Classi \201 cation criteria There are no validated classi \201 cation criteria for SAPHO though diagnostic criteria were suggested in 1988 (Benhamou 1988). Epidemiology The condition could be rare, although mild disease and disease characterized b y musculoskeletal lesions (not skin) alone is probably under-recognized. Etiology and pathphysiology \200 Skin \200 Most cases and case series have been reported with prominent acne lesions or obvious (palmo plantar or psoriatic) pustulosis. Skin lesions may not be concordant with the manifestation or detection of musculoskeletal lesions. Hidradenitis may be an associated feature, but ha s not been a consistent part of all descriptions of the condi- tion in the literature. Atte mpts to link the condition aetiopathologically to just one or two proprionibacterium specie s (infections or skin lesion \200\230colonization \200\231) might be too restrictive. SAPHO has been linked to skin lesion infection with Propionibacterium acnes in immunocompet ant people. P. acnes, an anaerobe, has been cultured from intervertebral disc and sternal l esions. The immunopathology and tissue pathological changes in SAPHO are virtually unknown. The principle features of SAPHO syndrome \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Anterior chest wall pain. Osteitis. Enthesopathy. Pustular skin lesions. Acneiform skin les ions. Hydradenitis. Hyperostosis. Within costal cartilages. Ankylosing axial arthritis of a nterior chest wall. Spondylodiscitis. Synovitis. Investigations Laboratory \200 Laboratory investigations are invariably normal although modest increases in ESR, CRP, or i mmunoglobulins can occur. Systemic neutrophilia has been reported. There is no known associ ation with HLA B27, but genetic association studies in large well-de \201 ned disease popu la- tions have not been done. Imaging Scintigraphy \200 Clinical features \200 Typical patterns of abnormality have been shown using 99mTc-MDP scintigraphy. Intense trace r localizing to structures around the upper sternum, viewed also from posterior chest acqui sitions, discriminate abnormal scans from false positive images. The most convincing combination of features are pustulosis or acneiform skin rash (acne ful minans, acne conglobata, or hidradenitis suppurativa) with pains and hyperostosis of anteri or chest wall structures. CHAPTER 7 The spondylarthropathies 237 MR spine may highlight other SAPHO-associated osteitis lesions. See Figure 7.12. Typical tracer uptake in manubrium and anterior part of the \201 rst ribs is referred to as \200\230the bullhorn sign \200\231. This is thought to be relatively speci \201 c for SAPHO. Biopsy and histology \200 Biopsy of bony or spondylodiscitis lesions and culture of material can show P. acnes growth . Data is derived from a few case reports only. Features seen in osteomyelitis can be prese nt. In one case, epithe- liod granulomas were seen. Differential diagnosis \200 Psoriatic arthritis or chronic sarcoidosis where pains are diffuse and suggestive of enthes itis/osteitis or periostitis lesions. Osteomyelitis and malignancy where there is clear pai nful soft-tissue and bone swelling. Septic or SpA-associated spondylodiscitis where there i s discogenic in \202 ammation. Treatment \200 An explanation of the condition at the outset is excep- tionally important especially to th ose who have had chronic unexplained symptoms or manifold explanations/ diagnoses given for their plight. NSAIDs, glucocorticoids, and analgesics have been used empirically. Antibiot ic use, most notably doxycycline, azithromycin, and clindamycin, have been reported as effe ctive in a few cases treated over a number of months. Where there is osteitis, particularly if biopsy shows an excessive number of multinucleate osteoclasts or features of increased bone turnover, bisphosphonate treatment may be a logical choice. A trial of a potent oral o r iv aminobisphosphonate in patients, recruited on the basis of osteitis lesions detected r eliably with imaging, is probably warranted. Figure 7.11 99mTc-MDP abnormality in SAPHO showing high tracer uptake in manubrium and manu briosternal joint. Prognosis and natural history SAPHO tends to cause chronic recurrent musculoskeletal sympto ms. Descriptions of the condition in the long-term are not available. Reports suggest the c ondition can persist for >20 years and follow an unpredictable course. References Ballara SC, Siraj QH, Maini RN, Venables PJW. Susteained response to doxycycline therapy on 2 patients with SAPHO syndrome. Arthritis Rheum 1999; 42: 819 \200\22321. Benhamou CL, Chamot AM, Kahn MF. Synovitis-acne-pustulosis- hyperostosis-osteomyelitis synd rome (SAPHO): a new syndrome among the spondylarthropathies? Clin Exp Rheumatol 1988; 6: 10 9 \200\22312. Chamot AM, Benhamou CL, Kahn MF, Beraneck L, Kaplan G, Prost A. Le syndrome acn pustulose hyperostose ost ite (SAPHO). R sultats d \200\231une enqu te nationale. 85 observations . Rev Rheum 1987; 54: 187 \200\22396. Figure 7.12 MR thoracic spine in SAPHO. Spondylodiscitis at contiguous levels. Note osteiti s at manubriosternal joint. Radiographs and CT \200 Dihlman W, Dihlmann SW, Hering L. Acquired Hyperostosis Syndrome \200\223 AHYS \200\223 ( sternocostoclavicular hyperostosis, pus- tulotic arthro-osteitis, SAPHO-syndrome): Bone sci ntigraphy of the anterior chest wall. Clin Rheumatol 1997; 16: 13 \200\22324. Hyperostosis lesions are characterized by sclerosing bone remodeling and erosions. Radiogra phs can show abnormal cartilage ossi \201 cation (e.g. costoclavicular ligament and anteri or rib). CT may be useful to help discriminate hyperostotic SAPHO lesions from tumors and o steomyelitis. K hler H, Uehlinger E, Kutzner J, et al. Sterno-kosto-klavikul re yperostose, ein bisher nicht beschriebenes Kranksheitsbild. Dtsch med Wschr 1975; 100: 1519 \200\22323. MR \200 SAPHO spondylodiscitis is not easily discriminated from other non-septic causes of discitis with MR. This page intentionally left blank 239 Chapter 8 Autoimmune connective tissue diseases Systemic lupus erythematosus 240 Sj gren \200\231s syndrome 254 Systemic sclerosis 264 Ant iphospholipid syndrome 274 Polymyositis 282 Dermatomyositis 290 Juvenile dermatomyositis 29 8 Inclusion body myositis 302 Undifferentiated (autoimmune) connective tissue disease 306 M ixed connective tissue disease 307 Overlap syndromes 308 Eosinophilic fasciitis 310 SYSTEMIC LUPUS ERYTHEMATOSUS 240 Systemic lupus erythematosus De \201 nition Systemic lupus erythematosus (SLE) is a systemic autoim- mune disease, whic h is associated with a plethora of autoan- tibodies including characteristic anti-nuclear a ntibodies. Table 8.1 ACR 1997 Revised criteria for the classi \201 cation of SLE Criterion Comments Malar rash Classi \201 cation The clinical manifestations of SLE are diverse and a series of classi \201 cation criteria have been published by the ACR, most recently in 1997 (Table 8.1). Alt hough the classi \201 ca- tion criteria were not designed as diagnostic criteria, they are frequently applied in this way. SLE may be diagnosed if a patient has four or more criteri a, serially, or simultaneously, providing they cannot be attributed to an alternative diag- nosis. When considering a diagnosis of SLE, it is important to note that: \200 Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Oral or nasopharyngeal NB must be objective synovitis Pleurisy (pleuritic rub/effusion) Pericarditis History of pericarditis New pleural thickening Some classi \201 cation criteria are highly speci \201 c for SLE (e.g. anti-dsDNA antibod ies), whereas others are not (e.g. mouth ulcers). Several clinical features that are not in cluded in the clas- si \201 cation criteria occur commonly in SLE, e.g. alopecia, Raynaud \200\231s phenomenon, constitutional symptoms, livedo reticularis, or vasculitic rashes. Peritonitis *Renal histology indicating immune- complex-mediated glomerulonephritis wRenal disorder Proteinuria >0.5 g/24 or 3+ Cellular casts: (RBC/hemoglobin/ granular/ tubular/mixed) Central or peripheral nervous sys tem involvement or psychiatric condition Haemolytic anemia or Symptoms and signs can occur in any organ system and are often transient; this may lead cli nicians to attribute them to a functional disorder. Neuropsychiatric disorder Hematological disorder Epidemiology The ratio of females to males with SLE is 10:1, with onset most commonly occ urring in the second and third decades. In the UK, prevalence is 45/100 000 for women and 4/100 000 for men. However, prevalence varies between racial groups and between countries, and most studies in- dicate that the incidence of SLE is higher in individuals with Africa n or Asian ancestry. It is likely that this re \202 ects both true differences between pop ulations and differences in clinical practice. Leucopaenia: <4000/ l on \211 2 occasions Lymphopaenia: <1500/ l on \211 2 occasions Thrombocytopaenia: <100 000/ l Anti-double-stranded DNA antibody Immunological disorder Anti-Sm antibody Antiphospholipid antibodies (either elevated anticardiolipin IgM or IgG or a positive lupus anticoagulant test) False positive serologic test for syphilis, positive for at least 6 months Etiology and pathophysiology Genetics The genetic contribution to SLE has been evident from the familial clustering of cases, with a monozygotic twin con- cordance rate of 24-58% and a sibling recurrence risk ( s) of 20. A combination of genome-wide linkage and asso- cia tion studies have revealed that genetic susceptibility to SLE is polygenic and probably inv olves approximately 10 loci. A number of loci have been implicated. \200 Positive LE preparation Low levels of complement C3/C4 Raised titre ANA Additional criteria proposed (and widely used) since 1982 publication are associated with SLE in Chinese, Japanese, and Thai patients; this may relate to the rel atively low inhibitory activity of the receptor encoded by the T232 allele. Conversely, an FcRGIIb promoter polymorphism is enriched in Caucasian SLE patients. Immunoglobulin recepto r homologues (FcRH): an FcRH3 promoter polymorphism is associated with SLE in Japanese pati ents; FcRH may modify the behavior of mature B cells. Protein kinases, phosphatises, and si gnaling mole- cules: SLE is associated with polymorphism in tyrosine kinase 2 (TYK2), inter feron regulatory factor 5 (IRF5) and protein tyrosine phosphatase N22 (PTPN22) are associat ed with SLE. Co-stimulatory/co-inhibitory molecules: programmed cell death-1 (PD-1) serves to down-regulate lymphocyte activity, particularly in non-lymphoid tissues; a polymor- phis m in the PDCD1 gene, which encodes PD-1, is asso- ciated with SLE in European and Mexican p opulations. The locus encoding CTLA-4, a negative regulator of X-chromosome: the preponderance of females with lupus may be attributable to the effects of female sex hormones; an alternative hypothesis is that X-linked TLR7/8 alleles (which enco de pattern recognition recep- tors for nucleic acid) fail to be completely inactivated on o ne of the two X-chromosomes), leading to excessive IFN production. HLA: HLA-DRB11501 (DR2) and DRB10301 (DR3) in white Caucasians. Complement C4 (A and B loci): either complete de \201 - ciency or copy number polymorphisms resulting in low levels of C4 production confer degrees of susceptibility. Fc Receptors (FcRG): the FcRGIIa R131 allele, which binds human IgG2 poorly, is associated with SLE. The FcRGIIIa F176 allele, which binds human IgG1 and I gG3 relatively weakly, is associated with SLE, particularly lupus nephritis. The T232 allel es of the inhibitory FcRGIIb CHAPTER 8 Autoimmune connective tissue diseases 241 greater use of hormone-replacement therapy, which is associated with a 2-fold increase ris k of SLE. Prenatal exposure to diethylstilboestrol (DES) has been associated with autoimmun e disease. Hyperprolactinaemia is seen in 20 \200\22330% of SLE patients may be involved in pregnancy-related \202 ares. Prolactin has been shown to increase survival and activatio n of autoreactive B cells. Drug-related lupus (DRL) may be caused by a range of agents, sev eral of which induce methylation changes in promoters of genes encoding immunologically act ive products, e.g. CD70, IL-2. TNFA blockade may also induce production of ANA and a lupus- like syndrome by decreasing the inhibition by TNFA of IFNG production. Furthermore, case re ports indicate that treatment of chronic viral infection with IFN is associated with the in duction of SLE. activated T cells, may be a modest susceptibility factor for SLE; data are inconsistent. Cy tokines and chemokines: polymorphisms of the monocyte chemotactic protein (MCP-1) locus hav e been suggested to be associated variably with either lupus nephritis or cutaneous vasculi tis in SLE. Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have also been implicated. Opsonins: a promoter polymorphism, which may in \202 uence CRP levels, and the G54D allele of mannose binding lection (MBL) have been reported in association with SLE. I t is clear that SLE is clinically and genetically heteroge- neous and distinct genetic in \202 uences are likely to emerge in different ethnic groups and in association with particu lar clinical phenotypes. Environmental Infectious triggers \200 Drugs implicated in drug-related lupus De \201 nite \200 \200 \200 \200 Epstein-Barr virus (EBV) has been implicated as trigger by epidemiological studies and in a nimal models. However, the high prevalence of EBV infection in the population indicates tha t exposure alone cannot account for the development of SLE. A recent case-control study rev ealed that EBV-IgA seropositivity was strongly associ- ated with SLE in African Americans a nd in white Caucasians over the age of 50 years. There was no asso- ciation of EBV-IgM or E BV-IgG seropositivity with SLE in any groups; this indicates that reactivation of EBV, givi ng rise to IgA production, may be important. The CTLA-4 promoter gene polymorphism was show n to modify the association of IgA-EBV in the African American popula- tion. There is also evidence for molecular mimicry involving EBV in SLE patients. In rodent models, antibod- ie s speci \201 c for the EBV antigen, EBNA-1 cross-react with epitopes of the Ro autoantigen . Cytomegalovirus (CMV) has been implicated with lupus-related vasculitis and thrombocytopa enia in case reports and there is the Carolina Lupus Study suggested a possible association between Anti-CMV seropositivity and SLE in African Americans. Hepatitis C virus (HCV): chr onic HCV infection can mimic SLE. Unsurprisingly, the prevalence of HCV infec- tion in pati ents diagnosed with SLE has been reported to be elevated ( 10%) compared with the backgroun d population ( 0.13%) Immunization: several case reports have implicated a variety of immun izations as triggers for lupus onset or \202 ares. The Carolina Lupus Study failed to sub stantiate any association between SLE and Hepatitis B vaccination. Several studies have ind icated that in \202 uenza vaccine is safe in patients with quiescent SLE, although it may be associated with a transient increase in autoantibody titres. A small evidence base sugge sts that vaccination against Pneumococcus is also safe. Hydralazine Minocycline Chlorpromazine Methyldopa. Isoniazid. Procainamide Quinidine Probable (for complete list, see Mongey 2008)* \200 \200 \200 \200 \200 \200 \200 \200 \200 Allopurinol Anti-TNFA agents Griseofulvin IFNA Nitrofurantoin Phenytoin Propanolol Sulindac Sulfasalazine Atenolol Enalapril Ibuprofen Lithium Penicillin Prophythiouracil Quinine Statins Tetracycli nes Where several agents within a class have been implicated, the class is listed instead of in dividual drugs. The in \202 uence of smoking as a risk factor for SLE is con- troversial. Current, rather than previous smoking is asso- ciated with anti-dsDNA antibodies and is probably also assoc iated with SLE. Exposure to silica. Association reported in humans; murine studies suggest and adjuvant, and pro-apoptotic effect of silica contribute to pathogenesis of SLE. Silicon e breast implants have received much publicity as potential triggers for AICTDs, but 3 larg e studies have failed to substantiate this. Exposure to organic solvents. Murine studies in dicate that trichloroethylene (TCE) elicits lupus-related anti- bodies in susceptible strai ns. There are no data showing a relationship between TCE and SLE in humans. Petroleum disti llates have been implicated in connective tissue disease, including SLE. Pesticides have be en suggested as a trigger for SLE, but only 1 of 4 studies has supported this. Hair dyes ha ve been associated with SLE in some studies, but this is controversial. Dietary factors, su ch as heavy metals, nightshade vegeta- bles, arti \201 cial sweeteners, and a range of oth er foodstuffs are implicated as risk factors for SLE on many websites, but there is little or no epidemiological evidence to sup- port these claims. Non-infectious triggers/promoters \200 SLE is more common in women than men and oestrogens exacerbate SLE in murine models. The Nu rses \200\231 Health Study suggested that use of the oral contraceptive might confer an inc reased risk of SLE, but other studies have failed to substantiate this or to associate the oral contra- ceptive with SLE \202 ares; progesterone-only contracep- tives may even be p rotective. Early menarche (age 10 versus 13 years) has been associated with 4.5 increased risk of SLE. An early menopause is also associated with increased risk of subsequent SLE; t his may relate to SYSTEMIC LUPUS ERYTHEMATOSUS 242 Ultraviolet light is well recognized as a trigger of cutane- ous lupus and, by increasing t he load of apoptotic cells, it may also contribute to activation of systemic disease. Chron ic stress and catastrophic life events have been implicated as triggers of SLE and other au toimmune dis- eases. It may be relevant that stress is associated with increased release of prolactin, which modi \201 es immune responses. dif \201 cult to differentiate primary from secondary APC defects. Secondary abnormalities of APC behavior may result from tissue damage, excessive apoptosis, drugs or microbial inf ection; viral infections, in particular, have been suspected since SLE patients have been s hown to produce large quantities of IFNA. Increased apoptotic activity results in increased clearance and presentation of autoantigens by APC. Immune complexes form between autoantib odies and autoantigen and these, in turn, are ingested by APCs via complement receptors and Fc receptors. Ingestion of immune complexes containing dsDNA causes APCs to release more I FNG. Aberrant T cell activity. Murine models of SLE indicate that primary T cell defects ca n contribute to initiation of SLE. In humans, a range of abnormal T cell behaviors have bee n observed, including abnormal signaling and calcium \202 ux, up-regulation of several co -stimulatory receptors and secreted molecules (e.g. CD40L, ICOS, BAFF), which facilitate co llaboration with APC and/or B cells and increased expression of molecules promoting T cell survival. Each of these abnormalities could increase the risk of an autoreactive T cell bec oming activated and resisting apoptotic death. Aberrant B cell activity may re \202 ect bo th primary and secondary B cell abnormalities. Aberrant T cell activity provides inappropri ate help for B cell activation. Plasmablasts (short-lived immunoglobulin-secreting cells) usually remain in the tissue where they were gen- erated, but in SLE patients they are det ectable in blood. Excessive production of immunoglobulin-secreting cells leads to the gener ation of autoantibodies, which are characteristic of SLE. Molecular mimicry, e.g. antibodie s speci \201 c for the EBV antigen, EBNA-1 cross-react with the autoantigen Ro. Failure of regulatory T cells. Environmental factors which decrease risk of SLE \200 Sex hormones: progesterone-only contraceptives may be protective. Breastfeeding \211 3 bab ies was associated with protection compared with breastfeeding none; the protective effect may be related to the duration of breastfeeding. Alcohol may exert a protective effect; thi s remains controversial. The active metabolite 1,25(OH)2 D3 exerts immunosup- pressive prop erties but the Nurses \200\231 Health Study cohort failed to reveal any effect of vitamin D 3 supplements on incidence of SLE. Omega-3 fatty acids and anti-oxidants delay the onset of SLE in susceptible mice. Immunopathology (Figure 8.1) Breaking tolerance The autoimmune response in SLE results from the failure of tolerance in T and B cells. Failure of central tolerance (thymic selection) and thymic defects have been reported in mice susceptible to SLE. In humans, a diminished thymic output has been reported. \200 Aberrant antigen-presenting cell (APC) activity. Intrinsic defects of APCs have been demons trated in mice susceptible to lupus and these appear to promote pres- entation of autoantig ens to T cells. In humans, it remains Plasma Cell Small Vessel Vasculitis Immune Complexes B cell Ultraviolet light Activation of autoreactive T and B cells Apoptosis CTL Th2 Anti-cellular Antibodies CD4 T cell Th1 Tissue damage DC or macrophage Viral infection IFN Activation of APC Figure 8.1 Overview of pathophysiology of SLE. CHAPTER 8 Autoimmune connective tissue diseases 243 Increased apoptotic activity results in increased presen- tation of intracellular autoantig ens to T and B cells and, hence, generation of autoantibodies and immune com- plexes. Nucle ar autoantigens, including dsDNA, are major targets, hence the characteristic autoantibody pro \201 les associated with SLE. Exposure to ultraviolet light has been shown to increase apoptotic activity and this may trigger a \202 are of cutaneous (or even systemic) lupus . Decreased clearance of apoptotic bodies and/or immune complexes. Primary or secondary de \201 ciencies of proxi- mal complement components, Fc receptors or other receptors for apo ptotic remnants are believed to increase in \202 ammatory activity via increased immune co mplex formation/deposition, and increased availability of cytoplasmic/nuclear antigens. is probably responsible for many migratory cutaneous, neurological and musculoskeletal symp toms and signs in SLE, as well as contributing to chronic in \202 ammation, e.g. glomerulo nephritis. The vegetations in Libman \200\223Sacks endocarditis have also been shown to con tain immu- noglobulin and complement components. Th1 responses: Th1 over-activity in SLE ha s been dem- onstrated in several studies. Th1 T cells secrete increased IL-2 and IFNG. IFNG causes up-regulation of MHC class II molecules, thereby increasing the potency of antigen- presenting cells as well as stimulating excessive secretion of other Th1 cytokines, e.g.IL -18, by macrophages. In the kidney, IL-18, in turn, up-regulates TNFA and nitric oxide prod uction, which promote apoptosis of renal parenchy- mal cells. CD4+Th1 cells also promote CD 8+ T cells proliferation and survival, and enhance autoantibody production by increased sec retion of BAFF. Th2 responses: although SLE was considered a Th2-mediated disease, recent s tudies indicate that Th1 cytokines are generally more prominent than Th1 cytokines in SLE. However, several studies indicate that Th2 cytokines are elevated. These may contribute to atopic clinical features present in some SLE patients. Cytotoxic CD8+ T cells receive \200 \230help \200\231 from Th1 CD4+ T cell effectors. The percentage of circulating granzyme B+ CD8+ T cells is related to disease activity in SLE and their killing activity probably con tributes to the availability of intracellular autoantigens for ingestion and presentation b y antigen-presenting cells. Complement activation (Figure 8.2) plays many roles in SLE, inc luding enhancement of local in \202 ammatory responses via opsonization, and enhanced anti gen pres- entation, anaphylatoxins and direct cytotoxicity via the membrane attack complex. Endothelial activation results in increased expression of certain adhesion molecules and c hemokines, thereby recruiting certain leucocytes into tissues; activated endothelium also p romotes local coagulation more than resting endothelium, and produces vasodilators and medi - ators of increased vessel permeability. Endothelial damage Effector mechanisms \200 Autoantibodies are generated to a range of cellular and soluble autoantigens. Autoantibodie s may interfere with the function of their target, e.g. anti-C1q antibodies amplifying the classical pathway of complement activa- tion (Figure 8.2), anti-phospholipid antibodies bin ding to and activating endothelial cells, neutrophils and platelets, or anti-Ro antibodies altering the electrophysiology of fetal myocytes. Alternatively, antibodies directed at mol ecules expressed on the cell surface may cause depletion of the cell subset, either via ops onization and phagocytosis of the cell or via antibody-dependent cell- mediated cytotoxicit y; this mechanism contributes to leucopaenia, thrombocytopaenia and haemolytic anemia. Overview of pathophysiology of SLE \200 Immune complexes form between autoantibodies and autoantigens. Antigen-presenting cells can ingest immune complexes by Fc receptor-mediated endocytosis; this enhances the presentatio n of autoantigens to T cells. Furthermore, deposition of immune complexes can occur in any microvascular bed; this may lead to local in \202 ammation, via either the classical pathw ay of comple- ment activation and/or by activation of immune cells via Fc receptors. Microv ascular immune complex deposition Lectin Pathway (MBL-carbohydrate) Alternative Pathway (C3b-Microbe) Classical Pathway (Antigen-Antibody) MBL MASPs C1qrs C2 C4 Factor B Factor D Factor P Stabilization of C3 convertase C3b C3b-C9 C3a C5a Membrane-attack Complex Opsonins Anaphylotoxins Phagocytosis of opsonised particle Inflammation Cell Lysis Figure 8.2 Summary of complement cascade. SYSTEMIC LUPUS ERYTHEMATOSUS 244 by inflammatory processes may trigger apoptosis; this triggers local angiogenesis and contr ibutes to the pro-coagulant tendency Risk factors for malignancy in SLE: age greater than 65 years, smoking; exposure to azathio prine, methotrexate or cyclophosphamide may increase risk of hematological malignancy. Pathophysiology of accelerated cardiovascular disease Accelerated atherosclerosis, in \202 ammatory and unstable plaques, and an increased thrombotic tendency all proba- bly contrib ute to the increased incidence of cardiovascular events. Traditional risk factors (with the exception of smoking) are increased in SLE patients, and contribute to endothelial damage and lipid deposition as in the general population. SLE-related non-traditional factors, inc lude many circulating mediators, which may exacerbate endo- thelial damage [e.g. immune com plexes, anti-endothelial antibodies (including anti-HSP antibodies), pro-in \202 ammatory cytokines, oxidized LDLc] and antibodies that may promote thrombosis (antiphospholipid anti bodies) or dyslipidaemia (anti-lipoprotein lipase antibodies). Clinical features General issues Fatigue, fever, night sweats, weight loss, lymphadenopathy are all common. Musculoskeletal \200 Polyarthralgia occurs in 90%, often with early morning stiffness. Arthritis (objective syn ovitis) occurs in 10% and deformity is usually due to tenosynovitis; this is known as Jacc oud \200\231s arthropathy (reducible deformity without radiological erosions). Chest pains may occur due to costochondritis. Osteoarthritis may coexist with SLE and 50% ful \201 l diagnostic criteria for \201 bromyalgia. Spontaneous tendon rupture (usually Achilles or patellar) may occur. Myalgia is present in the majority but a myositis occurs in 5%. Muscl e weakness may occur in relation to lupus-related muscle disease, thyroid disease or drugs (especially GCs). \200 Traditional risk factors \200 Hypertension. \200 Hyperlipidaemia. \200 Diabetes melli tus. \200 Smoking. \200 Increased BMI. \200 Sedentary lifestyle. \200 Elevated CRP. Mucocutaneous (see also p. 98) The malar or butter \202 y rash, discoid rashes, photosensi tivity, mouth or nasal ulcers and alopecia occur commonly. Less common cutaneous/subcutaneo us manifestations include urticaria, splinter hemorrhages, palpable purpura, hyper- pigment ation, vitiligo, subcutaneous nodules, calcinosis, pruritis, panniculitis, psoriaform lesio ns, and leg ulcers. \200 Non-traditional risk factors \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Treatment with glucocorticoids. Pro-in \202 ammatory high density lipoprotein (HDL). Anti- HSP antibodies. Increased oxidized LDLc. Circulating immune complexes. High systemic in \202 ammatory mediators (e.g. IL-6, TNFA). Antiphospholipid antibodies. Antibodies to lipop rotein lipase. Increased asymmetric dimethylarginine levels. Duration of SLE. Activity of S LE. Sub-acute cutaneous lupus erythematosus (SCLE) is sometimes diagnosed in patients with wide spread recur- ring, non-scarring annular or papulosquamous lesions, which occur in associat ion with ANA and anti-Ro anti- bodies. In the absence or renal or other severe systemic fea tures; SCLE is generally recognized as being at the mild end of the spectrum of SLE. Renal (see also p. 74) (see Plate 35). The majority of SLE patients will have abnormalities of urinalysis at some stage. \200 Protective factors \200 \200 \200 Nephritic syndrome ( 60%): acute renal failure with hypertension and \200\230active \200 \231 renal sediment (haematuria, cellular casts and, non-nephrotic range, proteinuria. This normally occurs in patients with proliferative glomerular changes on renal biopsy. Nephrot ic syndrome (peripheral oedema, hypoalbumi- naemia, hyperlipidaemia and nephrotic range pro teinuria \211 3.5 g/day) occurs in 10 \200\22320% of SLE patients and usually associated w ith membranous glomerular changes. A renal thrombotic microangiopathy may occur as part of APLS and this is associated with more severe hyper- tension and azotemia than in lupus neph ritis without APLS. Renal vein thrombosis may occur in association with APLS or nephrotic s yndrome. Tubulointerstitial nephritis may present with sterile pyu- ria, in the absence of haematuria or proteinuria and may cause renal tubular acidosis (RTA) type 1 or nephrogenic diabetes insipidus. Treatment with cyclophosphamide. Treatment with hydroxychloroquine. Management of conventio nal risk factors. Risk factors \200 \200 \200 \200 \200 \200 Female gender SLE in \201 rst-degree relative (see above). African or Asian ancestry. Exp osure to environmental agents (see above). Risk factors for cardiovascular disease in SLE ( see above). Risk factors for end-stage renal failure in SLE (see prognosis section below). Risk factors for osteoporosis in SLE: increasing age, low BMI, elevated CRP or ESR, low exe rcise levels, high damage (SLICC), renal impairment. Protective factor: hydroxychloroquine. Note: The net effect of corticoster- oids on BMD in SLE is unclear, presumably due to the protective effect of decreased in \202 ammation. Risk factors for infection in SLE: hypoco mplementae- mia, prednisolone >20 mg daily), cyclophosphamide (ever), splenic hypofunction, mannose binding lectin de \201 ciency (controversial). Neurological (see also p. 90) A wide variety of neurological or psychiatric conditions occu r in SLE (Table 8.2). Neurological manifestations occur in the majority of patients, with c ognitive dysfunction, CHAPTER 8 Autoimmune connective tissue diseases 245 Cardiovascular All layers of the heart may be affected in SLE and acceler- ated atheroscler osis is the major cause of premature mortality. Pericardial involvement is common, occurrin g in 66%; symptomatic in 33%. Subclinical myocarditis is probably also common, but signi \201 cant clinical features occur in 10%. Endocardial lesions are associated with anti-ph ospholipid antibodies (Libman \200\223Sacks endocarditis). The incidence of subacute bacter ial endocarditis may also be increased both by generalized immunosuppression in SLE and by pre-exisitng endocardial lesions. Incidence of MI and stroke is increased between 3- and 10 -fold. Table 8.2 Manifestations of neuropsychiatric lupus Central nervous system Peripheral nervous system Aseptic meningitis Guillain \200\223Barre syndrome Cerebrovascular disease Autonomic neuropathy Demyelinating syndrome Mononeuropathy Headache Myasthenia gravis Movement disorder Cranial neuropathy Myelopathy Plexopathy Seizures Polyneuropathy Other general issues \200 Acute confusional state Sj gren \200\231s syndrome occurs in up to 20% of SLE patients. Thyroid disease: hypothyro idism occurs in 6% SLE patients, compared with 1% of the general population. Hyperthyroid ism is not signi \201 cantly increased. Osteoporosis: approximately 25% of patients with S LE have densitometry-defined osteoporosis and 10% suffer fractures. Vitamin D deficiency: approximately 75% of SLE patients have vitamin D insuf \201 ciency (<30 ng/ml) and 15% ha ve vitamin D de \201 ciency (<10 ng/ml). Osteonecrosis has been estimated to occur in 10% of SLE patients and is associated with GC therapy. Infections are increased in SLE (relati ve risk of 1.6 compared with controls overall). UTI, pneumonia, and bacteraemia with unkno wn source are the commonest types of infection. E. coli is the most frequently isolated org anism. CNS infections are uncommon in SLE; organ- isms include M. tuberculosis, Cryptococcu s, Listeria, Klebsiella and Aspergillus. Septic arthritis is also rare in SLE, but most fre quently involves the hip and presents with avascular necrosis; Salmonella enteritidis is th e most common pathogen in septic joints. Malignancy: the standardized incidence ratio (SIR) for all malignancies in SLE 1.15. Notable associations include NHL SIR 3.6 and hepatobilia ry cancers SIR 2.6. Infertility is rarely a problem in SLE, but may be associ- ated with ac tive disease, renal failure, or use of NSAIDs, high dose GCs or cyclophosphamide. Miscarria ges are associated with antiphospholipid antibodies. Anxiety disorder Cognitive dysfunction Mood disorder Psychosis mood disorder, headache, cerebrovascular disease and seizures being the most common problem s. Attribution of neurological phenomena to SLE is problematic, since this relies on the ex clusion of another cause and some condi- tions, e.g. headache and depression are common in the general population. Hematological \200 Anemia is present in >70%.and may be normochromic normocytic, hypochromic microcytic (iron de \201 cient?), macrocytic (hypothyroid? vitamin B12 or folate de \201 - cient?), autoim mune or microangiopathic haemolytic. Lymphopenia is common and correlates with disease acti vity. Neutropaenia is uncommon, but may occur as a result of drug toxicity. Thrombocytopaen ia occurs in 20%, but serious bleeding is uncommon. APLS. Lymphadenopathy is common in SLE , but the incidence of non-Hodgkin \200\231s lymphoma is increased 7-fold. Functional hypo splenism occurs in 5% patients with SLE, probably due to blocking of Fc receptors by circu - lating immune complexes. This results in a susceptibility to infection with Pneumococcus, Meningococcus, Haemophilus in \202 uenzae., and occasionally protozoa. Key features in history Mucocutaneous involvement Enquire about malar rash, photosensitivit y (adult-onset?), alopecia, other rashes, and unusual mouth or nose ulcers. When urticarial lesions occur, ask if painful/lesions lasting >24 h (probably vasculitic) or itchy, and re solving within 24 h (probably allergic). Gastrointestinal (see also p. 82) Mouth ulcers are common. Mucosal ulceration may occur in the small intestine, occasionally leading to strictures. Oesophageal dysmotility may occur, but is rarely a serious problem. Similarly, hepato- and/or splenomegaly are found in 10 \200\22330%, but are rarely serious problems. \200 Patients with SLE frequently report episodic abdominal pain, bloating, constipation, and di arrhea. Rare, but serious complications include autoimmune hepatitis, malabsorption, coliti s, mesenteric vasculitis, and mesenteric or hepatic artery or vein thrombosis. Musculoskeletal Joint pains, swelling, duration of early morning stiffness; muscle pain/wea kness; note that a single disproportionately painful, swollen, warm joint may be septic. Hematological Enquire about history of thromboembolic disease (DVT, PE and fetal loss), whi ch may indicate APLS. Anemia may contribute to fatigue and dyspnoea. Enquire about sore thr oats and infections in patients with neutropaenia (uncommon \200\223 note risk of fungal i nfections) or severe lym- phopaenia (consider infection with atypical organisms). Easy brui sing/bleeding may be symptoms of thrombocyto- paenia. Ask about swollen lymph glands, and f evers and Pulmonary (see also p. 54) Pleurisy occurs in 50% and pleural effusion in 25%. Subtle abn ormalities of pulmonary function tests are com- mon but signi \201 cant interstitial lung disease (ILD) occurs in 20%. Recurrent pneumonia may occur, particularly in patients with splenic hypofunction. Pulmonary embolus is associated with antiphospholipid antibodies. Shr inking lung (related to diaphragmatic dysfunction) and pulmonary hypertension are rare. SYSTEMIC LUPUS ERYTHEMATOSUS 246 night sweats; while these all occur in active SLE, their presence should raise suspicion of lymphoma. Table 8.3 Mini-mental state examination Domain Maximum points Gastrointestinal Enquire about dyspepsia, nausea, vomiting, abdominal pain or distention, a nd diarrhea or constipation. Orientation Pulmonary Enquire about chest pain (pleuritic or chest wall tender- ness), dyspnoea, cough, sputum, haemoptysis, and history of pneumonia. What is the time, date, day, month, year? 5 What is the name of this ward, hospital, district, town, country? 5 Registration Cardiovascular Enquire about chest pains (pericarditic \200\223 relieved by sitting forwar d; angina \200\223 central, tight, radiating to L arm or jaw, exertional, associated with dyspnoea), palpitations, ankle swelling, and dyspnoea. 3 Name three objects once only. Score 1 point for each correct repetition. Repeat the objects until patient can repeat them accurately (for later recall) Attention and calculation Subtract 7 from 100 and then 7 from the result four more times 5 Neurological Enquire about and clarify the natures of \201 ts, \200\230funny turns \200 \231, headache, tingling/numbness, altered mood and dif \201 culty with concentration or m emory. An account from a close friend or relative is often revealing. A mini-mental state e xamination is useful if the presence of signi \201 cant cognitive dysfunction. Erectile dy sfunction may occur with autonomic neuropathy. Recall Repeat the names of the three objects registered earlier 3 Language Name 2 objects (e.g. pen and watch) 2 Repeat phrase \200\230No ifs, ands or buts \200\231 1 Other \200 \200 3 Perform a 3-stage command, e.g. \200\230With the index \201 nger of your right hand touc h your nose and then your left ear \200\231