional area in dermatitis herpetiformis (DH) and bullous pemphigoid (BP), as well as in the control group.,Skin biopsies were collected from 21 DH patients, from 20 BP patients, and from 10 healthy volunteers.,The localization and expression of selected STAT and JAK proteins were examined by immunohistochemistry and immunoblotting.,We found significantly higher expression of JAK/STAT proteins in skin lesions in patients with BP and DH, in comparison to perilesional skin and the control group, which may be related to proinflammatory cytokine network and induction of inflammatory infiltrate in tissues.,Our findings suggest that differences in the JAK and STAT expression may be related to distinct cytokines activating them and mediating neutrophilic and/or eosinophilic infiltrate.
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Until late in the 20th century, the therapy of rheumatic diseases relied on the use of drugs that had been developed through empirical approaches without detailed understanding of the molecular mechanisms involved.,That approach changed with the introduction of biologic therapeutics at the end of the 20th century and by the recent development of small-molecule inhibitors of intracellular signal transduction pathways.,Here we compare and discuss the advantages and disadvantages of those two groups of targeted anti-inflammatory therapeutics.,TNF-blocking biologic agents were introduced into the therapy of rheumatoid arthritis and other autoimmune and inflammatory diseases in the late 1990s.,Further biologic agents targeting cytokine networks or specific lymphocyte subsets have since been added to the armamentarium of anti-rheumatic therapy.,During the last few years, another wave of novel discoveries led to the development of a new class of small molecule anti-inflammatory compounds targeting intracellular signal transduction molecules, such as tyrosine kinases.,In all those cases, the specific targets of the drugs are well defined and significant knowledge about their role in the disease pathomechanism is available, qualifying them for being targeted therapeutics for inflammatory rheumatic diseases.,While both groups of targeted therapeutics offer significant clinical benefit, they clearly differ in several aspects, such as the localization of their targets, their route of administration and target specificity, as well as technical details such as manufacturing procedures and cost basis.,In this debate paper, we compare the advantages and disadvantages of the two different approaches, aiming to shed light on the possible future of targeted therapies.,Biologic therapeutics and small-molecule inhibitors both have significant advantages and disadvantages in the therapy of rheumatic diseases.,The future of targeted therapies is one of the most exciting questions of current rheumatology research and therapy.
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Type 1 diabetes mellitus (T1DM) causes progressive destruction of pancreatic beta cells leading to absolute insulin deficiency.,Treatment of T1DM requires insulin, and some evidence suggests that longer acting insulin analogues might have a higher effectiveness and greater safety profile compared to intermediate-acting insulin.,Our objective is to evaluate the comparative effectiveness, safety, and cost of long-acting insulin versus intermediate-acting insulin through a systematic review and network meta-analysis.,Studies examining long-acting versus intermediate-acting insulin or placebo preparations for adult T1DM patients will be included.,The primary outcome is glycosylated hemoglobin (A1C), and secondary outcomes include emergency department and physician visits, hospital admissions, weight gain, quality of life, microvascular complications (e.g., retinopathy), macrovascular complications (e.g., cardiovascular disease), all-cause mortality, incident cancers, and cost.,We will include experimental [randomized clinical trials (RCTs), quasi-RCTs, non-RCTs], quasi-experimental (controlled before-after, interrupted time series), observational (cohort), and cost studies, of any duration of follow-up, conducted during all time periods, and disseminated in any language.,We will conduct comprehensive searches of electronic databases from inception onwards, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE.,We will also search for difficult to locate and unpublished literature by searching dissertation databases, public health organization websites, and trial registries.,After a calibration exercise using our eligibility criteria and data abstraction forms, two reviewers will screen all citations, full-text articles, and abstract data in duplicate.,Conflicts will be resolved by team discussion.,Using a similar process, the Cochrane Effective Practice and Organization of Care Risk of Bias tool will be used to appraise the risk of bias of experimental and quasi-experimental studies, while the Newcastle Ottawa Scale will be used to assess the methodological quality of cohort studies.,If feasible and appropriate, we will conduct a random effects meta-analysis, as well as a network meta-analysis.,Our systematic review will be of utility to healthcare providers, policy-makers, T1DM patients and family members regarding treatment options of long-acting versus intermediate-acting insulin preparations.,PROSPERO registry number: CRD42013003610
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This randomized, controlled noninferiority trial aimed to compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) (both with prandial insulin aspart) in pregnant women with type 1 diabetes.,Patients were randomized and exposed to IDet or NPH up to 12 months before pregnancy or at 8-12 weeks gestation.,The primary analysis aimed to demonstrate noninferiority of IDet to NPH with respect to A1C at 36 gestational weeks (GWs) (margin of 0.4%).,The data were analyzed using linear regression, taking several baseline factors and covariates into account.,A total of 310 type 1 diabetic women were randomized and exposed to IDet (n = 152) or NPH (n = 158) up to 12 months before pregnancy (48%) or during pregnancy at 8-12 weeks (52%).,The estimated A1C at 36 GWs was 6.27% for IDet and 6.33% for NPH in the full analysis set (FAS).,IDet was declared noninferior to NPH (FAS, -0.06% [95% CI -0.21 to 0.08]; per protocol, -0.15% [-0.34 to 0.04]).,Fasting plasma glucose (FPG) was significantly lower with IDet versus NPH at both 24 GWs (96.8 vs.,113.8 mg/dL, P = 0.012) and 36 GWs (85.7 vs.,97.4 mg/dL, P = 0.017).,Major and minor hypoglycemia rates during pregnancy were similar between groups.,Treatment with IDet resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin.,Rates of hypoglycemia were comparable.
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Epidemiological studies suggest a role for Coxsackievirus B (CVB) serotypes in the pathogenesis of type 1 diabetes, but their actual contribution remains elusive.,In the present study, we have produced a CVB1 vaccine to test whether vaccination against CVBs can prevent virus-induced diabetes in an experimental model.,NOD and SOCS1-tg mice were vaccinated three times with either a formalin-fixed non-adjuvanted CVB1 vaccine or a buffer control.,Serum was collected for measurement of neutralising antibodies using a virus neutralisation assay.,Vaccinated and buffer-treated mice were infected with CVB1.,Viraemia and viral replication in the pancreas were measured using standard plaque assay and PCR.,The development of diabetes was monitored by blood glucose measurements.,Histological analysis and immunostaining for viral capsid protein 1 (VP1), insulin and glucagon in formalin-fixed paraffin embedded pancreas was performed.,The CVB1 vaccine induced strong neutralising antibody responses and protected against viraemia and the dissemination of virus to the pancreas in both NOD mice (n = 8) and SOCS1-tg mice (n = 7).,Conversely, 100% of the buffer-treated NOD and SOCS1-tg mice were viraemic on day 3 post infection.,Furthermore, half (3/6) of the buffer-treated SOCS1-tg mice developed diabetes upon infection with CVB1, with a loss of the insulin-positive beta cells and damage to the exocrine pancreas.,In contrast, all (7/7) vaccinated SOCS1-tg mice were protected from virus-induced diabetes and showed no signs of beta cell loss or pancreas destruction (p < 0.05).,CVB1 vaccine can efficiently protect against both CVB1 infection and CVB1-induced diabetes.,This preclinical proof of concept study provides a base for further studies aimed at developing a vaccine for use in elucidating the role of enteroviruses in human type 1 diabetes.,The online version of this article (10.1007/s00125-017-4492-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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The IFIH1 gene encodes the pattern recognition receptor MDA5.,A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D).,Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro.,Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection.,A strong IFN signature was associated with high expression of IFNλ1 and IFNλ2, linking rs1990760 to the expression of type III IFNs.,In the high-responding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positive-feedback on type III IFN transcription.,In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D.,It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.
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Immunoglobulins, antigens and complement can assemble to form immune complexes (IC).,ICs can be detrimental as they propagate inflammation in autoimmune diseases.,Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis.,We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy.,We find that the MPs in RA synovial fluid are highly heterogeneous in size.,The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs.,These mpICs frequently express the integrin CD41, consistent with platelet origin.,Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor.,Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs.,Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils.,Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs.
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High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a pro-inflammatory mediator following extracellular release.,HMGB1 has been increasingly recognized as a pathogenic mediator in several inflammatory diseases.,Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE).,However, the local expression of HMGB1 in active lupus nephritis (LN) is not known.,Here we aimed to study both tissue expression and serum levels of HMGB1 in LN patients with active disease and after induction therapy.,Thirty-five patients with active LN were included.,Renal biopsies were performed at baseline and after standard induction therapy; corticosteroids combined with immunosuppressive drugs.,The biopsies were evaluated according to the World Health Organization (WHO) classification and renal disease activity was estimated using the British Isles lupus assessment group (BILAG) index.,Serum levels of HMGB1 were analysed by western blot.,HMGB1 expression in renal tissue was assessed by immunohistochemistry at baseline and follow-up biopsies in 25 patients.,Baseline biopsies showed WHO class III, IV or V and all patients had high renal disease activity (BILAG A/B).,Follow-up biopsies showed WHO I to II (n = 14), III (n = 6), IV (n = 3) or V (n = 12), and 15/35 patients were regarded as renal responders (BILAG C/D).,At baseline HMGB1 was significantly elevated in serum compared to healthy controls (P < 0.0001).,In all patients, serum levels decreased only slightly; however, in patients with baseline WHO class IV a significant decrease was observed (P = 0.03).,Immunostaining revealed a pronounced extranuclear HMGB1 expression predominantly outlining the glomerular endothelium and in the mesangium.,There was no clear difference in HMGB1 expression comparing baseline and follow-up biopsies or any apparent association to histopathological classification or clinical outcome.,Renal tissue expression and serum levels of HMGB1 were increased in LN.,The lack of decrease of HMGB1 in serum and tissue after immunosuppressive therapy in the current study may reflect persistent inflammatory activity.,This study clearly indicates a role for HMGB1 in LN.
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Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability.,The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors.,Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed.,Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG.,This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls.,We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥60years) (OR 2.38, pc7.4×10−5).,DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, pc 4.71×10−4), a finding not previously described.,No significant association was found to the DRB1*07:01 allele (pnc = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others.,HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies.,The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.
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The aim was to collate all myasthenia gravis (MG) epidemiological studies including AChR MG and MuSK MG specific studies.,To synthesize data on incidence rate (IR), prevalence rate (PR) and mortality rate (MR) of the condition and investigate the influence of environmental and technical factors on any trends or variation observed.,Studies were identified using multiple sources and meta-analysis performed to calculate pooled estimates for IR, PR and MR.,55 studies performed between 1950 and 2007 were included, representing 1.7 billion population-years.,For All MG estimated pooled IR (eIR): 5.3 per million person-years (C.I.:4.4, 6.1), range: 1.7 to 21.3; estimated pooled PR: 77.7 per million persons (C.I.:64.0, 94.3), range 15 to 179; MR range 0.1 to 0.9 per millions person-years.,AChR MG eIR: 7.3 (C.I.:5.5, 7.8), range: 4.3 to 18.0; MuSK MG IR range: 0.1 to 0.32.,However marked variation persisted between populations studied with similar methodology and in similar areas.,We report marked variation in observed frequencies of MG.,We show evidence of increasing frequency of MG with year of study and improved study quality.,This probably reflects improved case ascertainment.,But other factors must also influence disease onset resulting in the observed variation in IR across geographically and genetically similar populations.
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To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis.,A panel of PTMPs was developed.,Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)-either a citrullinated, carbamylated or acetylated residue.,Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested.,Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis).,Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis.,The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups.,Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups.,We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies.
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We and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease.,Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score.,A case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden.,Patients with RA were identified from blood donors predating the onset of disease by years.,Matched controls were selected randomly from the same registers.,IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden).,Of 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses.,The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years).,The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM.,The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls.,IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3.,Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP.,IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals.,Anti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies.
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See Martinez-Martinez et al. (doi:10.1093/brain/awu153) for a scientific commentary on this article.,Carvajal-González et al. describe the first prospective cohort of patients with glycine receptor antibodies.,The majority have progressive encephalomyelitis with rigidity and myoclonus.,The antibodies bind to extracellular determinants on glycine receptor-α1 and to glycine receptors on spinal cord and brainstem neurons.,The patients make a good recovery with immunotherapies.,The clinical associations of glycine receptor antibodies have not yet been described fully.,We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses.,Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000.,In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study.,Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM).,Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study.,Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma.,Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis.,Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies.,At most recent follow-up, (2-7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments.,The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C.,Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1.,Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes.,Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus.,The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis.,The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required.
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In 70-80% of cases, neuromyelitis optica (NMO) is associated with highly specific serum auto-antibodies to aquaporin-4 (termed AQP4-Ab or NMO-IgG).,Recent evidence strongly suggests that AQP4-Ab are directly involved in the immunopathogenesis of NMO.,To assess the frequency, syndrome specificity, diagnostic relevance, and origin of cerebrospinal fluid (CSF) AQP4-Ab in patients with NMO spectrum disorders (NMOSD).,87 CSF samples from 37 patients with NMOSD and 42 controls with other neurological diseases were tested for AQP4-Ab in a cell based assay using recombinant human AQP4.,Twenty-three paired CSF and serum samples from AQP4-Ab seropositive NMOSD patients were further analysed for intrathecal IgG synthesis to AQP4.,AQP4-Ab were detectable in 68% of CSF samples from AQP4-Ab seropositive patients with NMOSD, but in none of the CSF samples from AQP4-Ab seronegative patients with NMOSD and in none of the control samples.,Acute disease relapse within 30 days prior to lumbar puncture, AQP4-Ab serum titres >1:250, and blood-CSF barrier dysfunction, but not treatment status, predicted CSF AQP4-Ab positivity.,A positive AQP4-specific antibody index was present in 1/23 samples analysed.,AQP4-Ab are detectable in the CSF of most patients with NMOSD, mainly during relapse, and are highly specific for this condition.,In the cohort analysed in this study, testing for CSF AQP4-Ab did not improve the sensitivity and specificity of the current diagnostic criteria for NMO.,The substantial lack of intrathecal AQP4-Ab synthesis in patients with NMOSD may reflect the unique localisation of the target antigen at the blood brain barrier, and is important for our understanding of the immunopathogenesis of the disease.
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Natalizumab is a monoclonal antibody highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients.,Despite its effectiveness, there are growing concerns regarding the risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCV), particularly after 24 doses and in patients who previously received immunosuppressive drugs.,Long-term natalizumab treated, immunosuppressive-pretreated, and JCV antibody-positive patients are asked to rediscuss natalizumab continuation or withdrawal after 24 doses.,Until now, there has not been a clear strategy that should be followed to avoid PML risk and in parallel reduce clinical and radiological rebound activity.,In this review, we analyzed the results of clinical trials and case reports in relation to the following situations: natalizumab continuation, natalizumab discontinuation followed by full therapeutic suspension or switch to other first or second line MS treatments.,Quitting all MS treatment after natalizumab increases MS activity occurrence.,The results regarding the therapeutic switch are not homogeneous, so at the moment there are no established guidelines regarding natalizumab treatment after 24 administrations; the choice is currently based on the professional experience of the neurologist, and on patients’ clinical features and preferences.
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Targeted immune tolerance is a coveted therapy for the treatment of a variety of autoimmune diseases, as current treatment options often involve nonspecific immunosuppression.,Intravenous (iv) infusion of apoptotic syngeneic splenocytes linked with peptide or protein autoantigens using ethylene carbodiimide (ECDI) has been demonstrated to be an effective method for inducing peripheral, antigen-specific tolerance for treatment of autoimmune disease.,Here, we show the ability of biodegradable poly(lactic-co-glycolic acid) (PLG) nanoparticles to function as a safe, cost-effective, and highly efficient alternative to cellular carriers for the induction of antigen-specific T cell tolerance.,We describe the formulation of tolerogenic PLG particles and demonstrate that administration of myelin antigen-coupled particles both prevented and treated relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a CD4 T cell-mediated mouse model of multiple sclerosis (MS).,PLG particles made on-site with surfactant modifications surpass the efficacy of commercially available particles in their ability to couple peptide and to prevent disease induction.,Most importantly, myelin antigen-coupled PLG nanoparticles are able to significantly ameliorate ongoing disease and subsequent relapses when administered at onset or at peak of acute disease, and minimize epitope spreading when administered during disease remission.,Therapeutic treatment results in significantly reduced CNS infiltration of encephalitogenic Th1 (IFN-γ) and Th17 (IL-17a) cells as well as inflammatory monocytes/macrophages.,Together, these data describe a platform for antigen display that is safe, low-cost, and highly effective at inducing antigen-specific T cell tolerance.,The development of such a platform carries broad implications for the treatment of a variety of immune-mediated diseases.
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The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men.,In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls.,Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96) whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91).,Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80).,Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86).,In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78), whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89).,In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93).,SNP-SNP interaction analysis of significant SNPs also showed a significant two-locus interaction model in women that was not seen in men.,This model consisted of Dectin-2 rs4264222 and Dectin-2 rs7134303 SNPs and suggested a synergistic effect between the variants.,These findings suggest that Dectin-2, MCP-1 and DC-SIGN polymorphisms may, at least in part, account for gender-associated differences in susceptibility to RA.
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Anti-tumor necrosis factor (anti-TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30-40% of patients treated.,Knowledge of the genetic factors that influence response may facilitate personalized therapy.,The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts.,Data from genome-wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti-TNF-treated RA patients.,Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single-nucleotide polymorphism (SNP) using an additive model.,Associated markers (P < 10−3) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed.,Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis.,The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient −0.27, P = 5.67−05).,The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37−04).,The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12.,Using a genome-wide strategy, we have identified and validated the association of 7 genetic loci with response to anti-TNF treatment in RA.,Additional confirmation of these findings in further cohorts will be required.
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Systemic juvenile idiopathic arthritis (JIA) and adult-onset Still’s disease (AOSD) are systemic inflammatory disorders that manifest as high-spiking fever, joint pain, evanescent skin rash, and organomegaly.,Their pathogenesis is unclear, but inflammation is triggered by activation of the innate immune system with aberrant production of proinflammatory cytokines.,Along with extrinsic factors, intrinsic pathways can trigger an unexpected immune response.,Damage-associated molecular patterns (DAMPs) induce the activation of innate immune cells, leading to sterile inflammation in systemic JIA and AOSD.,These endogenous proteins interact with Toll-like receptors (TLRs), which are pattern recognition receptors, and mediate immune signaling following stimulation by pathogen-associated molecular patterns and DAMPs.,Several DAMPs, such as S100 proteins, play a role in the development or severity of systemic JIA and AOSD, in which their interactions with TLRs are altered.,Also, the expression levels of genes encoding DAMPs contribute to the susceptibility to systemic JIA and AOSD.,Herein, we review reports that TLR and DAMP signaling initiates and/or maintains the inflammatory response in systemic JIA and AOSD, and their correlations with the clinical characteristics of those diseases.,In addition, we assess their utility as biomarkers or therapeutics for systemic JIA and AOSD.
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Background: Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation.,Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown.,The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity.,Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release.,Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID.,Results: Patients with SJIA and active systemic features demonstrated a higher proportion of CD16+CD62Llo neutrophil population compared to controls.,This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features.,Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils.,Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts.,Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils.,Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes (DEG) compared to neutrophils from healthy controls.,The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4.,Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation.,Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8.,Conclusion: We identify features of neutrophil activation in SJIA patients with both active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation.,Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.
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We characterized a unique group of patients with neuromyelitis optica spectrum disorder (NMOSD) who carried autoantibodies of aquaporin-4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG).,Among the 125 NMOSD patients, 10 (8.0%) were AQP4- and MOG-ab double positive, and 14 (11.2%) were MOG-ab single positive.,The double-positive patients had a multiphase disease course with a high annual relapse rate (P=0.0431), and severe residual disability (P<0.0001).,Of the double-positive patients, 70% had MS-like brain lesions, more severe edematous, multifocal regions on spinal magnetic resonance imaging (MRI), pronounced decreases of retinal nerve fiber layer thickness and atrophy of optic nerves.,In contrast, patients with only MOG-ab had a higher ratio of monophasic disease course and mild residual disability.,Spinal cord MRI illustrated multifocal cord lesions with mild edema, and brain MRIs showed more lesions around lateral ventricles.,NMOSD patients carrying both autoantibodies to AQP4 and MOG existed and exhibited combined features of prototypic NMO and relapsing-remitting form of MS, whereas NMOSD with antibodies to MOG only exhibited an “intermediate” phenotype between NMOSD and MS.,Our study suggests that antibodies against MOG might be pathogenic in NMOSD patients and that determination of anti-MOG antibodies maybe instructive for management of NMOSD patients.
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A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).,To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.,Retrospective multicenter study.,The sex ratio was 1:2.8 (m:f).,Median age at onset was 31 years (range 6-70).,The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae.,Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %.,Perioptic enhancement was present in several patients.,Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %).,Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %.,Fourty-one percent had a history of simultaneous ON and myelitis.,Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one).,CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %.,Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal.,Full recovery was achieved by plasma exchange in some cases, including after IVMP failure.,Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids.,Methotrexate was effective in 5/6 patients.,Interferon-beta was associated with ongoing or increasing disease activity.,Rituximab and ofatumumab were effective in some patients.,However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion.,Coexisting autoimmunity was rare (9 %).,Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %.,Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.,Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD.,The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.
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Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture.,We conducted an association study with replication in 4,492 SLE cases and 12,675 controls from six East-Asian cohorts, to identify novel and better localize known SLE susceptibility loci.,We identified 10 novel loci as well as 20 known loci with genome-wide significance.,Among the novel loci, the most significant was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta=3.75×10−117, OR=2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6.,We localized the most likely functional variants for each locus by analyzing epigenetic marks and gene regulation data.,Ten putative variants are known to alter cis- or trans-gene expression.,Enrichment analysis highlights the importance of these loci in B- and T-cell biology.,Together with previously known loci, the explained heritability of SLE increases to 24%.,Novel loci share functional and ontological characteristics with previously reported loci, and are possible drug targets for SLE therapeutics.
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Female mice lacking DEF6 and SWAP70 develop a lupus-like syndrome through dysregulation of IRF4 in activated B cells and plasma cells.,Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments.,Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE).,Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions.,In CD4+ T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation.,IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70.,Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4+ T cell IL-21 production and increased IL-21 B cell responsiveness.,We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner.,Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive T-B cell interactions.
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Oligodendrocytes that survive demyelination can remyelinate, including in Multiple Sclerosis (MS), but how they do so is unclear.,Here, using zebrafish, we found that surviving oligodendrocytes make few new sheaths and frequently mistarget new myelin to neuronal cell bodies, a pathology we also found in MS.,In contrast, oligodendrocytes generated after demyelination make abundant and correctly targeted sheaths, indicating that they likely also have a better regenerative potential in MS.
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Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults.,Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented.,Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions.,Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach.,However, this generally accepted concept has been challenged recently.,To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia.,Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage.,These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions.,Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.,The online version of this article (10.1007/s00401-020-02189-9) contains supplementary material, which is available to authorized users.
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Antibodies are critical for defence against a variety of microbes but may also be pathogenic in some autoimmune diseases.,Many effector functions of antibody are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs).,DCs are important antigen presenting cells and play a central role in inducing antigen-specific tolerance or immunity1,2.,Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via lymphatics to present antigen to T cells.,In this study we demonstrate that FcγR engagement by IgG immune complexes (IC) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes.,In vitro, IC-stimulated murine and human DCs showed enhanced directional migration in a CCL19 gradient and increased CCR7 expression.,Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilisation.,We confirmed that dermal DC migration to lymph nodes was CCR7-dependent and increased in the absence of the inhibitory receptor, FcγRIIb.,These observations have relevance to autoimmunity, because autoantibody-containing serum from mice and humans with SLE also increased dermal DC migration to lymph nodes in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localisation of autoantigen-bearing DCs.
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Transient, genetic elimination of a specialized group of cells called plasmacytoid dendritic cells (pDCs) reverses many features of lupus in mice.,Disease reduction was attributed in part to decreased expression of inflammatory molecules called interferons, which are produced primarily by pDCs.,Plasmacytoid dendritic cells (pDCs) have long been implicated in the pathogenesis of lupus.,However, this conclusion has been largely based on a correlative link between the copious production of IFN-α/β by pDCs and the IFN-α/β “signature” often seen in human lupus patients.,The specific contribution of pDCs to disease in vivo has not been investigated in detail.,For this reason, we generated a strain of BXSB lupus-prone mice in which pDCs can be selectively depleted in vivo.,Early, transient ablation of pDCs before disease initiation resulted in reduced splenomegaly and lymphadenopathy, impaired expansion and activation of T and B cells, reduced antibodies against nuclear autoantigens and improved kidney pathology.,Amelioration of pathology coincided with decreased transcription of IFN-α/β-induced genes in tissues.,PDC depletion had an immediate impact on the activation of immune cells, and importantly, the beneficial effects on pathology were sustained even though pDCs later recovered, indicating an early pDC contribution to disease.,Together, our findings demonstrate a critical function for pDCs during the IFN-α/β-dependent initiation of autoimmune lupus and point to pDCs as an attractive therapeutic target for the treatment of SLE.
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Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS).,This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1.,LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide.,Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate.,Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide.,Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin.,Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA).,Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function.,Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology.,Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS).,The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology.,NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology.,This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.
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Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS).,Mitochondria are now established to play a part in the pathogenesis of MS.,Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system.,We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.,Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.,Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls.,The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions.,Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS.,The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level.,Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.,Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation.,We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.
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Anti-CD20 B-cell depletion has not shown superior efficacy to standard immunosuppression in patients with systemic lupus erythematosus (SLE).,Besides trial design, potential explanations are incomplete B-cell depletion in relation to substantial surges in B-cell-activating factor (BAFF).,To improve B-cell targeting strategies, we conducted the first study in SLE patients aimed at investigating immunological effects and feasibility of combining rituximab (RTX; anti-CD20) and belimumab (BLM; anti-BAFF).,Reported is the long-term follow-up of a Phase 2 proof-of-concept study in 15 patients with SLE including 12 (80%) with lupus nephritis (LN).,In 10/15 (67%) patients, a clinical response was observed by achievement of lupus low disease activity state, of which 8 (53%) continued treatment (BLM + ≤7.5 mg prednisolone) for the complete 2 years of follow-up.,Five patients (33%) were referred to as ‘non-responders’ due to persistent LN, major flare or repetitive minor flares.,Out of 12 LN patients, 9 (75%) showed a renal response including 8 (67%) complete renal responders.,All anti-dsDNA+ patients converted to negative, and both anti-C1q and extractable nuclear antigen autoantibodies showed significant reductions.,CD19+ B cells showed a median decrease from baseline of 97% at 24 weeks, with a persistent reduction of 84% up to 104 weeks.,When comparing responders with non-responders, CD20+ B cells were depleted significantly less in non-responders and double-negative (DN) B cells repopulated significantly earlier.,Combined B-cell targeted therapy with RTX and BLM prevented full B-cell repopulation including DN B cells, with concomitant specific reduction of SLE-relevant autoantibodies.,The observed immunological and clinical benefits in a therapy-refractory SLE population prompt further studies on RTX + BLM.
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To examine the effects of treatment with belimumab on corticosteroid dose in patients with systemic lupus erythematosus (SLE) over 52 weeks in 2 randomized, controlled trials.,Data on patients who were taking corticosteroids at baseline in the Study of Belimumab in Subjects with SLE trials were pooled post hoc to compare patients who received belimumab 10 mg/kg plus standard therapy with those who received placebo plus standard therapy.,The primary end point was cumulative change from baseline in corticosteroid dose (prednisone equivalent) through week 52.,Further analyses specifically examined oral corticosteroid dose.,At baseline, 966 of 1,125 patients (86%) were receiving corticosteroids (478 belimumab 10 mg/kg and 488 placebo).,Most were women (94%), their mean age was 37.1 years, mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index score was 9.8, and mean corticosteroid dosage was 12.5 mg/day.,Over 52 weeks, there was a smaller increase in mean cumulative corticosteroid dose for the belimumab group than for the placebo group (531.2 mg versus 916.3 mg; P < 0.0001).,Compared with placebo, the mean of all decreases in cumulative corticosteroid dose was higher with belimumab (P = 0.0165), and the mean of all increases was lower (P = 0.0005).,More patients in the belimumab group had decreases in oral corticosteroid dose (38.5% versus 30.9%), and fewer had increases in dose (18.4% versus 30.7%), compared with placebo.,Adverse events were comparable across groups.,Our findings show a significantly smaller increase in cumulative corticosteroid dose over 1 year, more patients with decreases in oral corticosteroid dose, and fewer patients with increases in oral corticosteroid dose in the belimumab group compared with the placebo group.,These data suggest that belimumab may be steroid sparing.
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Background: Bullous pemphigoid is a subepidermal blistering skin disease, associated with autoantibodies to hemidesmosomal proteins, complement activation at the dermal-epidermal junction, and dermal granulocyte infiltration.,Clinical and experimental laboratory findings support conflicting hypotheses regarding the role of complement activation for the skin blistering induced by pemphigoid autoantibodies.,In-depth studies on the pathogenic relevance of autoimmune complement activation in patients are largely lacking.,Therefore, the aim of this study was to investigate the pathogenic relevance of complement activation in patients with bullous pemphigoid.,Complement activation by autoantibodies in vivo as measured by the intensity of complement C3 deposits in the patients' skin and ex vivo by the complement-fixation assay in serum was correlated with the clinical disease activity, evaluated by Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Bullous Pemphigoid Disease Area Index (BPDAI), as well as, with further immunopathological findings in patients with bullous pemphigoid.,Results: Complement-activation capacity of autoantibodies ex vivo, but not deposition of complement in the perilesional skin of patients, correlates with the extent of skin disease (measured by ABSIS and BPDAI) and with levels of autoantibodies.,Conclusions: Our study provides for the first time evidence in patients for a pathogenic role of complement activation in bullous pemphigoid and should greatly facilitate the development of novel diagnostic tools and of more specific therapies for complement-dependent autoimmune injury.
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Thrombosis and cardiovascular complications are common manifestations of a variety of pathological conditions, including infections and chronic inflammatory diseases.,Hence, there is great interest in determining the hitherto unforeseen immune role of the main blood coagulation executor-the platelet.,Platelets store and release a plethora of immunoactive molecules, generate microparticles, and interact with cells classically belonging to the immune system.,The observed effects of platelet involvement in immune processes, especially in autoimmune diseases, are conflicting-from inciting inflammation to mediating its resolution.,An in-depth understanding of the role of platelets in inflammation and immunity could open new therapeutic pathways for patients with autoimmune disorders.,This review aims to summarize the current knowledge on the role of platelets in the patomechanisms of autoimmune disorders and suggests directions for future research.
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Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained.,Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective.,The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status.,This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain).,Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial.,To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich.,Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group).,To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature.,The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks.,The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline.,The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28.,Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]).,In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI −11 to 33], p=0·31).,However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035).,Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups.,The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification.,Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab.,Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice.,Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.
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To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally.,144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation.,Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes.,Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression.,Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) d iffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells.,Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months.,Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months.,Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression.,We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.
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Background.,Patients facing a high-stakes clinical decision are often confronted with an overwhelming array of options.,High-quality decisions about treatment should reflect patients’ preferences as well as their clinical characteristics.,Preference-assessment instruments typically focus on pre-selected clinical outcomes and attributes chosen by the investigator.,Objective.,We sought to develop a patient-centered approach to elicit and compare the treatment goals of patients with multiple sclerosis (MS) and healthcare providers (HCPs).,Methods.,We conducted five nominal group technique (NGT) meetings to elicit and prioritize treatment goals from patients and HCPs.,Five to nine participants in each group responded silently to one question about their treatment goals.,Responses were shared, consolidated, and ranked to develop a prioritized list for each group.,The ranked lists were combined.,Goals were rated and sorted into categories.,Multidimensional scaling and hierarchical cluster analysis were used to derive a visual representation, or cognitive map, of the data and to identify conceptual clusters, reflecting how frequently items were sorted into the same category.,Results.,Five NGT groups yielded 34 unique patient-generated treatment goals and 31 unique HCP-generated goals.,There were differences between patients and HCPs in the goals generated and how they were clustered.,Patients’ goals tended to focus on the impact of specific symptoms on their day-to-day lives, whereas providers’ goals focused on slowing down the course of disease progression.,Conclusions.,Differences between the treatment goals of patients and HCPs underscore the limitations of using HCP- or investigator-identified goals.,This new adaptation of cognitive mapping is a patient-centered approach that can be used to generate and organize the outcomes and attributes for values clarification exercises while minimizing investigator bias and maximizing relevance to patients.
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Treatment satisfaction in patients with relapsing-remitting multiple sclerosis (RRMS) may impact adherence and thus clinical outcomes.,The objective of this study was to measure the satisfaction of patients with RRMS with injectable disease-modifying therapies (DMTs) and to evaluate the factors associated with treatment satisfaction.,In this observational retrospective study conducted in the neurology departments of 35 hospitals throughout Spain, demographic data, disease characteristics, and information on treatment with injectable DMTs were collected at a single scheduled visit.,Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM), version 1.4.,Patients also answered complementary questions about the factors that might affect treatment satisfaction.,The data collected were analyzed descriptively.,A regression model was used to explore the factors associated with treatment satisfaction.,The study included 445 patients (mean±SD age, 41±10.2 years; two-thirds women).,The percentages treated with each DMT were Avonex 28.5%, Rebif 44 μg 24.5%, Copaxone 22.5%, Betaferon 13.0%, Rebif22 μg 8.3% and Extavia 3.1%.,The mean±SD overall satisfaction according to the TSQM was 68.8±18.6 and the highest overall satisfaction was reported for Rebif 22 μg (72.4±20.3) and the lowest for Extavia (61.7±23.7).,In the regression analysis, rehabilitation, interference with social life, pain on injection and number of MS treatments received were significantly associated with a decrease in overall TSMQ score.,A small but significant negative correlation was found between EDSS scores and TSMQ scores (rho = -0.11, p = 0.02) and effectiveness (rho = -0.17, p<0.001).,A perceived inconvenience of injections was reflected by the stated preference of 83% for once-daily oral treatment over other administration routes.,Patients on stable injectable DMT therapy were reasonably satisfied with their treatment.,Our results suggest that the main source of dissatisfaction with the current treatment is the inconvenience of the administration regimen.
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Background: MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA), obesity, and altered metabolism.,Although RA is associated with both obesity and altered metabolism, expression of RA-related microRNA in the setting of these cardiometabolic comorbidities is unclear.,Our objective was to determine relationships between six RA-related microRNAs and RA disease activity, inflammation, body composition, and metabolic function.,Methods: Expression of plasma miR-21, miR-23b, miR-27a, miR-143, miR-146a, and miR-223 was measured in 48 persons with seropositive and/or erosive RA (mean DAS-28-ESR 3.0, SD 1.4) and 23 age-, sex-, and BMI-matched healthy controls.,Disease activity in RA was assessed by DAS-28-ESR.,Plasma cytokine concentrations were determined by ELISA.,Body composition was assessed using CT scan to determine central and muscle adipose and thigh muscle tissue size and tissue density.,Plasma and skeletal muscle acylcarnitine, amino acid, and organic acid metabolites were measured via mass-spectroscopy.,Plasma lipoproteins were measured via nuclear magnetic resonance (NMR) spectroscopy.,Spearman correlations were used to assess relationships for microRNA with inflammation and cardiometabolic measures.,RA and control associations were compared using Fisher transformations.,Results: Among RA subjects, plasma miR-143 was associated with plasma IL-6 and IL-8.,No other RA microRNA was positively associated with disease activity or inflammatory markers.,In RA, microRNA expression was associated with adiposity, both visceral adiposity (miR-146a, miR-21, miR-23b, and miR-27a) and thigh intra-muscular adiposity (miR-146a and miR-223).,RA miR-146a was associated with greater concentrations of cardiometabolic risk markers (plasma short-chain dicarboxyl/hydroxyl acylcarnitines, triglycerides, large VLDL particles, and small HDL particles) and lower concentrations of muscle energy substrates (long-chain acylcarnitines and pyruvate).,Despite RA and controls having similar microRNA levels, RA, and controls differed in magnitude and direction for several associations with cytokines and plasma and skeletal muscle metabolic intermediates.,Conclusion: Most microRNAs thought to be associated with RA disease activity and inflammation were more reflective of RA adiposity and impaired metabolism.,These associations show that microRNAs in RA may serve as an epigenetic link between RA inflammation and cardiometabolic comorbidities.
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Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis.,MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA.,The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients.,IL-17 producing cells were expanded from CD4+T cell.,MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells.,Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients.,Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium.,Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells.,The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration.,MiR-146a intensely expressed in RA synovium in comparison to OA.,MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity.,Double staining revealed that miR-146a expressed in IL-17 expressing cells.,These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients.,There is the possibility that miR-146a participates in the IL-17 expression.
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The objective of this study is to describe the characteristics and outcomes of rheumatic and musculoskeletal disease (RMD) patients who were treated with rituximab and had suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.,In this descriptive study, RMD patients who were treated with rituximab in the last 12 months at the Rheumatology Department of our hospital were screened for SARS-CoV-2 infection via telephone interview and a comprehensive review of clinical health records (01/02/2020-26/05/2020).,Those with probable or confirmed SARS-CoV-2 infection were included.,In total, 76 patients were screened.,Of these, 13 (17.1%) had suspected or confirmed SARS-CoV-2 infection.,With regard to these 13 patients, the median age at coronavirus disease (COVID-19) diagnosis was 68 years (range 28-76 years) and 8 (61.5%) were female.,Five patients had rheumatoid arthritis, three had systemic vasculitis, two had Sjögren syndrome, and two had systemic lupus erythematosus.,Additionally, seven patients (53.8%) had pulmonary involvement secondary to RMD.,Eight patients (61.5%) developed severe disease leading to hospitalization, and seven developed bilateral pneumonia and respiratory insufficiency.,Of the eight hospitalized patients, five (62.5%) fulfilled the acute respiratory distress syndrome criteria and three developed a critical disease and died.,Our cohort had a high rate of severe disease requiring hospitalization (61.5%), with bilateral pneumonia and hyperinflammation leading to a high mortality rate (23.1%).,Treatment with rituximab should be considered a possible risk factor for unfavorable outcomes in COVID-19 patients with RMD.,However, further study is required to confirm this association.
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To describe clinical characteristics of patients with rheumatic and musculoskeletal diseases (RMDs) and immunosuppressive therapies with Coronavirus disease 2019 (COVID-19) at an academic rheumatology center in Madrid and to identify baseline variables associated with a severe infection requiring hospitalization.,We identified SARS-CoV-2 positive cases by polymerase chain reaction performed at our center within an updated RMDs database in our clinic.,Additional RMDs patients were identified when they contacted the clinic because of a positive infection.,Data extraction included diagnosis, demographics, immunosuppressive treatment, comorbidities, and laboratory tests.,Comparisons between patients with or without hospitalization were performed.,Multivariate logistic regression was used to analyze associations between baseline variables and need for hospitalization.,A total of 62 patients with COVID-19 and underlying RMDs were identified by April 24, 2020.,Median age was 60.9 years, and 42% men.,Forty-two patients required hospitalization; these were more frequently men, older and with comorbidities.,There were no statistically significant between-group differences for rheumatologic diagnosis and for baseline use of immunosuppressive therapy except for glucocorticoids that were more frequent in hospitalized patients.,Total deaths were 10 (16%) patients.,In multivariate analysis, male sex (odds ratio [OR], 8.63; p = 0.018), previous lung disease (OR, 27.47; p = 0.042), and glucocorticoids use (> 5 mg/day) (OR, 9.95; p = 0.019) were significantly associated to hospitalization.,Neither specific RMD diagnoses or exposures to DMARDs were associated with increased odds of hospitalization.,Being male, previous lung disease and exposure to glucocorticoids were associated with higher odds of hospitalization in RMDs patients.
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•Neurological complications related to SARS-CoV-2 are being reported around the world.,•The more “rare” cases reported, causality and strong conclusions can be established.,•Facial Diplegia and Guillain-Barré Syndrome have been connected to SARS-CoV-2 twice.,Neurological complications related to SARS-CoV-2 are being reported around the world.,The more “rare” cases reported, causality and strong conclusions can be established.,Facial Diplegia and Guillain-Barré Syndrome have been connected to SARS-CoV-2 twice.,We present a case of facial diplegia after 10 days of SARS-CoV-2 confirmed infection symptoms in a 61 year old patient without prior clinically relevant background.,There are few known cases of Guillain-Barré Syndrome (GBS) related to SARS-CoV-2 infection; we propose this case as a rare variant of GBS in COVID-19 infection context, due to Its chronology, clinical manifestations and cerebrospinal fluid (CSF) findings.
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•Coronoviruses not only affect the respiratory system, but also have deleterious effects on the central nervous system.,•Most neurological diseases could be caused by coronoviruses invasion.,•Coronoviruses cause nerve damage via diverse pathways.,Coronoviruses not only affect the respiratory system, but also have deleterious effects on the central nervous system.,Most neurological diseases could be caused by coronoviruses invasion.,Coronoviruses cause nerve damage via diverse pathways.,Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage.,Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases.,It is reported that CoV can be found in the brain or cerebrospinal fluid.,The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system.,Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.
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The prevalence and incidence of type 1 diabetes mellitus (T1DM) in all age groups and the prevalence of metabolic syndrome in patients with T1DM in Korea were estimated.,The incidence and prevalence of T1DM between 2007 and 2013 were calculated using the Korean National Health Insurance Service (NHIS) datasets of claims.,Clinical characteristics and prevalence of metabolic syndrome in individuals with T1DM between 2009 and 2013 were determined using the database of NHIS preventive health checkups.,The prevalence of T1DM in Korea between 2007 and 2013 was 0.041% to 0.047%.,The annual incidence rate of T1DM in Korea in 2007 to 2013 was 2.73 to 5.02/100,000 people.,Although the incidence rate of typical T1DM was highest in teenagers, it remained steady in adults over 30 years of age.,In contrast, the incidence rate of atypical T1DM in 2013 was higher in people aged 40 years or older than in younger age groups.,Age- and sex-adjusted prevalence of metabolic syndrome in patients with T1DM was 51.65% to 55.06% between 2009 and 2013.,T1DM may be more common in Korean adults than previously believed.,Metabolic syndrome may be a frequent finding in individuals with T1DM in Korea.
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The aim of this prospective study was to determine the incidence of type 1 diabetes mellitus in 15-34-year-aged Lithuanian males and females during 1991 - 2008,A contact system with general practitioners covering 100% of the 15-34-year-aged Lithuanian population was the primary data source.,Reports from regional endocrinologists and statistical note-marks of State patient insurance fund served as secondary sources for case ascertainment.,The average age-standardized incidence rate was 8.30 per 100,000 persons per year (95% Poisson distribution confidence interval [CI] 7.90-8.71) during 1991 - 2008 and was statistically significantly higher among males (10.44 per 100,000 persons per year, 95% CI 9.82-11.10) in comparison with females (6.10 per 100,000, 95% CI 5.62-6.62).,Male/female rate ratio was 1.71 (95% CI 1.63-1.80).,Results of the linear 1991 - 2008 regression model showed that the incidence of Type 1 diabetes in 15-34-year-aged males and females decreased slightly over the time (r = -0.215, p > 0.05).,Our data demonstrated the male predominance in primary incidence of type 1 diabetes mellitus in 15-34-year-aged population in Lithuania.,The incidence of type 1 diabetes mellitus in 15-34-year-aged males and females decreased slightly during 1991-2008.
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Yellow Fever (YF) vaccination is suggested to induce a large number of adverse events (AE) and suboptimal responses in patients with autoimmune diseases (AID); however, there have been no studies on 17DD-YF primary vaccination performance in patients with AID.,This prospective non-interventional study conducted between March and July, 2017 assessed the safety and immunogenicity of planned 17DD-YF primary vaccination in patients with AID.,Adult patients with AID (both sexes) were enrolled, along with healthy controls, at a single hospital (Vitória, Brazil).,Included patients were referred for planned vaccination by a rheumatologist; in remission, or with low disease activity; and had low level immunosuppression or the attending physician advised interruption of immunosuppression for safety reasons.,The occurrence of AE, neutralizing antibody kinetics, seropositivity rates, and 17DD-YF viremia were evaluated at various time points (day 0 (D0), D3, D4, D5, D6, D14, and D28).,Individuals evaluated (n = 278), including patients with rheumatoid arthritis (RA; 79), spondyloarthritis (SpA; 59), systemic sclerosis (8), systemic lupus erythematosus (SLE; 27), primary Sjögren's syndrome (SS; 54), and healthy controls (HC; 51).,Only mild AE were reported.,The frequency of local and systemic AE in patients with AID and HC did not differ significantly (8 vs. 10% and 21 vs. 32%; p = 1.00 and 0.18, respectively).,Patients with AID presented late seroconversion profiles according to kinetic timelines of the plaque reduction neutralization test (PRNT).,PRNT-determined virus titers (copies/mL) [181 (95% confidence interval (CI), 144-228) vs.,440 (95% CI, 291-665), p = 0.004] and seropositivity rate (78 vs. 96%, p = 0.01) were lower in patients with AID after 28 days, particularly those with SpA (73%) and SLE (73%), relative to HC.,The YF viremia peak (RNAnemia) was 5-6 days after vaccination in all groups.,In conclusion, consistent seroconversion rates were observed in patients with AID and our findings support that planned 17DD-YF primary vaccination is safe and immunogenic in patients with AID.
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Gene expression profiling of peripheral blood mononuclear cells (PBMCs) has revealed a crucial role for type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE).,However, it is unclear how particular leucocyte subsets contribute to the overall type I IFN signature of PBMCs and whole blood samples.Furthermore, a detailed analysis describing the differences in the IFN signature in autoimmune diseases from that observed after viral infection has not been performed to date.,Therefore, in this study, the transcriptional responses in peripheral T helper cells (CD4+) and monocyte subsets (CD16− inflammatory and CD16+ resident monocytes) isolated from patients with SLE, healthy donors (ND) immunised with the yellow fever vaccine YFV-17Dand untreated controls were compared by global gene expression profiling.It was striking that all of the transcripts that were regulated in response to viral exposure were also found to be differentially regulated in SLE, albeit with markedly lower fold-change values.,In addition to this common IFN signature, a pathogenic IFN-associated gene signature was detected in the CD4+ T cells and monocytes from the lupus patients.,IL-10, IL-9 and IL-15-mediated JAK/STAT signalling was shown to be involved in the pathological amplification of IFN responses observed in SLE.,Type I IFN signatures identified were successfully applied for the monitoring of interferon responses in PBMCs of an independent cohort of SLE patients and virus-infected individuals.,Moreover, these cell-type specific gene signatures allowed a correct classification of PBMCs independent from their heterogenic cellular composition.,In conclusion, our data show for the first time that monocytes and CD4 cells are sensitive biosensors to monitor type I interferon response signatures in autoimmunity and viral infection and how these transriptional responses are modulated in a cell- and disease-specific manner.
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SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19.,However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients.,We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination.,Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution.,By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination.,Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming.,Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses.,These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans.,Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.,SARS-CoV-2-specific antibodies and memory B cells are significantly reduced, but CD4+ and CD8+ T cells are robustly activated, in patients with multiple sclerosis on anti-CD20 monotherapy versus healthy controls after BNT162b2 or mRNA-1273 mRNA vaccination.
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Little is known about COVID-19 mRNA vaccine humoral immune responses in patients with central nervous system autoimmune demyelinating diseases, multiple sclerosis (MS) and neuromyelitis optica (NMO), who are on B-cell depleting therapies (BCDT) and other disease modifying therapies (DMTs).,We conducted a single center prospective study to identify the clinical and immunological features associated with vaccine-induced antibody response in 53 participants before and after COVID-19 mRNA vaccination.,This is the first report on the anti-spike RBD and anti-nucleocapsid antibody response, along with pre- and post-vaccine absolute lymphocyte counts (ALC) and flow cytometry analysis of CD19 and CD20 lymphocytes in patients with MS and NMO.,We tested the hypothesis that patients on BCDT may have impaired COVID-19 vaccine humoral responses.,Among patients on BCDT, 36.4% demonstrated a positive antibody response to spike RBD, in comparison to 100% in all other groups such as healthy controls, untreated MS, and patients on non-B cell depleting DMTs (p < 0.0001).,Immunological data revealed lower baseline (pre-vaccination) levels of IgM in patients on BCDT (p = 0.003).,Low CD19 and CD20 counts and a shorter interval from the last B cell depleting therapy infusion to the first vaccine dose were associated with a negative spike RBD antibody response (non-seroconverter) in patients on BCDT.,Age, body mass index (BMI) and total treatment duration did not differ between seroconverters and non-seroconverters.
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To review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases.,We systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and “breastmilk,” “breast milk,” “breastfeeding,” or “lactation.”,From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria.,One additional study was added after the literature search based on expert knowledge of an additional article.,These 30 studies were reviewed.,These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women.,Drug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion.,Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab.,Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated).,Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.,The current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.
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To assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation.,We identified 23 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received MAbs (17 natalizumab and 6 anti-CD20) during lactation.,Thirteen were already exposed to natalizumab during the third trimester of pregnancy, and 1 received ocrelizumab during pregnancy.,Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum.,Natalizumab concentration in mother’s milk was analyzed in 3 patients and natalizumab serum concentration in 2 of these patients and their breastfed infants.,We did not observe a negative impact on infant health and development attributable to breast milk exposure after a median follow-up of 1 year.,Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life.,The concentration of natalizumab in breast milk and serum of infants was low; B cells normal in infants breastfed under anti-CD20.,More data on the effect of Mab exposure during pregnancy are needed.,Otherwise, our data suggest that treatment with natalizumab, ocrelizumab, or rituximab during lactation might be safe for breastfed infants.
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MicroRNAs (miRNAs) have been reported as deregulated in active brain lesions derived from patients with multiple sclerosis (MS).,In there, these post-transcriptional regulators may elicit very important effects but proper identification of miRNA candidates as potential biomarkers and/or therapeutic targets is scarcely available.,The aim of the study was to detect the presence of a set of candidate miRNAs in cell-free cerebrospinal fluid (CSF) and to determine their association with gadolinium-enhancing (Gd+) lesions in order to assess their value as biomarkers of MS activity.,Assessment of 28 miRNA candidates in cell-free CSF collected from 46 patients with MS (26 Gd+ and 20 Gd− patients) was performed by TaqMan assays and qPCR.,Variations in their relative abundance were analyzed by the Mann-Whitney U test and further evaluated by receiver operating characteristic (ROC) analysis.,Signaling pathways and biological functions of miRNAs were analyzed using bioinformatic tools (miRTarBase, Enrichr, REVIGO, and Cytoscape softwares).,Seven out of 28 miRNA candidates were detected in at least 75% of CSF samples.,Consistent increase of miR-21 and miR-146a/b was found in Gd+ MS patients.,This increase was in parallel to the number of Gd+ lesions and neurofilament light chain (NF-L) levels.,Gene Ontology enrichment analysis revealed that the target genes of these miRNAs are involved in biological processes of key relevance such as apoptosis, cell migration and proliferation, and in cytokine-mediated signaling pathways.,Levels of miR-21 and miR-146a/b in cell-free CSF may represent valuable biomarkers to identify patients with active MS lesions.
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Multiple sclerosis is the most common autoimmune disease of the central nervous system.,It is believed that the increased migration of autoreactive lymphocytes across the blood-brain barrier (BBB) may be responsible for axonal demyelination of neurons.,In this review, we discuss microRNAs participating in the pathological processes of MS, including periphery inflammation, blood-brain barrier disruption, and CNS lesions, and in its therapeutic response, in order to find biomarkers of disease severity and to predict the response to therapy of the diseases.
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Objective.,To evaluate a multi-biomarker disease activity (MBDA) score, a novel index based on 12 serum proteins, as a tool to guide management of RA patients.,Methods.,A total of 125 patients with RA from the Behandel Strategieën study were studied.,Clinical data and serum samples were available from 179 visits, 91 at baseline and 88 at year 1.,In each serum sample, 12 biomarkers were measured by quantitative multiplex immunoassays and the concentrations were used as input to a pre-specified algorithm to calculate MBDA scores.,Results.,MBDA scores had significant correlation with DAS28-ESR (Spearman’s ρ = 0.66, P < 0.0001) and also correlated with simplified disease activity index, clinical disease activity index and HAQ Disability Index (all P < 0.0001).,Changes in MBDA between baseline and year 1 were also correlated with changes in DAS28-ESR (ρ = 0.55, P < 0.0001).,Groups stratified by European League Against Rheumatism disease activity (DAS28-ESR ≤ 3.2, 3.2-5.1 and > 5.1) had significantly different MBDA scores (P < 0.0001) and MBDA score could discriminate ACR/EULAR Boolean remission with an area under the receiver operating characteristic curve of 0.83 (P < 0.0001).,Conclusion: The MBDA score reflects current clinical disease activity and can track changes in disease activity over time.
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To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.,Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies.,The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm.,The performance of the scores was evaluated relative to clinical disease activity assessments.,Change in MBDA score over time was assessed by paired Wilcoxon rank sum test.,Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.,The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7.,In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures.,Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001).,Neither MBDA score nor clinical variables were predictive of radiographic progression.,This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study.,Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
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Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood.,Various diseases causing neuronal damage have resulted in elevated CSF concentrations.,We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).,sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0-4.0).,We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.,sNfL levels were higher in both MS cohorts than in HC (p < 0.001).,We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001).,Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003).,Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034).,These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.,Ann Neurol 2017;81:857-870
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The gut environment has been found to significantly influence autoimmune diseases such as multiple sclerosis; however, immune cell mechanisms are unclear.,Here we show that the gut epithelium of myelin oligodendrocyte glycoprotein(35-55)-specific T-cell receptor transgenic mice contains environmental stimuli-induced intraepithelial lymphocytes (IELs) that inhibit experimental autoimmune encephalomyelitis on transfer.,These cells express surface markers phenotypical of ‘induced' IELs, have a TH17-like profile and infiltrate the central nervous system (CNS).,They constitutively express Ctla4 and Tgfb1 and markedly upregulate Lag3 expression in the CNS, thereby inhibiting inflammation.,We also demonstrate the suppressive capability of CD4+ IELs with alternative antigen specificities, their proliferation in response to gut-derived antigens and contribution of the microbiota and dietary aryl hydrocarbon receptor ligands to their induction.,Thus, the gut environment favours the generation of autoreactive CD4+ T cells with unique regulatory functions, potentially important for preventing CNS autoimmunity.,Experimental autoimmune encephalomyelitis (EAE) involves inflammatory cell infiltration into the central nervous system (CNS) and models the human disease multiple sclerosis.,Here the authors show that transferred CD4+ gut intraepithelial lymphocytes can migrate into the CNS and inhibit inflammation in recipient mice with EAE.
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B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies.,During development and differentiation, B cells undergo drastic changes in their physiology.,It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell.,The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this.,Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.
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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antibody-mediated encephalitis.,There are several studies on B cell repertoire of anti-NMDAR encephalitis in Caucasians.,Here, the cerebrospinal fluid (CSF) samples of 12 Chinese patients with first-episode anti-NMDAR encephalitis were collected to investigate the B cell receptor (BCR) binding to NMDAR by single cell amplification of BCR and Sanger sequencing.,BCR data of healthy persons, and of patients with anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis, multiple sclerosis (MS), and neuromyelitis optica spectrum disorder (NMOSD) from the public databases were used as control.,A heavy chain common clone IGHV1-18*04,IGHD1-26*01/ IGHD2-2*03/IGHD2-8*01, IGHJ3*02_(CDR3) ARVGSKYGFETFDI was found in 11 of 12 enrolled patients but not in the comparison data set.,In addition, 4 shared clonotypes were found among these patients, and three of them contained the common clone.,This study also revealed that the antibody gene family usage preference between patients and healthy controls were different, while they had similar antibody mutation rate.,Our findings may have potential clinical implications for the diagnosis of anti-NMDAR encephalitis.
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Dimethyl fumarate (DMF), recently approved as an oral immunomodulatory treatment for relapsing-remitting multiple sclerosis (MS), metabolizes to monomethyl fumarate (MMF) which crosses the blood-brain barrier and has demonstrated neuroprotective effects in experimental studies.,We postulated that MMF exerts neuroprotective effects through modulation of microglia activation, a critical component of the neuroinflammatory cascade that occurs in neurodegenerative diseases such as MS.,To ascertain our hypothesis and define the mechanistic pathways involved in the modulating effect of fumarates, we used real-time PCR and biochemical assays to assess changes in the molecular and functional phenotype of microglia, quantitative Western blotting to monitor activation of postulated pathway components, and ex vivo whole-cell patch clamp recording of excitatory post-synaptic currents in corticostriatal slices from mice with experimental autoimmune encephalomyelitis (EAE), a model for MS, to study synaptic transmission.,We show that exposure to MMF switches the molecular and functional phenotype of activated microglia from classically activated, pro-inflammatory type to alternatively activated, neuroprotective one, through activation of the hydroxycarboxylic acid receptor 2 (HCAR2).,We validate a downstream pathway mediated through the AMPK-Sirt1 axis resulting in deacetylation, and thereby inhibition, of NF-κB and, consequently, of secretion of pro-inflammatory molecules.,We demonstrate through ex vivo monitoring of spontaneous glutamate-mediated excitatory post-synaptic currents of single neurons in corticostriatal slices from EAE mice that the neuroprotective effect of DMF was exerted on neurons at pre-synaptic terminals by modulating glutamate release.,By exposing control slices to untreated and MMF-treated activated microglia, we confirm the modulating effect of MMF on microglia function and, thereby, its indirect neuroprotective effect at post-synaptic level.,These findings, whereby DMF-induced activation of a new HCAR2-dependent pathway on microglia leads to the modulation of neuroinflammation and restores synaptic alterations occurring in EAE, represent a possible novel mechanism of action for DMF in MS.,The online version of this article (doi:10.1007/s00401-015-1422-3) contains supplementary material, which is available to authorized users.
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Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases.,Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results.,In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered.,Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible.,We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents.,Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells).,Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE.,Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents.,Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases.
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Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acid‐mediated inflammation relevant to the pathogenesis of systemic autoimmunity.,Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus.,Reduced processing of either RNA:DNA hybrid or genome‐embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid‐sensing pathway.,Here, we establish Rnaseh2b A174T/A174T knock‐in mice as a subclinical model of disease, identifying significant interferon‐stimulated gene (ISG) transcript upregulation that recapitulates the ISG signature seen in AGS patients.,The inflammatory response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING and is associated with reduced cellular ribonucleotide excision repair activity and increased DNA damage.,This suggests that cGAS/STING is a key nucleic acid‐sensing pathway relevant to AGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood‐onset interferonopathy and adult systemic autoimmune disorders.
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Neutrophil extracellular traps (NETs) are implicated in autoimmunity but how they are generated and their roles in sterile inflammation remain unclear.,Ribonucleoprotein immune complexes, inducers of NETosis, require mitochondrial ROS for maximal NET stimulation.,During this process, mitochondria become hypopolarized and translocate to the cell surface.,Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro and, when injected into mice, stimulates type-I interferon (IFN) signaling through a pathway dependent on the DNA sensor, STING.,Mitochondrial ROS is also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus (SLE).,This was also observed in individuals with chronic granulomatous disease (CGD), which lack NADPH-oxidase activity, but still develop autoimmunity and type I-IFN signatures.,Mitochondrial ROS inhibition in vivo reduces disease severity and type-I IFN responses in a mouse model of lupus.,These findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.
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Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability.,RA affects as much as 1% of the population worldwide.,To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood.,The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients’ functional capacity and their quality of life.,As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS-fibroblast-like synoviocytes) activity when it is necessary.,It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results.,Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable “liquid biopsy”, thus providing a reliable template for assessing molecular markers of various diseases, including RA.,Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA.,In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.
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The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC).,We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy.,FcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease).,Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation.,FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined.,Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients.,HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001).,The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003).,FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers.,Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation.,This monocyte subset may contribute to non-response to methotrexate therapy.
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High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts.,The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels.,Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis.,Regional analyses and comparisons with 2013 data were conducted.,A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population).,MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist.,The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years.,Females are twice as likely to live with MS as males.,The global prevalence of MS has risen since 2013, but good surveillance data is not universal.,Action is needed by multiple stakeholders to close knowledge gaps.
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Cortical lesions constitute an important part of multiple sclerosis pathology.,Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood.,We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis.,In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis).,In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls.,More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes.,Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites.,Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.
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This open‐label prospective phase I/IIa clinical study used autologous bone marrow‐derived mesenchymal stromal cells (BM‐MSCs) followed by mesenchymal stromal cells conditioned media (MSC‐CM) for the first time to treat multiple sclerosis (MS) patients.,The primary goal was to assess the safety and feasibility and the secondary was efficacy.,The correlation between the MSC‐CM content and treatment outcome was investigated.,Ten MS patients who failed conventional therapy were enrolled.,Adverse events were recorded to assess safety.,The Expanded Disability Status Scale (EDSS) was the primary efficacy measurement, the secondary included clinical (25WFT, 9‐PHT), cognitive (MMS), ophthalmology (OCT, VEP), and radiological (MRI lesion and volume) tests.,The MSCs‐CM concentration of 27 inflammatory biomarkers was investigated.,The treatment protocol was well tolerated by patients.,There was an overall trend of improvement in all the tests, except the lesion volume which increased significantly.,A decrease of 4 and 3.5 points on the EDSS was achieved in two patients.,We report a correlation between a decreased lesion number at baseline and higher IL‐6, IL‐8, and VEGF MSC‐CM content.,The used protocol was safe and feasible with possible efficacy.,The addition of MSC‐CM could be related to the magnitude of EDSS improvement observed.
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The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles.,However, the optimum frequency of the MSCs transplantation (MSCT) is unknown.,This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation.,Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT.,Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events.,SLE disease activity index (SLEDAI) and serologic features were evaluated.,Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup.,This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients.
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Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovitis, hyperplasia, and the destruction of bone and cartilage.,A variety of immunosuppressive biological agents have been developed because the pathogenesis of RA is related predominantly to the inflammatory response.,However, rheumatoid arthritis fibroblast-like synovial cells (RAFLS), which are known to play an important role in RA progression, exhibit resistance to immunosuppressants through cancer-like properties.,In this study, we identified a novel therapeutic compound for RA, which reduced inflammation and the abnormal proliferation of RAFLS in natural product library made from Korean native plants.,Eupatorium japonicum Thunb.,(EJT) extract, a component of the natural product library, most effectively reduced viability through the induction of ROS-mediated apoptosis in a dose-dependent manner.,In addition, the increased ROS induced the expression of ATF4 and CHOP, key players in ER stress-mediated apoptosis.,Interestingly, EJT extract treatment dose-dependently reduced the expression of IL-1β and the transcription of MMP-9, which were induced by TNF-α treatment, through the inhibition of NF-κB and p38 activation.,Collectively, we found that EJT extract exerted apoptotic effects through increases in ROS production and CHOP expression and exerted anti-inflammatory effects through the suppression of NF-κB activation, IL-1β expression, and MMP-9 transcription.
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Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is a major cause of disability.,The nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway has been reported to be involved in the pathogenesis of RA with unclear mechanisms.,Therefore, this study aims to explore the effect of NF-κB pathway on proliferation, apoptosis, and angiogenesis of human fibroblast-like synovial cells (HFLS) in RA.,Normal HFLS and RA-HFLS were selected as the normal and control groups, respectively.,RA-HFLS were treated by BAY11-7082 (an inhibitor of NF-κB) in different concentrations, namely 2.5 μmol/L BAY11-7082, 5 μmol/LBAY11-7082 and 10 μmol/L BAY11-7082.,MTT assay was employed to detect cell proliferation.,Cell apoptosis was determined by flow cytometry at 24, 48, and 72 hours after culture.,Western blot analysis was employed to detect the expressions of NF-κB, angiogenesis-related factors (VEGF, Ang1, and Ang2).,Initially, we found that BAY11-7082 inhibited NF-κB expression in a concentration-dependent manner.,According to the findings of MTT assay and flow cytometry, we understood that RA-HFLS treated by BAY11-7082 (an inhibitor of NF-κB), the inhibition of NF-κB pathway, suppressed RA-HFLS proliferation and induced RA-HFLS apoptosis in a concentration and time-dependent manner.,Furthermore, RA-HFLS treated by BAY11-7082 presented decreased VEGF, Ang1 and Ang2 expressions in a concentration-dependent manner.,The study concluded that inhibition of NF-κB pathway induced cell apoptosis and suppressed proliferation and angiogenesis of RA-HFLS, which could serve as a novel target in the treatment of RA.
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To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy.,Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group.,Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13).,Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy.,Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed.,Three women had severe infections during pregnancy.,All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy.,Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum.,Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD.,Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.
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Neuromyelitis optica (NMO) is a severe inflammatory autoimmune disorder of the central nervous system and often results in paralysis or blindness.,Rituximab (RTX) is a mouse-human chimeric monoclonal antibody specific for the CD20 antigen on B lymphocytes and used to treat many autoimmune diseases.,Disability and relapses were measured using the Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR) ratio to evaluate the effectiveness of RTX.,This review performed a meta-analysis of the efficacy of RTX in NMO.,We searched through the databases of PubMed, Embase, and Cochrane Library.,We compiled 26 studies, in which 18 used ARR ratio, 22 used EDSS score, and 14 used both variables.,Differences in the ARR ratio and EDSS score before and after RTX therapy were used as the main efficacy measures.,Publication bias was evaluated after the consistency test, and a sensitivity analysis was performed with mean difference (MD) of the efficacy of RTX.,A meta-analysis of 26 studies with 577 participants was conducted.,Antibodies against aquaporin-4 autoantibody were recorded in 435 of 577 (75.39%) patients with NMO.,RTX therapy resulted in a mean (WMD) − 1.56 (95% CI, − 1.82 to − 1.29) reduction in the mean ARR ratio and a mean (WMD) − 1.16 (95% CI, − 1.36 to − 0.96) reduction in the mean EDSS score.,A total of 330 of 528 patients (62.9%) reached the relapse-free state.,A total of 95 of 577 (16.46%) patients had adverse reactions.,RTX has acceptable tolerance, reduces the relapse frequency, and improves disability in most patients with NMO.,Future studies should focus on reducing the health-care costs, improving the functional outcomes, and reducing the adverse effects associated with RTX treatment.
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In the present study, the CA III and IV autoantibodies, CA activity, antioxidant enzymes and cytokines in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), diabetes, hypertensive renal disease, and heart failure were investigated.,The anti-CA III antibody titers in patients with RA, SLE, and type 1 diabetes (T1D) were significantly higher than that in control groups (P < 0.05).,The anti-CA IV antibody titers in patients with RA, SLE, type 1 diabetic nephropathy (T1DN), and heart failure were significantly higher than that in control groups (P < 0.05) while anti-CA IV antibody could suppress the total CA activity.,The SOD and GPx levels in patients with RA, SLE, and T1DN were significantly lower than that in control groups (P < 0.05).,IL-6, IL-17, IFN-γ, and TNF-α levels were significantly higher in SLE group compared with the control group (P < 0.05).,Weak but significant correlations were found between anti-CA III antibodies and ESR in RA (r = 0.403, P = 0.013) and SLE patients (r = 0.397, P = 0.007).,These results suggested that the generation of CA III and IV autoantibodies, antioxidant enzymes, and cytokines might influence each other and CA autoantibodies might affect the normal physiology function of CA.
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Not only is nephritis a common complaint in systemic lupus erythematosus, but it is also the most life-threatening complication of the disease.,Anti-double-stranded DNA antibodies (Abs), which are found in up to 80% of these patients, might be nephritogenic per se.,That is, they may cross-react with mesangial cell (MC) surface proteins, such as alpha-actinin and annexin A2, they may cross-react with mesangial matrix protein such as laminine and fibronectin, or they may recognize chromatin material previously deposited in the glomeruli.,The consequence of the binding of anti-MC Abs may be their internalization, which results in activation and proliferation of these MCs.,In turn, these activated MCs are suspected of promoting immune complex formation by sequestering and thereby protecting chromatin from degradation.,The present paper will explain the mechanisms through which such autoAbs may initiate nephritis.
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Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction.,A gut microbiota-immunological interplay is involved in the pathophysiology of T1D.,We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).,Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months.,Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months.,Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition.,Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months.,Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively).,Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.,FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset.,Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function.,This study provides insight into the role of the intestinal gut microbiome in T1D.,NTR3697.
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To examine duration of breastfeeding and timing of complementary foods and risk of islet autoimmunity (IA).,The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes (T1D) in the U.S., Finland, Germany, and Sweden.,This study included 7,563 children with at least 9 months of follow-up.,Blood samples were collected every 3 months from birth to evaluate IA, defined as persistent, confirmed positive antibodies to insulin (IAAs), GAD, or insulinoma antigen-2.,We examined the associations between diet and the risk of IA using Cox regression models adjusted for country, T1D family history, HLA genotype, sex, and early probiotic exposure.,Additionally, we investigated martingale residuals and log-rank statistics to determine cut points for ages of dietary exposures.,Later introduction of gluten was associated with increased risk of any IA and IAA.,The hazard ratios (HRs) for every 1-month delay in gluten introduction were 1.05 (95% CI 1.01, 1.10; P = 0.02) and 1.08 (95% CI 1.00, 1.16; P = 0.04), respectively.,Martingale residual analysis suggested that the age at gluten introduction could be grouped as <4, 4-9, and >9 months.,The risk of IA associated with introducing gluten before 4 months of age was lower (HR 0.68; 95% CI 0.47, 0.99), and the risk of IA associated with introducing it later than the age of 9 months was higher (HR 1.57; 95% CI 1.07, 2.31) than introduction between 4 and 9 months of age.,The timing of gluten-containing cereals and IA should be studied further.
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We investigated interactions between genetically and autoimmune-mediated coagulopathies by inducing experimental antiphospholipid syndrome (eAPS) in mice carrying the factor V Leiden (FVL) mutation.,eAPS was induced in heterozygous and homozygous FVL transgenic mice (C57BL/6 background) by immunization with β2-glycoprotein I (β2-GPI).,Autoantibody levels were measured at 1 and 5 months post-immunization.,Mice were tested at 4 months post-immunization for behavior and cognitive function in the staircase, elevated plus-maze, and swim T-maze tests.,Brains were removed and analyzed by immunohistochemistry for inflammatory markers and neurodegenerative processes.,A single immunization with β2-GPI induced significantly higher and longer-lasting immune responses, and this was dependent on the number of FVL alleles.,At 1 and 5 months post-immunization, levels of antibodies rose from 1.17 ± 0.07 to 1.62 ± 0.17 (optical density units; ODU) in homozygous FVL mice, compared with stable levels of 0.59 ± 0.17 and 0.48 ± 0.16 ODU in heterozygous FVL mice and a drop from 1.62 ± 0.21 to 0.61 ± 0.13 ODU in wild-type mice.,Behavioral and cognitive clinical features of eAPS were also correlated with FVL allele load, as assessed by the elevated plus-maze (altered anxiety), staircase (hyperactivity and higher exploration), and swim T-maze (impaired learning) tests.,Histological studies identified significant neurodegenerative changes in both grey and white matter in the eAPS-FVL brains.,In spite of the potential interaction of two prothrombotic disease states, there were no ischemic lesions seen in this group.,The results indicate that genetically mediated coagulopathies increase the risk of developing coagulation-targeted autoimmune responses, and suggest the importance of antibody-mediated neurodegenerative processes in the brain in APS.
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A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported.,We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation.,The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test.,Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient.,The distributions of ID births significantly differed from that of the general population (P = 5e-12) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P < 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P < 0.0001).,Stratification by disease subtype showed seasonality in all ID but Crohn's disease.,The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003).,The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID.,Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.
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Environmental factors contribute to Type 1 diabetes (T1D) susceptibility.,The gut microbiome, which includes bacteria, viruses, and fungi, contributes to this environmental influence, and can induce immunological changes.,The gut viral component of the microbiome, related to T1D has mostly focused on coxsackieviruses and rotavirus.,The role of norovirus, another common enteric virus, in susceptibility to T1D was hitherto unknown.,Norovirus is highly infectious and encountered by many children.,We studied the mouse norovirus 4 (MNV4), related to human noroviruses, in the Non-obese diabetic (NOD) mouse model, to determine its role in influencing susceptibility to T1D.,We infected MNV-free NOD mice with MNV4 by exposing the mice to MNV4-positive bedding from an endemically-infected mouse colony to mimic a natural infection.,Control MNV-free NOD mice were exposed to MNV-free bedding from the same colony.,Interestingly, MNV4 infection protected NOD mice from the development of T1D and was associated with an expansion of Tregs and reduced proinflammatory T cells.,We also found MNV4 significantly modified the gut commensal bacteria composition, promoting increased α-diversity and Firmicutes/Bacteroidetes ratio.,To elucidate whether T1D protection was directly related to MNV4, or indirectly through modulating gut microbiota, we colonized germ-free (GF) NOD mice with the MNV4-containing or non-MNV4-containing viral filtrate, isolated from filtered fecal material.,We found that MNV4 induced significant changes in mucosal immunity, including altered Tuft cell markers, cytokine secretion, antiviral immune signaling markers, and the concentration of mucosal antibodies.,Systemically, MNV4-infection altered the immune cells including B cell subsets, macrophages and T cells, and especially induced an increase in Treg number and function.,Furthermore, in vitro primary exposure of the norovirus filtrate to naïve splenocytes identified significant increases in the proportion of activated and CTLA4-expressing Tregs.,Our data provide novel knowledge that norovirus can protect NOD mice from T1D development by inducing the expansion of Tregs and reducing inflammatory T cells.,Our study also highlights the importance of distinguishing the mucosal immunity mediated by bacteria from that by enteric viruses.
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The etiopathogenesis of type 1 diabetes (T1D), a common autoimmune disorder, is not completely understood.,Recent studies suggested the gut microbiome plays a role in T1D.,We have used public longitudinal microbiome data from T1D patients to analyze amyloid-producing bacterial composition and found a significant association between initially high amyloid-producing Escherichia coli abundance, subsequent E. coli depletion prior to seroconversion, and T1D development.,In children who presented seroconversion or developed T1D, we observed an increase in the E. coli phage/E. coli ratio prior to E. coli depletion, suggesting that the decrease in E. coli was due to prophage activation.,Evaluation of the role of phages in amyloid release from E. coli biofilms in vitro suggested an indirect role of the bacterial phages in the modulation of host immunity.,This study for the first time suggests that amyloid-producing E. coli, their phages, and bacteria-derived amyloid might be involved in pro-diabetic pathway activation in children at risk for T1D.
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IgA nephropathy is diagnosed by renal biopsy, an invasive procedure with a risk of significant complications.,Noninvasive approaches are needed for possible diagnostic purposes and especially for monitoring disease activity or responses to treatment.,In this pilot project, we assessed the utility of urine samples as source of biomarkers of IgA nephropathy.,We used spot urine specimens from 19 healthy controls, 11 patients with IgA nephropathy, and 8 renal-disease controls collected on day of renal biopsy.,Urine samples were analyzed using untargeted metabolomic and targeted proteomic analyses by several experimental techniques: liquid chromatography coupled with mass spectrometry, immunomagnetic isolation of target proteins coupled with quantitation by mass spectrometry, and protein arrays.,No single individual biomarker completely differentiated the three groups.,Therefore, we tested the utility of several markers combined in a panel.,Discriminant analysis revealed that combination of seven markers, three metabolites (dodecanal, 8-hydroxyguanosine, and leukotriene C4), three proteins (α1-antitrypsin, IgA-uromodulin complex, and galactose-deficient IgA1), and heparan sulfate, differentiated patients with IgA nephropathy from patients with other renal diseases and healthy controls.,Future studies are needed to validate these preliminary findings and to determine the power of these urinary markers for assessment of responses to therapy.
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Tubulointerstitial injury plays an important role in the progression of immunoglobulin A nephropathy (IgAN), and neutrophil gelatinase-associated lipocalin (NGAL) is among the most sensitive tubular biomarkers.,We investigated whether serum or urine NGAL predicts prognosis in patients with IgAN.,The present study enrolled patients with biopsy-proven IgAN from January 2005 to December 2010, whose serum and urine samples at the time of kidney biopsy were preserved by freezing.,We retrospectively reviewed patient clinical data and followed patients until October 2012.,Serum and urine NGAL levels were measured using an enzyme-linked immunosorbent assay kit.,Renal progression was defined as an estimated glomerular filtration rate decline by > 50% or progression to end-stage renal disease.,There were 121 patients enrolled in this study.,During the median follow-up period of 41.49 months, renal progression was found in nine patients (7.4%).,Serum or urine NGAL alone could not predict renal progression; however, when serum and urine NGAL levels were combined, belonging to the high NGAL group independently predicted renal progression (hazard ratio [HR], 5.56; 95% confidence interval [CI], 1.42 to 21.73; p = 0.014), along with tubular damage graded according to the Oxford classification as T2 (HR, 8.79; 95% CI, 2.01 to 38.51; p = 0.004).,In addition, a Kaplan-Meier curve of renal survival showed significantly higher renal progression in patients in the high NGAL group (log rank, p = 0.004).,In patients with IgAN, high serum and urine NGAL levels at the time of kidney biopsy predict renal progression.
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