Corticosteroids and cyclophosphamide can be used for nonmalignancy-associated type I diseas e during acute \202 ares. Types II and III cryoglobulinemia Mild symptoms (arthralgias, myalgia, fatigue) without evi - dence of end-organ damage can be treated conservatively with analgesia and cold avoidance . NSAIDs can be helpful, and low-dose corticosteroids can be used in those without symptoma tic relief from NSAIDs. Disease with evidence of end-organ damage requires immunosuppressiv e therapy. hyaline thrombi in the subendothelial space or in capillary lumen (seen in 70% of cases) (F ig. 4.6.1); intense leukocytic (monocyte) in \201 ltration of glomeruli; \201 brinoid ne crosis of extraglomerular arterioles/arteries (seen in up to 30% of cases). \200 Immuno \202 uorescence microscopy demonstrates IgM, IgG and C3 in a granular capillary wal l distribution. Electron microscopy reveals subendothelial and mesangial electron-dense dep osits. These deposits may have an organized substructure ( \200\230fingerprint-like \200 \231 appearance). These are not speci \201 c and can be seen in others situations, e.g. lu pus nephritis. Immunosuppression/plasmapheresis For an acute flare with progressive renal dysfunction, sev ere neuropathy, or necrosis of extremities, the following regimen may be used: \200 IV methylprednisolone 1 g/day for 3 days then 60 mg prednisolone/day followed by a slow tap er over 2 \200\2233 months. Cyclophosphamide 2 mg/kg/day orally for 2 months. Plasmapheresi s: 1 plasma volume exchange on alternate days for 2 \200\2233 weeks. Alternatively, cryo \201 ltration (double \201 ltration plasmapheresis with a cooling unit on the sec- ond \201 lter) can be used in order to selectively remove the CG. Management The optimal management of CG-related disease has not been well-de \201 ned. The disease tends to follow a relapsing and remitting pat- tern. Data suggest that prolonged i mmunosuppression has no effect on the risk of developing progressive renal dys- function; t herefore such treatment is usually reserved for acute \202 ares. Treatment of the underly ing disease process (i.e. lympho- proliferative disorder, viral disease, connective tissue dis- ease) is important, however. The general management principles for patients with glome rular disease should be adopted, i.e. blood pressure control, treatment of hyperlipidemia, and reduction of pro- teinuria using renin \200\223angiotensin system inhibition. \200 Improved renal function can be seen in 50 \200\22380% of patients with this regimen. Monito ring of the cryocrit is not necessarily helpful given the poor correlation between the cryo crit and the severity of disease. Therefore the length of the course of plas- mapheresis is determined by the clinical response. Immunosuppression may theoretically be complicated by enhanced replication of underlying HCV, and exacerbation of low-grade non-Hodgkin lymphoma (in addition to the conventional risks of treatment, i.e. infection, bone marrow suppressi on, late malignancy, etc.). Type I cryoglobulinemia Chemotherapy (and radiotherapy) for the underlying lymphoproliferat ive disease is required. CHAPTER 4.6 Mixed cryoglobulinemia and hepatitis C infection 179 Antiviral therapy For HCV-related disease, antiviral therapy is appropriate. Antiviral trea tment should be delayed for 3 \200\2234 months after an acute \202 are that requires immu nosuppressive treatment. The treatment of choice is a combination of: \200 \200 Approximately 5 \200\22310% of patients with type II cryoglob- ulinemia develop a lymphopro liferative disorder (usually B-cell non-Hodgkin lymphoma), usually 5 \200\22310 years after diagnosis. This risk is 35 times higher than that of the gen- eral population. Risk factor s for a poor outcome are: renal failure, infection, hypertension, and four or more extra-re nal manifesta- tions. Pegylated interferon-A 1 g/kg weekly for 48 weeks. Ribavirin 1000 mg/day for 48 weeks. This regimen should not be used in those with a GFR <50 mL/min (ribavirin is contraindicate d and the prolonged half-life of pegylated interferon-A in this setting raises con- cerns a bout its use). For those with renal impairment, nonpegylated interferon- A can be used alon e. The optimal dose is unclear but inter- feron-A 3 million units 3 times a week for 12 mon ths has been used with success. This regimen is less effective than combination therapy, bu t can lead to a virological and clinical response in 60% of patients. Cessation of treatmen t almost invariably results in viral relapse. HCV-related renal disease (without cryoglobulinemia) HCV infection can also cause MCGN type I without evi- dence of CG production. It has also been associated with membranous nephrop athy in some patients. In both conditions if there is evidence of severe, progressive glome rular disease (i.e. severe nephrosis, progressive renal function decline), antiviral therap y (as described above) should be considered (although in membranous nephropa- thy a causal role for HCV has not been established). Further reading Braun GS, Horster S, Wagner KS, Ihrler S, Schmid H. Cryoglobulinaemic vascu litis: classi \201 cation and clinical and thera- peutic aspects. Postgrad Med J 2007; 83: 87 \200\22394. Other treatments Rituximab (monoclonal anti-CD20 antibody) has been evaluated in small stud ies with apparent clinical success, although at the expense of increased HCV RNA levels. It s role remains to be determined but it can be considered in patients who do not respond to the treatments described above. Fabrizi F, Colucci P, Ponticelli C, Locatelli F. Kidney and liver involve- ment in cryoglobulinemia. Semin Nephrol 2002; 22: 309 \200\223318. Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006; 69: 436 \200\223439. Meyers CM, Seeff LB, Stehman-Breen CO, Hoofnagle JH. Hepatitis C and renal disease: an upda te. Am J Kidney Dis 2003; 42: 631 \200\223657. Dialysis and renal transplantation The outcome on hemodialysis or peritoneal dialysis is si milar to that seen in the matched dialysis population. Renal transplantation should not be precluded in patients with CG-related disease even though 50 \200\22370% of renal allo- gra ft recipients develop clinically signi \201 cant disease. This is not usually a cause of g raft failure. The transplant immunosuppression appears to have no clinically signi \201 ca nt effect on HCV replication. Internet resources Review article about cryoglobulinemia: http://www.kidneyatlas.org/book4/adk4-09.pdf See also Immunological investigation of the patient with renal disease, p. 36 Proteinuria a nd/or hematuria, p. 76 Nephrotic syndrome, p. 80 Mesangiocapillary glomerulonephritis, p. 1 12 Infection-related glomerulonephritis, p. 128 Prognosis Overall survival at 10 years after symptom onset and time of diagnosis is 70% and 50% respectively. Death is usually due to liver disease, cardiovascular disease or infecti on. The risk of developing renal failure appears to be highest in those with HCV-related di sease (up to 40%). D. JAYNE 180 Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is the most common multisystem autoimmune disease. It ha s variable presentations and outcomes and can poten- tially be fatal. Kidney involvement is the most frequent severe manifesta- tion and it can lead to end-stage renal disease. Immune complexes such as anti-dsDNA \200\223nucleosome complexes, deposit in tissues and: \200 \200 \200 activate complement; attract in \202 ammatory cells; initiate acute in \202 ammation. Lymphocyte activation There is increased T-cell:B-cell activation and interaction through c o-stimulatory ligands (e.g. CD40:CD40 ligand), antigen presentation, and B-cell-stimulating cytokines (e.g. Blys, APRIL). De \201 nition SLE represents a spectrum of disease characterized by: \200 acute and chr onic in \202 ammation in multiple organs; \200 circulating antinuclear autoantibodies (A NA); \200 pathology featuring immune complex deposition and complement consumption. Apoptosis There is excess apoptosis and defective removal of apop- totic debris. Autoantige ns present on apoptotic blebs trig- ger antigen-driven immune responses. Overlapping presentations with other autoimmune syn- dromes are common. Persistence of in \202 ammation results in tissue damage, loss of organ function and incapacity. Cytokine production There is increased interferon-A and interleukin-10 activity with upregu lation of interferon-dependent in \202 ammatory genes. The role of TNF-A remains controver sial. Epidemiology Nine-fold female preponderance. Five-fold preponderance among Blacks compared with Caucasians. Peak age of diagnosis is 20 \200\22340 years but it may occur at any age. Diagnosis is often delayed in the elderly. Prevalence of 40 \200\223200 per 100 000. Natural history SLE may resolve after one episode but it usually follows a relapsing-remitt ing course. Outcomes are variable and depend on disease severity and treatment response. Mo rtality is increased. In Europe (1990 \200\2232000) this was 5% at 10 years for nonrenal SL E and 12% at 10 years for lupus nephritis. Chronic morbidity and incapacity is frequent as a result of chronic in \202 ammation and organ damage, and the conse- quences of therapy, especially glucocorticoids. There is a greatly increased risk of cardiovascular disease and possibly an increased risk of malignancy. Quality of life is impaired due to chronic fatig ue, \201 bro-myal- gia, depression, neurocognitive dysfunction and incapacity. Etiology There is a multifactorial genetic susceptibility including contributions from: \200 \200 \200 \200 \200 \200 C-reactive protein; Fc gamma receptor; complement components; Toll-like receptor 5; MHC cla ss II and III; B-lymphoid tyrosine kinase. Concordance rate for monozygotic twins is 25%, and 2% for dizygotic twins. Drug-induced SLE (procainamide, hydralazine, quinidine) usually affects the skin and joints. Renal and CNS involve- ment is rare. Infection often precedes the initial presentation or relapse. Patien ts have a higher prevalence of EBV and CMV infec- tion than controls. Ultraviolet radiation causes a photosensitive rash and increases the relapse risk. Presentation The presentation of SLE is very variable. There is often a prodomal phase of s everal months or years of constitutional disturbance and other symptoms before the diagnosi s is made. Acute presentations are more common in younger patients. Subacute or atypical pr esentations are more common in those aged >50 years. Pathogenesis The pathogenesis of SLE is complex with dysregulation of many levels of the im mune system. Prodomal phase Serological abnormalities can precede clinical manifesta- tions by several y ears. Organ-speci \201 c autoimmunity, e.g. idiopathic thrombocyto- penic purpura, can pre cede SLE. Autoantibody and immune complex formation Antinuclear antibodies are present in the circula tion in >97% of cases and pathogenic anti-dsDNA antibodies are deposited in the kidneys and other sites of in \202 am- mation. Other pathogenic antibodies can occur: \200 \200 Acute presentation Fever, rash, polyarthritis and organ-speci \201 c manifestations, such as nephritis. Subacute presentation Remitting, relapsing course with constitutional distur- bance, especi ally fatigue and organ-speci \201 c features, such as polyarthralgia/polyarthritis, rash, pleuritic chest pain. antibody-mediated cytopenias; fetal heart disease mediated by anti-Ro antibodies. CHAPTER 4.7 Systemic lupus erythematosus 181 Differential diagnosis The diagnosis of SLE \201 rst requires suspicion of the diagno- si s, exclusion of other possible causes for the presenting symptoms, and then integration of the clinical features with the results of serological and other investigations. There are n o consensus diagnostic criteria for clinical prac- tice but the American College of Rheumat ology criteria for inclusion into clinical trials (4/11 required) are widely used (Table 4. 7.1). Antiphospholipid antibodies Antiphospholipid antibodies (aPL) comprise a family of antibodi es reactive with epitopes on proteins which are themselves complexed with negatively charge d phospholi- pid and include: \200 \200 \200 \200 \200 B2-glycoprotein I; annexin V; protein C; protein S; prothrombin. Table 4.7.1 American College of Rheumatology (ACR) criteria for inclusion into clinical tri als (requires at least four) The presence of aPL is determined using immunoassays that typically use cardiolipin as the antigen (and detect anti- cardiolipin antibodies (aCL)), but some methods use phos- phatidy lserine. Anticardiolipin antibodies: There is debate over the importance of the aCL isotype . IgG antibodies may be more clinically signi \201 cant, although IgM aCL appear to be ass ociated with thrombotic events and miscarriage in some series. Tests for IgA antibodies may not be clinically informative and their use is not currently recommended. Anti-B2-GP-I ant ibodies: Many aPL require B2-glycoprotein I (B2-GP-I), a phospholi- pid-binding plasma prot ein with weak anticoagulant activ- ity, for binding to acidic phospholipids such as phospha tidylserine and cardiolipin. The precise relationships among B2-GP-I, phospholipid and auto antibody are disputed. B2-GP-I antibody assays show higher precision and better correlation with the thromboembolic complications in APS and SLE than assays for aCL and are less like ly to show transient positive results in association with infection. 1. Malar erythema Mucocutaneous (4) 2. Erythematous raised patches 3. Photosensitivity 4. Oral or nasopharyngeal ulceration 5. Arthritis Organ-speci \201 c (4) 6. Serositis 7. Nephritis 8. CNS 9. Cytopenia Hematology or serology (3) 10. Speci \201 c autoantibodies 11. ANA Limited and early lupus presentations may not meet these criteria \200\223 a diagnosis of SLE should not be ruled out in this setting. Almost all SLE patients are ANA positive at di agnosis (except some with cutaneous SLE). Some patients with antiphospholipid syndrome (APS ) without ANA may have features of SLE. In the absence of ANA a diagnosis of SLE should alw ays be treated with suspicion and other conditions should be con- sidered. These include: \200 \200 Lupus anticoagulant This is an in vitro anomaly where there is prolongation of phospholipid -dependent coagulation due to the presence of a phospholipid-dependent inhibitor (aPL). A p rolonged activated partial thromboplastin time (APTT) suggests the presence of a lupus anti coagulant. The presence of a lupus anticoagulant is con \201 rmed with the diluted Russell \200\231s viper venom test (DRVVT). malignancy and paraneoplastic syndromes; other organ speci \201 c or multisystem autoimmun e dis- eases, such as vasculitis. Immunoglobulins Total IgG levels are often raised but are nonspeci \201 c. Infections, especially chronic viral infections such as HIV, can cause multisystem chronic in \202 ammation and ANA positivity. ANCA P-ANCA and myeloperoxidase (MPO)-speci \201 c ANCA can be \200\230false positive \200\231 in SLE and have no clinical signi \201 cance in this setting. Investigation Serology Antinuclear antibodies Although sensitive, ANA has a low speci \201 city for SLE. Speci \201 city is increased by: \200 Histology Skin biopsy has characteristic features with immune com- plex deposition at the d ermal \200\223epidermal junction. Renal biopsy: see below. con \201 rmation of ANA positivity by immuno \202 uorescence on Hep 2 cells; anti-dsDNA o r ENA positivity (e.g. Ro, La, Jo, Sm, RNP); specificity of anti-dsDNA assay is increased b y the crithidia immuno \202 uorescence test. \200 Treatment Initial subclassi \201 cation depends on the presence/absence of organ-threateni ng features. Complement Usually there is reduced C3 or C4. An isolated low C4 level can be a normal vari ant. If complement is low and ANA is normal, consider an alter- native cause of complement consumption, such as cry- oglobulinemia or chronic infection. Without organ-threatening features Consider: \200 \200 hydroxycholoroquine; prednisolone. D. JAYNE 182 urea and electrolytes, creatinine, liver function tests and C-reactive protein; anti-dsDNA, C3 and C4 levels. Hydroxycholoroquine 200 \200\223400 mg/day, especially for skin and joint disease (mepacrin e is an alternative). Long-term hydroxychloroquine reduces cardiovascular and SLE relapse r isk. It is often continued despite the requirement for other agents. Prednisolone, orally i n doses of <0.5 mg/kg/day reduced to 5 \200\22310 mg/day. Consider immunosuppressive if dos e cannot be reduced below 10 mg/day without relapse. Frequency of evaluation At least every 3 months for organ-threatening disease and/ or treat ment with immune suppression. At least every 6 months for mild/moderate disease. Lupus nephritis Classi \201 cation The 1982 WHO histological classification has been repla ced by the 2003 ISN/RPS system (Table 4.7.2). With organ-threatening features Use a combination of: \200 daily oral prednisolone with an immunosuppressive (see lupus nephritis treatment below). Acute \202 are Consider: \200 \200 Table 4.7.2 The 2003 International Society of Nephrology/Renal Pathology Forum (ISN/RPF) cl assi \201 cation of lupus nephritis IV methylprednisolone (e.g. 500 mg/day \227 3 doses); or higher-dose oral prednisolone. Refractory disease Consider: \200 \200 \200 \200 \200 Normal. Class O Light microscopy normal, immune deposits on immuno \202 uorescence. Class I IV methylprednisolone; an alternative immunosuppressive; rituximab; high dose IV immunoglob ulin; plasma exchange. Class II Mesangial deposits and hypercellularity. Class III Focal proliferative glomerulonephritis (<50% glomeruli) with leukocyte in \201 ltration. I mmune deposits in the mesangium and subendothelium. The role of autologous stem cell transplantation is uncer- tain. Class IV Diffuse proliferative glomerulonephritis (>50% glomeruli). May also see glomerular crescent s and \201 brinoid necrosis. Hormonal therapy Trials of dehydroepiandrosterone have been disappointing. Female hormone r eplacement therapy increases relapse risk. The oral contraceptive pill appears safe. Class V Membranous nephropathy with uniform thickening of capillary walls and subepithelial immune complex deposition. Class VI Glomerulosclerosis Monitoring This is multidimensional. Classes III and IV are subdivided into active (a), chronic (c) or mixed (a/c). Class IV is also subdivided into segmental or global. Mixed membranous and proliferative glomerulonephr itis is termed class III + V or IV + V. Disease activity Can be guided by validated tools such as: SLEDAI: http://www.rheumatology.org/sections/pediat- ric/sledai.asp?aud=mem BILAG index: Membranoproliferative nephritis is now III + V or IV + V, instead of subsets of V. Prolifer ative lesions (class III and IV) are now subclassi \201 ed as active (a), chronic (c) or m ixed (a/c), and segmental or global. The prognostic signi \201 cance of the 2003 system ha s not been determined. Previous studies have found the worst prognosis with class VI, then class IV, then III, but there are con \202 icting data on the outcome of class V due to di fferences in de \201 nition. The 2003 system only re \202 ects proliferative and membra- nous glomerulonephritis. Other important renal pathologies occur in SLE, including: \200 \200 \200 http://www.limathon.com/BLIPS%20Bilag.htm Blood pressure and urine dipstick for blood and p rotein at every evaluation. Treatment toxicity and infections End-organ damage Can be guided by validated tools such as : The SLICC/ACR Damage Index: http://www.rheumatology.org/publications/clas- sification/guide4.asp?aud=mem tubulointerstitial nephritis; thrombotic microangiopathy; podocytopathy (presents as \200 \230minimal change \200\231 glomeru- lopathy); arteritis; renal artery stenosis. Comorbidity Particular attention should be paid to: \200 \200 \200 cardiovascular risk; malignancy; bone disease. \200 Quality of life and neurocognitive function Laboratory studies should include: \200 Presentation Asymptomatic hematuria/leukocyturia or proteinuria. Nephrotic syndrome. full blood count, ESR; CHAPTER 4.7 Systemic lupus erythematosus 183 (a) (b) (c) (d) Fig. 4.7.1 (a) H&E-stained section showing two glomeruli from a biopsy with class IVa (g) n ephritis. There is global proliferation, segmental necrosis with leukocyte in \201 ltratio n (arrow), and crescent formation (arrowheads). (b) Immuno \202 uorescence micrograph from a biopsy with class IVa (g) nephritis demonstrating C3 deposition in a mesangial and capil lary loop distribution. (c) Photomicrograph of a Toluidine Blue- stained glomerulus from a biopsy demonstrating class IVa (g) lupus nephritis. Extensive deposits can be identi \201 ed in the subendothelial (arrow) and intramembranous/subepithelial (arrowheads) compartment s. (d) Electron micrograph of a tangentially sectioned glomerular basement membrane demonst rating multiple subendothelial (white arrows) and intramembranous/subepithelial (black arro ws) electron- dense deposits. The line of the GBM is indicated by the arrowheads. (Courtesy of Prof. Peter Furness, Consultant Histopathologist, University Hospitals of Leicester, UK .) Induction of remission The induction period necessary to induce remission is 6 \200\223 24 months. Class I and II lupus nephritis with proteinuria: glucocorti- coids are used alone. Class III, IV and V lupus nephritis: induction of remission requires the use of combination glucocorticoid/immuno- suppressive therapy. Nephritic syndrome, often with declining renal function, \200\230rapidly progressive glome rulonephritis \200\231. Hypertension. Treatment Aims of treatment are to: \200 induce a renal response or partial remission then a full remission (Table 4.7.3); prevent r elapse. Glucocorticoids There is no consensus on the optimum regimen. Two common approaches are: \200 Table 4.7.3 Renal response and remission criteria Partial remission (response) Full remission Criterion IV methylprednisolone 500 mg/day \227 3, followed by oral prednisolone 0.5 mg/kg/day reduc ing in steps (Eurolupus); or oral prednisolone 1 mg/kg/day reducing in steps with no IV glu cocorticoid. <50% baseline <500 mg/24 h Proteinuria <30 rbc/hpf, no cellular casts <5 rbc/hpf, no cellular casts Hematuria Stable, or <10% decrease from baseline Stable and within 10% of normal GFR Immunosuppression IV cyclophosphamide and oral mycophenolate mofetil are equally effective and have a similar early toxicity pro \201 le. Cyclophosphamide causes ovarian failure and an increased malignancy risk. Azathioprine is an alternative. rbc/hpf, red blood cells per high-powered \201 eld; GFR, glomerular \201 ltration rate. De \201 nitions of renal response and remission vary between consensus statements and betw een clinical trials. De \201 nitions of full remission often require a period of observati on, e.g. >1 month, and concomitant medication to be below a threshold, e.g. prednisolone \211 10 mg/day. D. JAYNE 184 Calcineurin inhibitors are alternatives for class V lupus nephritis. Methotrexate is also a n alternative but avoid with renal impairment. Cyclophosphamide: Most clinicians use \200 \230sequential \200\231 regimens with 3 \200\2236 months of cyclophosphamide followed by my cophenolate mofetil or azathioprine. Two cyclophosphamide regimens are in common use: \200 500 mg every 2 weeks \227 6 doses ( \200\230Eurolupus \200\231); or \200 0.75 g/m2/mon th \227 6 doses, adjusted to a neutrophil nadir of 3 \200\2234 \227 109/L ( \200\230NIH \200\231). Hematuria: look for dysmorphic erythrocytes and consider lower urinary tract origin. Blood pressure rise can indicate renal relapse. Role of repeat biopsy has not been determined but may be used: \200 in relapse, for diagnosis, to identify change of pathology and score activity and chronicit y; in remission, when there is poor association between urinary abnormalities and renal his tology to score activ- ity and chronicity and guide therapy. Other organ manifestations Skin Assess using standardized classi \201 cation. Therapy with hydroxychloroquine, dapsone, topical tac- rolimus, thalidomide, or as for general SLE. Consider bladder protection with prehydration and MESNA (sodium 2-sulfanylethanesulfonate). Consider ovarian protection with gonadotrophin antago- nism. Mycophenolate mofetil: The ta rget dose is 2 \200\2233 g/day. Lower doses may be effective for intolerant patients. There is no effect of age, sex, weight or ethnicity on phar- macokinetics. Central nervous system Assess with brain MR and diffusion-weighted imaging, CSF examination and neurology opinion. Psychiatric evaluation may be required. Consider infection, APS, em bolization, drug effects and hypertensive encephalopathy (especially in lupus nephritis). T reat with high-dose glucocorticoid and immunosuppres- sive (current evidence supports cyclo phosphamide). For treatment failure, consider an alternative immunosuppres- sive or rituxim ab. Treatment failure 20% of patients will be intolerant of either cyclophospha- mide or mycoph enolate mofetil and a further 20% will fail to achieve remission. For these cases a switch between immunosuppressives or a switch to rituximab should be considered. Consider azathiop rine for intolerance. Lung and heart Pulmonary pathology includes the following. Parenchymal disease: \200 \200 \200 \200 Progressive disease First, switch between immunosuppressive agents and administer IV methyl prednisolone 500 mg/kg/day \227 3 doses. Then, consider rituximab or plasma exchange. pneumonitis; alveolar hemorrhage; pulmonary \201 brosis; shrinking lung syndrome. Pulmona ry vascular disease: \200 \200 Prevention of relapse There is no consensus on drugs or duration. The typical duration of t reatment is 3 \200\2235 years. Relapse risk is increased by: \200 thromboembolism; nonembolic pulmonary hypertension. Assess with CT scanning, pulmonary function tests and, rarely, lung biopsy. Cardiac patholo gy includes: \200 \200 \200 \200 \200 hydroxychloroquine, glucocorticoid or immunosuppres- sive removal; shorter duration of ther apy; persisting positive anti-dsDNA or low complement lev- els; infection. pericarditis; myocarditis; endocarditis; valvular lesions; coronary atheroma. \200 Blood pressure control Maintain good BP control and consider ACEIs or ARBs as long-term the rapy for all patients. \200\230Libman \200\223Sachs \200\231 endocarditis is associated with APS. Assess with ech ocardiography and cardiac MR, angiogra- phy and right-heart catheterization when indicated. Treat as for general SLE with \200\230organ-threatening \200\231 disease. Transplantation There is a high risk of early thrombotic complications with APS. There is a n increased early infective risk due to SLE and prior treatment exposure. Long-term outcome s are otherwise similar to other causes of ESRD. Antiphospholipid syndrome APS is de \201 ned as: \200 positive aCL and/or lupus anticoagulant (LAC) detected on two occasions; spontaneous arteri al or venous thrombosis. Primary APS is the disease occurring as a sole entity and secondary APS is the disease occu rring in the context of SLE. Thrombosis risk in SLE is increased without APS. Monitoring As for general SLE above. Proteinuria quanti \201 cation (albumin/creatinine ra tio or 24 h collection) at every visit. CHAPTER 4.7 Systemic lupus erythematosus 185 Patient advice Areas to be considered when counseling patients: \200 \200 \200 \200 Positive aCL and/or LAC without thrombosis in SLE indicates further increased risk and is u sually treated with aspirin. A \201 rst thrombotic event then requires prolonged, possibl y lifelong, anticoagulation. Catastrophic APS is a clinical presentation of multiple and pr ogressive thromboses. Treatment can include IV methyl prednisolone, plasma exchange and ant icoagulation. about SLE and outcomes; drug information and management of toxicity; fertility, conception and pregnancy counseling; management of cardiovascular and malignancy risk, e.g. smoking av oidance, cervical screening and mammography. Encourage patient involvement in monitoring of disease, e.g. blood pressure, urine dipstick analysis. Patient support groups, e.g. Lupus UK. APS and the kidney \200 \200 \200 Thrombotic microangiopathy. Renal artery thrombosis. Increased risk of renal biopsy due to hemorrhage and withdrawal of anticoagulation. Increased risk of early thrombotic complicati ons post- transplantation. Further reading Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the m anagement of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Com mittee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008; 67: 1 95 \200\223205. Pregnancy Preconception counseling is necessary to consider: \200 \200 \200 \200 \200 \200 Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC. Treatment for lupus nep hritis. Cochrane Database Syst Rev 2004; CD002922. fertility; risk of miscarriage; risk of pregnancy to the baby and to the mother; risk of lu pus \202 are; preconception medication; medications during and after pregnancy and breast feed- ing. Ponticelli CB, Moroni G. Systemic lupus erythematosus (Clinical). In: Davison AC, Grunfeld J-P; Ponticelli C, Ritz E, Winearls C, van Ypersele C (eds), Oxford textbook of clinical ne phrology. Oxford: Oxford University Press; 2006. 4.7.2. Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR. Mycophenolate mofetil for in duction therapy of lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Ne phrol 2007; 2: 968 \200\223975. The following drugs should be avoided at conception and during pregnancy: \200 \200 \200 \200 \200 Walsh M, Jayne D. Rituximab in the treatment of anti-neutrophil cytoplasm antibody associat ed vasculitis and systemic lupus erythematosus: past, present and future. Kidney Int 2007; 72: 676 \200\223682. mycophenolate mofetil; cyclophosphamide; methotrexate; warfarin; ACEIs and ARBs. Weening JJ, D \200\231Agati VD, Schwartz MM, et al. The classi \201 cation of glomerulonep hritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65: 521 \200\223530. Hydroxychloroquine, prednisolone and azathioprine can be continued during pregnancy. Consid er aspirin throughout pregnancy and low molecular weight heparin for patients with a histor y of: \200 \200 \200 \200 Yee CS, Farewell V, Isenberg DA, et al. British Isles Lupus Assessment Group index is valid for assessment of 2007. Arthritis Rheum 2004; 56: 4113 \200\2234119. Internet resources British Society of Hematology Guidelines for Investigation and Managemen t of Antiphospholipid syndrome: miscarriage; thrombosis; antiphospholipid syndrome; signi \201 cant proteinuria. http://www.blackwell-synergy.com/links/doi/ 10.1046/ j.1365-2141.2000.02069.x/full/ Lupus F oundation of America: Do not reduce the intensity of therapy during pregnancy as the lupus \202 are risk remain s. Use IV methylprednisolone or high dose IV immunoglobu- lin for \202 ares. Withdraw ACE Is and ARBs before or after conception and replace with labetolol or methyldopa until after delivery. Monitor lupus activity, blood pressure, proteinuria, fetal growth and uterine ar tery Doppler during pregnancy. If anti-Ro positive, monitor fetal heart rate. There is a 1 in 20 risk of fetal complete heart block. Relapse risk is highest immediately after deliver y, high-dose oral prednisolone or IV methylprednisolone should be considered as prophylaxis . There is an increased risk of HELLP syndrome. www.lupus.org/ Lupus UK: http://www.lupusuk.com/ The lupus site: http://www.uklupus.co.uk/ See also Immunological investigation of renal disease, p. 36 Rheumatoid arthritis, connecti ve tissue diseases and Sj gren \200\231s syndrome, p. 188 Glomerulonephritis, vasculitis, and nephrotic syndrome, p. 340 H. PENN AND C. DENTON 186 Scleroderma \200\223systemic sclerosis Table 4.8.1 Autoantibody associations with scleroderma Systemic sclerosis (SSc) is a heterogeneous autoimmune rheumatic disease of uncertain etiol ogy, characterized by in \202 ammation and \201 brosis in skin and other organs, and vas - cular abnormalities including Raynaud \200\231s phenomenon. It is classi \201 ed into di ffuse cutaneous systemic sclerosis (dcSSc: skin involvement proximal to the elbows and knee s) and limited cutaneous systemic sclerosis (lcSSc: distal skin involvement only). These ha ve distinct associations with organ involvement and outcomes. Autoantibody target % of SSc Clinical association ACAa (anticentromere ab) 30% lcSSc Pulmonary arterial hypertension Scl-70a (topoisomerase-1) RNA polymerasea PM-Scla 20% dcSSc Pulmonary \201 brosis 12% High risk of renal crisis Epidemiology It is more common in women (female:male 5:1). The onset peaks at 40 \200\22360 years of age. There is an association with silica and solvent exposure. The prevalence is estimated to be 3 \200\22324 per 100 000. 4% Overlap with myositis Anti \201 brillarina (U3-RNP) 5% dcSSc PAH Myositis U1-RNP 10% Overlap with SLE, myositis, arthritis Autoantibodies and SSc Autoantibodies associated with SSc are listed in Table 4.8.1. These are valuable for diagnosis and for identifying cases at risk of particular complications. Th/To <5% lcSSc with lung \201 brosis a Scleroderma-de \201 ning antibody. lcSSc, limited cutaneous systemic sclerosis; dcSSc, diffuse cutaneous systemic sclerosis; P AH, pulmonary arterial hypertension. Renal disease in systemic sclerosis This may be divided into: \200 \200 \200 Investigations Urinalysis: non-nephrotic range proteinuria; microscopic hematuria. Blood \201 lm: microangiopathic hemolytic anemia (MAHA) with schistocytes is found in 50%. Renal biopsy shows intimal proliferation, thrombotic microangiopathy, and often fibrinoid necrosi s. It also excludes other pathology (Fig. 4.8.1). Echocardiography commonly demonstrates re duced left ventricular systolic function. This will usually resolve as afterload falls with successful treatment. Pericardial effusions are common, but tamponade occurs infrequently (<5%). Tachy- or bradyarrhythmias may occur and are associated with a poor prognosis. scleroderma renal crisis; other acute presentations; chronic kidney disease. Renal function should be routinely monitored in all cases of SSc with estimated GFR determi nation and urinalysis at least every 6 months, and close home-monitoring of BP in dcSSc cas es. Scleroderma renal crisis De \201 nition Scleroderma renal crisis (SRC) is a clinical syndr ome of acute renal failure and accelerated hypertension in the presence of systemic scleros is. Frequency It occurs in 5% of all SSc patients (15% of dcSSc cases, and 2% of lcSSc cases). Treatment The target for antihypertensive treatment is to bring the systolic BP down by 20 mmHg and the diastolic by 10 mmHg per 24 h, into the normal range, while avoid- ing periods of hypotension. An arterial line and central venous catheter may aid in monitoring the res ponse to treatment. ACEIs must be instituted since they have been shown to reduce mortality . Captopril has a short half-life and may be easiest to titrate to the blood pressure initi ally, but longer-acting ACEI are usually more convenient in the long term. Intravenous pros tacyclin (0.2 \200\2232 ng/kg/min) increases renal perfusion, and also may help to normaliz e blood pressure. ARBs can be safely added if required once ACEIs are at full dose. Alpha-b lockers and calcium antagonists are also help- ful for refractory hypertension. Plasma exch ange may be of use in profound MAHA. Renal support with hemodialysis is required in approxi - mately two-thirds of all cases. Risk factors \200 \200 \200 \200 \200 \200 \200 Recent-onset diffuse scleroderma. Active, progressive skin disease. Tendon friction rubs. A nemia. New cardiac events. Steroid use ( \211 15 mg prednisolone/day). Presence of anti-RNA polymerase III. Clinical features Patients with SRC will typically have an acute or subacute presentation w ith \202 uid overload and/or symptoms of end- organ complications of hypertension. Often nonspeci \201 c systemic symptoms (malaise, exertional breathlessness) are present for wee ks before presentation with: \200 \200 \200 \200 \200 \200 acute kidney injury. new-onset hypertension (>90%). pulmonary edema (>50%). encephalopathy (20%). seizures (10%). hypertensive retinopathy (>60%). CHAPTER 4.8 Scleroderma \200\223systemic sclerosis 187 Prognosis Of the two-thirds of patients who require dialysis, one-half of these will be abl e to discontinue dialysis by 2 years after the onset of SRC. A poor renal outcome is predic ted by low blood pressure at presentation, and the presence of \201 brinoid necrosis and mucoid intimal thickening on renal biopsy. Mortality is signi \201 cant (30% at 3 years) a nd is highest in those requiring permanent dialysis. Renal transplantation may be considere d in patients who still require dialysis at 2 years. Survival rates are similar to transpla nt recipients with other connective tissue diseases. Recurrence of SRC is rare in patients concordant with medication, and uncommon (5%) following transplanta- tion. with high levels of collagen in the interstitium, the mesan- gium, and around blood vessels . Use of drugs such as NSAIDs, cyclosporin and penicilla- mine may also contribute to renal \201 brosis. Follow-up studies of SSc patients with CKD do not dem- onstrate signi \201 cant rates of progression to dialysis how- ever. Table 4.8.2 Practical tips in scleroderma renal crisis Patients may present with normal BP/serum creatinine in the normal range. Fluid balance is dif \201 cult due to the high peripheral vascular resistance \200\223 use small volume \202 uid challenges. BP is often labile initially. ACEIs are \201 rst-line therapy but additional agents often also required. Manage in the HDU/ITU setting with central venous and Prevention There is no evidence that ACEI or ATII receptor blockade is effective in prevent ing SRC. Patients at risk of SRC should avoid doses of steroid >10 mg prednisolone/day. Fur ther practical advice on the management of SRC is described in Table 4.8.2. arterial monitoring. Biopsy is safe when BP is controlled, and excludes alternative diagnoses. Anti-RNA polymerase III antibody is suggested by the presence of \201 ne speckled pattern of ANA in the absence of other routine ENA positivity. Fistula formation is safe in those requiring long-term hemodialysis (despite secondary Raynaud \200\231s phenomenon). \200 Line-related sepsis i s a common complication in these patients due to abnormal skin function. Peritoneal dialysis is well-tolerated in those with suf \201 cient intrinsic renal function. Recovery of renal function can occur up to 2 years after SRC and renal transplantation shou ld only be considered after this time. HDU, high dependency unit; ITU, intensive therapy unit. References Bunn CC, Denton CP, Shiwen X, et al. Anti-RNA polymerases and other autoantibody specificities in systemic sclerosis. Br J Rheumatol 1998; 37: 15 \200\22320.