Other co-morbidities \200 \200 Dyspepsia: proton pump inhibitors and anti-acids. Constipation: stool softeners and bulking agents, e.g. lactulose and fybogel. Diarrhea \200\223 loperamide. Malabsorption: refer to dietician and check tTG anti- bodies to rule out coeliac disease. Consider using cal- cium , folate and iron supplements and parenteral administration of vitamin B12. Chronic renal f ailure: liaise with renal team - phosphate binders, alfacalcidol, erythropoietin, BP contro l and, ultimately, dialysis may be required. Hypothyroidism: replacement therapy. Depressio n: SSRIs (e.g. citalopram; \202 uoxetine may have some ef \201 cacy for RP also), amitri ptyline, or duloxetine may be useful in patients with coexisting \201 bromyalgia. Sicca s ymptoms: see Sj gren \200\231s syndrome, p. 254 Interstitial lung disease: vaccinate again st in \202 uenza, Pneumococcus and Haemophilus influenzae; prompt treatment of intercurren t infection. Menopausal symptoms: generally avoid HRT, since it increases risk of breast ca rcinoma, thrombosis and accel- erates atherosclerosis. However, HRT may be considered in pa tients with premature ovarian failure (particularly <45 years) or for very troublesome meno pausal symp- toms. A history of breast cancer or thromboembolic disease is a contraindicati on to using HRT. The presence of anti-cardiolipin antibodies or a lupus anticoagulant shoul d be considered a relative contra-indication. Hyposplenism: vaccinate against Pneumococcus, Meningococcus and Haemophilus in \202 uenzae, and check antibody titres to con \201 rm s uccessful vaccination. Advise against visiting any endemic malarial zone. Provide prophylac tic antibiotics or stand-by antibiotics. \200 \200 Management of associated morbidity Cardiovascular disease. There is currently no standard p ractice for cardiovascular risk reduction and a dearth of appropriate clinical trials to in form management. However, it is clear that SLE patients are at substantially increased risk . General principles \200 Stop smoking. \200 Optimize BP (<140/85). \200 Aim for BMI of 22 \200\22325. \200 Control disease activity, using a minimal dose of GCs. \200 Includ e hydroxychloroquine in treatment regime. \200 Use antiplatelet agents in patients with S LE/APLS. The threshold for use of aspirin in other SLE patients is CHAPTER 8 Autoimmune connective tissue diseases 251 Laboratory investigations: FBC and differential, ESR, CRP, Creatinine and electrolytes (wit h estimation of creati- nine clearance by Cockcroft \200\223Gault formula), liver func- tio n tests, bone function tests including vitamin D and PTH, creatine kinase, thyroid function tests, vitamin B12, folate, ferritin, total cholesterol (low risk group), fasting lipid pr o \201 le (medium and high risk groups), ANA (and ENA), anticardiolipin antibodies, lupus anticoagulant, complement C3 and C4, immunoglobulin, and protein electrophoresis. Consider also DXA scan, ECG, ECHO, lung function tests (including spirometry and transfer factor). Infections: liaise with infectious diseases team to select appropriate antimicrobial therap y according to current local policies. Bronchiectasis: physiotherapy to teach lung clearanc e techniques; vaccination against in \202 uenza, Pneumococcus and Haemophilus in \202 uen zae; rotating courses of antibiotics (continuous or covering winter months only). Multidisciplinary therapy \200 \200 \200 \200 \200 \200 \200 \200 Renal physician. Dermatologist. Dentist and oral medicine specialist. Chest physician. Gast roenterologist. Ophthalmologist. Orthopedic surgeon and vascular surgeon. Physiotherapist \200\223 exercises to retain mobility and to optimize chest function. Occupational therapis t. Hand exercises and aids/strategies for overcoming disabilities. Dietician \200\223 weig ht reduction, management of hyperten- sion, hyperlipidaemia, renal failure, malabsorption, or functional gastrointestinal symptoms. Monitoring lupus nephritis 10-year survival rate is 70%, but a signi \201 cant proportion (ranges from 5 to 50% in different series) progress to end-stage renal failure (ESRF) with in 5 years. Risk factors for ESRF include: \200 \200 Abnormal renal function at presentation. Delay between detection of renal disease and \201 rst renal biopsy (probably because appropriate treatment is delayed). Male. Haemotolog ical features of SLE. Younger age of diagnosis of lupus nephritis. Antiphospholipid antibod ies. Low socio-economic group. African-American or Hispanic ancestry. Failure to achieve cl inical remission with treatment. Flares of lupus nephritis. \200 \200 \200 \200 \200 \200 \200 Patient advice \200 \200 Avoid smoking. Avoid exposure to ultraviolet light \200\223 use high spf sunblock and skin -shielding clothing. For patients with Raynaud \200\231s keep core and extremities warm, e. g. put coat on several minutes before leaving house, use thermal gloves and socks in cold t emperatures. For patients with sicca symptoms maintain careful oral hygiene and arrange reg ular dental checks. Gentle regular aerobic exercise to maintain cardiovascular/ respiratory \201 tness. Education regarding cardiovascular risk and importance of regular aerobic ex ercise and healthy diet. Education regarding drug monitoring and important adverse effects (e.g. hydroxychloroquine \200\223 regular eye checks; cytotoxic/antiproliferative drugs \200\223 monthly FBC, LFTs; report cough or dyspnoea with methotrexate). Recognizing cardiovascular disease (CVD) risk CVD accounts for most of the premature mortal ity in SLE. Incidence of cardiovascular events in SLE is increased between 3 \200\22310-fol d. Traditional risk factors Assess for regularly and address accordingly: \200 \200 \200 \200 \200 \200 \200 Hypertension. Hyperlipidaemia. Diabetes mellitus. Smoking. Increased BMI. Sedentary lifesty le. Elevated CRP. Follow up \200 Patients with very active disease and/or commencing new therapies may need 1 \200\2233-mont hly review. Six-monthly follow up is recommended for patient with signi \201 cant disease activity. Annual follow-up may be appropriate for patients with mild or quiescent disease. BMI, urinalysis, and blood pressure monitoring should be routinely performed in the follow up visits. Non-traditional risk factors \200 Treatment with GCs. Optimize dose, don \200\231t over-treat and use immunosuppressant \200 \230steroid sparing \200\231 therapy. Pro-in \202 ammatory HDL. Anti-HSP antibodies. Incre ased oxidized LDLc. Circulating immune complexes. High in \202 ammatory mediators (e.g. IL -6, TNFA). Antiphospholipid antibodies. Antibodies to lipoprotein lipase. Increased asymmet ric dimethylarginine levels. Duration of SLE. Activity of SLE. \200 \200 \200 \200 \200 \200 \200 \200 \200 At annual review \200 Enquire about dyspnoea, chest pains, dental care, smoking, incidence of premature cardiovas cular disease in \201 rst- degree relatives, fragility fractures, patient-led drug monito ring (e.g. annual eye check for patients on hydrox- ychloroquine). Examination to include a ssessment of pallor, lymphadenop- athy, BMI, BP, peripheral pulses, cardiac and carotid aus culta- tion, chest expansion, and auscultation, GALS examination (or similar musculoskeleta l screen), basic neurological examination and urinalysis. A formal activity (SLEDAI or BILA G) or damage (SLICC) score may be performed. Protective factors \200 \200 \200 Treatment with cyclophosphamide. Treatment with hydroxychloroquine. Management of conventio nal risk factors. SYSTEMIC LUPUS ERYTHEMATOSUS 252 Resources Assessment tools British Isles Lupus Assessment Group (BILAG) index. SLE Disease Activity Index (SLEDAI) Europaean Consensus Lupus Activity Measurement (ECLAM). SLE Lupus A ctivity Measure (SLAM). Systemic Lupus International Collaborating Clinics (SLICC) Damage I ndex. For detail of SLEDAI, ECLAM, SLICC with discussion of utility, see Grif \201 ths et al 2005. BILAG, SLICC damage index and references for other activity scores at: Costa M, Colia D. Treating infertility in autoimmune patients. Rheumatology 2008; 47 Suppl 3: iii38 \200\22341. Croker JA, Kimberly RP. Genetics of susceptibility and severity in systemic lupus erythemat osus. Curr Opin Rheumatol 2005; 17: 529 \200\22337. Cross J, Jayne D. Diagnosis and treatment of kidney disease. Best Pract Res Clin Rheumatol. 2005; 5: 785 \200\22398. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparis on of worldwide disease burden. Lupus 2006; 15: 308 \200\22318. Davidson RN, Wall RA. Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 2001; 7: 657 \200\22360. Dooley MA, Aranow C, et al. Review of ACR r enal criteria in systemic lupus erythematosus. Lupus 2004; 13: 857 \200\22360. Elliott JR, Manzi S. Induction therapy for active lupus nephritis: mycophenolate mofetil is superior to cyclophosphamide. Nat Clin Pract Rheumatol 2006; 2: 354 \200\2235. http://www.rheumatology.org/publications/ abbreviations/s.asp?aud=prs Fessler BJ, Alarcon GS, et al. SLE in three ethnic groups: XVI. Association of hydroxychlor oquine use with reduced risk of damage accrual. Arthritis Rheum 2005; 52: 1473 \200\22380. Patient organizations Lupus UK St James House, Eastern Road, Romford, Essex RM1 3NH. Tel: 0 1708 731251. www.lupusuk.com Goldstein LH, Dolinsky G, et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol 2007; 79: 696 \200\223701. Hughes Syndrome Foundation (antiphospholipid syndrome) The Rayne Institute, St Thomas \200 \231 Hospital, London SE1 7EH. Tel: 020 7960 5561. www.hughes-syndrome.org Gordon C, Ramsey-Goldman R. Systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2005; 19: 1 \200\223859. Grammer AC, Lipsky PE. B cell abnormalities in systemic lupus erythematosus. Arthritis Res Ther 2003; 5: S22 \200\2237. Internet sites Neuropsychiatric lupus case definitions. Available at: www.rheumatology.org/ publications/ar/1999/ aprilappendix.asp; Holvast B, Huckriede A, et al. In \202 uenza vaccination in SLE: safe and protective? Autoimmun Rev 2007; 6: 300 \200\2235. Grif \201 ths B, Mosca M, Gordon C. Assessment of patients with SLE and the use of lupus d isease activity indices. Best Pract Res Clin Rheumatol. 2005; 19: 685 \200\223708. ICD-10 codes M32/32.1 SLE/SLE with organ or system involvement M32.0 I39* I32.8* J99.1 N08* N16* M32.8 Hall FC, Dalbeth N. Disease modi \201 cation and cardiovascular risk reduction: two sides of the same coin? Rheumatology 2005: 44: 1473 \200\22382. Drug-induced SLE Libman \200\223Sacks endocarditis Lupus pericarditis Respiratory disorders in SLE Glomerular disorders in SLE Renal tubulointerstitial disorders in SLE Other forms o f SLE Huang JL, Huang JJ, et al. Septic arthritis in patients with systemic lupus erythematosus: salmonella and non-salmonella infections compared. Semin Arthritis Rheum 2006; 36: 61 \200 \2237. Jara LJ, Vera-Lastra O, et al. Prolactin in human systemic lupus erythematosus. Lupus 2001; 10: 748 \200\22356. Karp DR. Complement and systemic lupus erythematosus. Curr Opin Rheumatol 2005; 17: 538 \200\22342. References ACR. The American College of Rheumatology nomenclature and case de \201 nitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42: 599 \200\223608. Lee C, Almagor O, et al. Self-reported fractures and associated factors in women with SLE. J Rheumatol 2007; 34: 2018 \200\22323. Mongey A, Hess EV. Drug insight: autoimmune effects of medica- tions \200\223 what \200 \231s new? Nat Clin Pract Rheumatol 2008; 4: 136 \200\22344. Nagy G, Koncz A, et al. T- and B-cell abnormalities in systemic lupus Ahmed M, Berney SM, et al. Prevalence of active hepatitis C virus infection in patients with SLE. Am J Med Sci 2006; 331: 252 \200\2236. erythematosus. Crit Rev Immunol 2005; 25: 123 \200\22340. Almehed K, Forsblad d \200\231Elia H, et al. Prevalence and risk factors of osteoporosis in female SLE patients \200\223 extended report. Rheumatology 2007; 46: 1185 \200\22390. Nived O, Sturfelt G. ACR classi \201 cation criteria for SLE: complement components. Lupus 2004; 13: 877 \200\2239. Parks GC, Cooper GS, et al. Association of Epstein \200\223Barr virus with systemic lupus e rythematosus: effect modi \201 cation by race, age and cytotoxic T lymphocyte-associated a ntigen 4 genotype. Arthritis Rheum 2005; 52: 1148 \200\22359. Bernatsky S, Joseph L, et al. The relationship between cancer and medication exposures in s ystemic lupus erythematosus: a case-cohort study. Ann Rheum Dis 2008; 67: 74 \200\2239. Bernatsky S, Ramsey-Goldman B et al. Malignancy and autoimmunity. Pyne D, Isenberg DA. Autoimmune thyroid disease in systemic Curr Opin Rheumatol 2006; 18: 129 \200\22334. lupus erythematosus. Ann Rheum Dis 2002; 61: 70 \200\2232. Bijl M, Kallenberg CG. Ultraviolet light and cutaneous lupus. Lupus Ruiz-Irastorza G, Egurbide MV, et al. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatol 2008; 47: 920 \200\2233. 2006; 15: 724 \200\2237. Bosch X, Guilabert A, et al. Infections in SLE: a prospective and controlled study of 110 patients. Lupus 2006; 15: 584 \200\2239. Simard JF, Costenbader KH. What can epidemiology tell us about Bruce IN. Cardiovascular disease in lupus patients: should all patients be treated with sta tins and aspirin? Best Pract Res Clin Rheumatol 2005; 5: 823 \200\22338. SLE? Int J Clin Pract 2007; 61: 1170 \200\22380. Stojsnovich L, Stojanovich R, et al. Neuropsychiatric lupus favoura- ble response to low do se i.v. cyclophsophamide and prednisolone (pilot study). Lupus 2003; 12: 3 \200\2237. Camous L, Melander C, et al. Complete remission of lupus nephritis with rituximab and stero ids for induction and rituximab alone for maintenance therapy. Am J Kidney Dis 2008; 52: 34 6-52. Tan EM, Cohen AS, et al. The 1982 revised criteria for the classi \201 ca- tion of SLE. Arthritis Rheum 1982; 25: 1271 \200\2237. Clarke A. Proposed modi \201 cations to 1982 ACR classi \201 cation criteria for systemic lupus erythematosus: serositis criterion. Lupus 2004; 13: 855 \200\2236. Tarjan P, Sipka S, et al. No short-term immunological effects of Pneumococcus vaccination i n patients with SLE. Scand J Rheumatol 2002; 31: 211 \200\22315. Clowse ME, Magder L, et al. Hydroxychloroquine in lupus Westerweel PE, Luyten R, et al. Premature atherosclerotic cardio- pregnancy. Arthritis Rheum 2006; 54: 3640 \200\2237. vascular disease in SLE. Arthritis Rheum 2007; 56: 1384 \200\22396. This page intentionally left blank SJ \226GREN \200\231S SYNDROME 254 Sj gren \200\231s syndrome De \201 nition Sj gren \200\231s syndrome (SS) is an autoimmune condition, char- acterize d by dysfunction and destruction of exocrine glands, particularly salivary and lacrimal gla nds. However, constitutional symptoms are common, multi-organ involve- ment may occur and S S is associated with an increased incidence of lymphoid malignancy. Primary Sj gren \200 \231s syn- drome (pSS) occurs alone, whereas secondary Sj gren \200\231s syndrome (sSS) oc curs in the context of another autoim- mune disease. Diagnostic criteria The American-European classi \201 cation criteria are used to diagnose SS as follows: Diagnosis of primary SS \200 Presence of 4 of 6 criteria, including either IV (histopa- thology) or VI serology. Presenc e of 3 of 4 objective criteria (III, IV, V, VI). Diagnosis of secondary SS In the presence of a well-de \201 ned connective tissue disease, the presence of symptoms of dry eyes or mouth (I or II) plus 2 other criteria from III, IV , and V; note that serology is not used as a criterion, since it may have been used to di- agnose the \200\230primary \200\231 connective tissue disease. Classi \201 cation Developing classi \201 cation criteria for SS has proved chal- lenging , since the prevalence of symptoms of dry eyes and mouth are common and non-speci \201 c. The most widely- used criteria currently are those agreed by the American- European Consens us group (Table 8.6). Exclusion criteria History of head/neck radiation, HCV or HIV infection, pre- existing lymp homa, sarcoidosis, graft-versus-host disease or recent use of anti-cholingeric agents. Table 8.6 Sjogren \200\231s syndrome: classi \201 cation criteria Despite the European-American consensus, criteria for diagnosing SS remain controversial. F urther criteria have been proposed to improve sensitivity and speci \201 city of diagnosis , including a score of IgA+ plasma cells in salivary gland histological sections or measure ment of salivary IgA anti M3 muscarinic antibodies. I Ocular symptoms: 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months? 2. Do you have a recurrent sensation of sand or gravel in the eyes? Epidemiology The prevalence of SS, diagnosed according to the American- European consensus criteria is 1% and it is therefore one of the most common autoimmune diseases. The female: male ratio is 9:1 and onset is usually 45 \200\22355 years. 3. Do you use a tear substitute more than 3 times a day? Oral symptoms: II 1. Have you had a daily feeling of dry mouth for more than 3 months? 2. Have you had recurrently or persistently swollen salivary glands as an adult? Aetiologyand pathophysiology Genetic factors HLA associations Several groups have published association of HLA-DR alleles with SS. A recent re-evaluation indicates, however, that the HLA association is with the presence of autoanti- bodies, rather than with primary SS per se. HLA-DR15 appears to be associated with development of anti-Ro antibodies, whereas HLA-D R3 is associated with both anti- Ro and anti-La antibodies. There is tight linkage disequil ib- rium between HLA-DR and DQ loci and it has been sug- gested that HLA-mediated susceptib ility relies upon expression of a permissive HLA-DQ molecule. Interest- ingly, secondary SS , in association with RA, is associated with HLA-DR4 rather than HLA-DR3 or 15. 3. Do you frequently drink liquids to aid in swallowing dry foods? Objectively dry eyes: III Positive Schirmer \200\231s Test ( \211 5 mm in 5 min) or Rose Bengal score. Histopathology: IV Minor salivary gland (MSG) biopsy reveals focus score of \211 1 (see below). Objectively dry mouth ( \211 1 of): V 1. Unstimulated whole salivary \202 ow \211 1.5 ml in 15 min. 2. Parotid sialography showing diffuse sialectasias without major duct obstruction. 3. Salivary scintigraphy showing delayed uptake of tracer. Regulators of complement activation (RCA) A recent study suggests that certain haplotypes o f the RCAA block (encoding complement regulatory genes such as CR1 and MCP) interact epista tically with the HLA haplotype to modify susceptibility to SS. An HLA-DR3 haplotype is know n to encode the C4A null allele and to confer a relative de \201 ciency of C4 VI Serology 1. Either anti-Ro or anti-La antibodies, or both. 2. Exclusions: previous head and neck radiation 3. Hepatitis C infection 4. Acquired immunode \201 ciency disease (AIDS) 5. Pre-existing lymphoma Interleukin-10 IL-10 promoter polymorphisms have been reported to be associated with primar y SS but remains controversial. 6. Sarcoidosis 7. Graft-versus-host disease Environmental factors Infectious triggers \200 8. Use of anti-cholinergic drugs Epstein \200\223Barr virus (EBV) has been proposed to be a trig- ger for SS, since EBV DNA has been detected in salivary CHAPTER 8 Autoimmune connective tissue diseases 255 and lachrymal glands. However, there is no evidence that it drives in \202 ammation at the se sites. Retroviruses are known to infect and modulate behavior of lymphocytes. An in \201 ltrative sialadenitis (mostly CD8+ T cells) has been described in association with HIV infec- tion. Human T-leukemia retrovirus-1 (HTLV-1) has also been implicated and may under lie SS in up to 20% of Japanese patients. Hepatitis C virus (HCV) infection is associated w ith sicca symptoms, but this (and HIV infection) is an exclusion to the diagnosis of primar y SS tissues. Evidence for excessive somatic mutation and B cell receptor editing in B cells is consistent with antigen-driven (?auto)immune responses. Marked elevation of BAFF, a potenti al B cell activation/survival factor is implicated in the aberrant B cell behavior. T cell over-activity CD4+ T cells dominate in the lymphocytic in \201 ltrates of salivary glands in SS. Approximately a third of the in \201 ltrat- ing CD4+ T cells also express pe rforin, which implies that they may have a directly cytotoxic function. Regula- tory (CD4+, CD25+, FoxP3+) T cells are rare in the salivary gland in \201 ltrate and their numbers in peripheral blood of pSS are reduced compared with healthy controls; impaired regulation ma y contribute to T and B cell over-activity. Non-infectious triggers/promoters \200 Androgen de \201 ciency has been proposed as a contributing factor in SS, since it leads t o altered meibomian gland lipid pro \201 les and tear \201 lm instability. Microchimeris m has been suggested as a driver for chronic aberrant immunological activity in SS. Seeding of fetal leucocytes into the maternal bloodstream occurs during most pregnancies. Two stud ies have reported male fetal DNA to be detectable in MSG biopsies (but not peripheral blood ) of 36 \200\22350% SS patients, but in 0 \200\22312% controls. However, a third study fail ed to demon- strate fetal DNA in any of the SS samples. Ectopic germinal centers Ectopic lymphoid tissue formation is characteristic of SS. Germina l centers are structures, within secondary lym- phoid tissue, in which provision of antigen -speci \201 c T cell help to B cells results in activation and proliferaton of B cells, cl ass-switching and somatic hypermutation within the genes encoding the immunoglobulins, and differentiation into plasma cells. Clusters of lymphocytes, resembling ger- minal centers, are found in the minor and major salivary glands of patients with SS. This suggests that an tigens ex- pressed locally in salivary glandular tissue are driving auto- immune T and B ce ll responses. Immunopathology (Figure 8.3) B cell over-activity A decrease in circulating memory CD27+ B cells has been attributed to a combination of B cell traf \201 cking to target Malginant Transformation Autoantibodies and immune complexes Small Vessel Vasculitis Plasma Cell Activation of autoreactive T and B cells IL-6 & IFN Complement activation L-12 B cell pDC IFN Th2 Blockade of M3 muscarinic receptors? BAFF CD4 T cell Anti-M3 Antibodies Th1 DC or macrophage or epithelial cell IFN Epithelial damage Viral infection? Apoptosis CTL Activation of APC Virus? Immune complexes? Apoptoic parides? Fas-mediated, or periorin/granzyne-mediated cylotoxicity? High MHC class II expression Anti-Ro/La/bdnin Antibodies Figure 8.3 The Immunopathology of Sj gren \200\231s syndrome. Both innate and adaptive imm une systems are involved in the aberrant in \202 ammatory response which leads to the dest ruction of glandular epithelium in lacrimal and salivary glands. Circulating cells and solu ble mediators are also implicated in the systemic features evident in many patients. SJ \226GREN \200\231S SYNDROME 256 stimulated by IFNA, and it is has been proposed that this re \202 ects a viral disease tri gger and/or perpetuation by auto- antibodies to nucleosomal components. Antigen-presenting cell-derived Th1 cytokines, IL-12, and IL-18 have been detected at increased levels in MSG tissue from patients with pSS, compared with disease controls. However, since both Th1 and Th2 cytokines have been variably reported to be elevated in SS, and it cannot be considered either a predominantly Th1- or Th2-mediated disease. The role of Th17- associated cytokine s remains to be clari \201 ed. Macrophages and dendritic cells These antigen-presenting cells are present in the salivary gland in \201 ltrates, particularly in the ectopic germinal centers. These cells may inges t and present antigens from apoptotic salivary epithelial cells. Expression of the APC-deri ved Th1 cytokines, IL-12 and IL-18 have been shown to be elevated in salivary biopsy gland specimens from SS patients, compared with disease controls. Autoantibodies Anti-Ro antibodies are present in 65% and anti-La anti- bodies in 50% pati ents with pSS; these autoantibodies also occur in patients with SLE and SLE/sSS. Ro and La are expressed in blebs on the surface of apoptotic cells and this may contribute to their h igh immunogenicity. Their role in pathogenesis is unclear. Rheumatoid factors (RFs) and ANA may also occur in SS. Recently, A-fodrin (a molecule involved in apoptosis) and the muscar inic acetyl- choline receptor-3 (M3) have been suggested as targets for autoantibodies in S S. The latter has particular appeal since anti-M3 antibodies could cause exocrine glandular dysfunc- tion. The putative association of anti-fodrin and anti-M3 antibodies with SS, and the role of these autoantibodies in pathogenesis, requires further investigation. Autoanti bodies specific for calcium channels, A1-adrenoceptors and purinoceptors have all been impl icated in the autonomic dysfunction, which may occur in primary SS. However, it is unclear whether any of these autoantibodies has the ability to interfere with the function of their respective targets. Autoantibodies to islet cell antigen 69 (ICA69) have been detected in pSS and studies in animal models of SS indicate that ICA69 may be an important therapeutic target. Apoptosis Increased apoptosis of salivary epithelial cells has been demonstrated both in hu mans with SS and in murine models. Ro and La are both present in vesicular structures, whic h form on the surface of apoptotic cells; this location and increased apoptosis may contrib ute to their autoantigenicity in SS. A-Fodrin is a candidate autoantigen in SS; it is cleav ed from the ubiquitous cytoskeletal protein Fodrin during apoptosis, again implicating exce ssive or dysregulated apoptosis in SS. Both autoantibodies and T cells may medi- ate epithe lial cell destruction. Autoantibodies may bind to targets, such as the M3 receptor on epith elial cells and \201 x complement, causing cell death. Direct interaction of T cells with endothelial cells may also trigger apoptosis. Salivary gland function It has been assumed that xerostomia is the sequel to sali- vary aci nar destruction. However, correlation between salivary \202 ow rates and histological evi dence of acinar atro- phy is poor. Furthermore, in murine models of SS, salivary gland hypo function has been demonstrated prior to tissue destruction. It has been proposed that chang es in cytokine levels or other local mediators are responsible for acinar hypofunction. Cryoglobulins Occur in 15% patients with pSS. They are predominantly comprised of a monocl onal IgM RhF, which binds to poly- clonal IgG. Cryoglobulins occur in 35% patients with H CV infection, which itself frequently give rise to sicca symptoms. In the context of pSS, c ryoglobulins are an indicator of clonal B cell dysregulation and are a risk factor for deve loping lymphoma. Aquaporins are a family of water-transporting proteins. AQP1 is expressed on corneal epithe lium and AQP 5 on the corneal and lacrimal gland epithelia. Abnormalities in the expression of each of these has been reported in pa- tients with SS, although these \201 ndings are still controversial. Risk factors \200 Immune complexes Are deposited in the microvasculature and give rise to pur- puric rashes, glomerulonephritis, mononeuritis multiplex, and hypocomplementaemia; all features are assoc iated with an increased risk of lymphoma. Family history of autoimmune disease: individuals with a \201 rst-degree relative with an autoimmune disease have an odds ratio of 7 of developing SS. History of pregnancy confers an odds ratio of 2 of developing SS. BAFF BAFF is a membrane-bound molecule, which can be cleaved to a soluble form; it is expre ssed by monocytes, neutrophils, epithelial cells and, at lower levels, by T cells. It is a critical B cell survival factor and BAFF over-expression, in transgenic murine models, favo rs the accumulation of low-af \201 nity autoreactive B cells. BAFF can also co-stimulate T cell activation and differentiation. BAFF levels are mark- edly elevated in patients with SS and may contribute to the development of the disease by promoting auto-reactive plasmabl ast survival, supporting the development of ecto- pic germinal centers and by co-stimulatin g proliferation and cytokine release by CD4+ T cells. Indeed, BAFF levels have been reporte d to correlate with the titre of serum autoantibodies. The stimulatory, pro-survival effect s of BAFF may also contribute to the development of lymphoid malignancies in SS patients. Clinical features \200 \200 Xerostomia: dry mouth; dysphagia. Keratoconjunctivitis sicca: dry eyes, blurred vision, pho tophobia. Parotid swelling: often recurrent. Dental caries: this is accelerated by decrease d secre- tion of alkaline saliva that contains immunologically active molecules Interstitia l lung disease is evident on HRCT chest in up to 30% of SS patients, although this is subcl inical in the majority of patients. Lung disease may present with a dry cough or exertional dyspnoea. Dyspareunia: due to decreased vaginal secretions. Oesophagitis or gastritis: due to impaired mucosal secretions. Malabsorption: due to impaired pancreatic or small intesti nal mucosal function; elevated amylase has been reported in 25% of patients. Gastrointestin al involve- ment is usually mild. \200 \200 Cytokines. IFNA, IFNG TNFA, and IL-10 are increased in the serum of SS patients. Salivary a nd conjunctival epithelial cells have been shown to exhibit up-regulated expression of gene s CHAPTER 8 Autoimmune connective tissue diseases 257 \200 Key features on examination Keratoconjunctivitis sicca Palpebral injection of the conjuncti va, manifest as dilated conjunctival blood vessels, particularly around the hori- zontal me ridian of the eye, indicates a response to chronic dryness, most marked at the site of maxi mal evaporation. Slit-lamp examination (by an ophthalmologist), using Rose Bengal (an anili ne dye, which stains damaged corneal or conjunctival epithelium), may reveal \201 lamenta ry keratitis. Fluorescein staining is used to reveal abnormal break-up of the tear \201 l m (time between last blink and appearance of non- \202 uorescent area in tear \201 lm). A positive Schirmer \200\231s test is de \201 ned as \211 10 mm wetting of a standard str ip of \201 lter paper in 5 min, after the end of the paper has been placed in the inferio r conjunctival sac. Interstitial cystitis. Rashes and skin dryness: a variety of rashes may occur, including bo th palpable purpura (small vessel vasculitis) and \202 at purpura (often associated with hypergamma- globulinaemia), urticaria, and annular lesions. Dryness of the skin ( 50% of pa tients) may result from lymphocytic in \202 iltration of the eccrine glands of the skin. F atigue: occurs in 70% of patients and is often the most debilitating symptom in SS. In \202 ammatory arthritis: occurs in 50% patients with SS; this is rarely erosive. Mononeuri tis multiplex Demyelinating syndromes occur in 1% of SS patients. Autonomic neuropathy: pa rasympathetic dysfunction has been documented in 15% of SS patients. Raynaud \200\231s phe nomenon occurs in 30% of SS, but rarely leads to serious sequelae. Purpuric vasculitis is common, particularly on the legs. Renal tubular acidosis: sometimes complicated by urolithi asis. Muscle weakness (rare) may be caused by hypokalaemia in SS-associated RTA. Lymphadeno pathy should prompt suspicion of lymphoma. \200 \200 \200 Key features in history Eliciting symptoms of keratoconjunctivitis sicca \200 Have you had daily, persistent, troublesome dry eyes for more than 3 months? Do you have a recurrent sensation of sand or gravel in the eyes? \200 Do you use a tear substitute more than 3 times a day? Many patients experience dry, gritty, or sticky eyes, and sometimes di f \201 culty opening the eyes in the morning. Figure 8.4 Schirmer \200\231s Test. Place \201 lter paper in the inferior conjunctival sa c, lateral to the cornea, and ask the patient to close their eyes. Eliciting symptoms of xerostomia \200 Have you had a daily feeling of dry mouth for more than 3 months? Have you had recurrently or persistently swollen salivary glands as an adult? Do you frequently drink liquids to aid in swallowing dry foods? The cream cracker sign refers to the inability to swallow dry f oods without sips of \202 uid. Xerostomia May be evident at the bedside as a reduced salivary pool and/or by a dry, \201 ssured tongue. Accelerated dental caries is a common and important feature. \200 Parotid and submandibular salivary glands should be palpated for swelling; nodules raise co ncern regarding lymphomatous transformation. Lymphadenopathy at cervical, submandibular and axillary sites could indicate lymphoma. Also ask the patient about their dental health and ensure that they have regular dental sur veillance. Enquire about smoking history; apart from the general Signi \201 cant interstitial lung disease May be suggested by \201 ne basal inspiratory crepitations, which fail to clear on coughing. health implications, smoking exacerbates sicca symptoms. Eliciting symptoms of other exocrine involvement. Ask about dry hair and skin, vaginal dryn ess and dyspareunia (problems for 30%), dyspepsia, abdominal pain, bloating, constipation. Rashes Examine skin, particularly legs, for palpable and impalpable purpura, urticaria, and annular lesions. The skin may also be dry. Eliciting symptoms of extraglandular involvement. Ask about: \200 \200 Other \200 Constitutional symptoms ( 70%; fatigue, fever, sweats). Pain and stiffness in joints, and t he occurrence/duration of early morning stiffness ( 30% have in \202 ammatory arthritis). Dyspnoea or cough ( 25% have abnormal lung function). Rashes. Cold/blue/white hands ( 30%). Dysuria, urinary frequency, urgency, or nocturia. Rashes. Weakness, numbness, or paraesthe siae. Weight or BMI: a drop may indicate lymphomatous transformation or malabsorption. Urinalysis : blood and protein may indicate UTI or urolithiasis. \200 \200 \200 \200 \200 Co-morbidities Lymphoma About 5% patients with SS eventually develop lymphoma and the relat ive risk of developing non-Hodgkins lym- phoma (NHL) in this group is 44. This may present as SJ \226GREN \200\231S SYNDROME 258 nodular lymphadenopathy, salivary gland enlargement or pulmonary nodules. Histological subt ypes of NHL in SS include follicle center lymphomas, lymphoplasmacytoid lymphomas, diffuse large B cell lymphomas and mucosa- associated lymphoid tissue lymphomas. Laboratory Hematology \200 FBC with differential; mild anemia of chronic disease occurs in 25% and leucopenia in 10% . Blood \201 lm if lymphomatous transformation is suspected. ESR is elevated in the major ity. \200 Risk factors for the development of lymphoma in SS patients are: \200 \200 \200 \200 \200 \200 \200 Biochemistry \200 Presence of autoantibodies. CD4+ T cell lymphopenia. Monoclonal gammopathies. Decrease in s erum Ig and disappearance of RF. Cyoglobulins. Low complement C4. Immune complex-mediated d isease (e.g. purpuric rash, glomerulonephritis, mononeuritis). Nodular lymphoid/glandular s wellings. Pre-malignant lesions, e.g. myoepithelial sialadenitis. Creatinine and electrolytes (note: hypokalemia may indicate renal tubular acidosis). Estima ted creatinine clearance. Liver function tests. Thyroid function tests. Bone function tests ; consider vitamin D and parathor- mone levels if malabsorption or RTA suspected. CRP is us ually normal, unless the patient has an infection. Vitamin B12, folate, and ferritin levels if patient is anemic, or if malabsorption suspected. Fasting lipid pro \201 le. SS has be en reported to be associ- ated with low/normal total cholesterol but with low HDL cholester ol, suggesting an increased risk of cardio- vascular disease. Lactate dehydrogenase (LDH) i f lymphoma suspected. If RTA is suspected: Blood and urine pH (early morning urine sample p refer- able); pH > 5.3 despite metabolic acidosis in RTA. Plasma bicarbonate (<21 mmol/l in RTA). 24 h urinary calcium can be checked if RTA is suspected and to monitor response to t reatment. \210\222 >21 mmol/l, but Acid load test (used if plasma HCO3 RTA still suspected ). 100 mg/kg ammonium chloride is administered orally. Urine pH is monitored hourly and \200\223 drops below \200\223 at 3 h; in RTA, HCO3 plasma HCO3 21 mmol/l, but urine pH rem ains <5.3. B2 microglobulin measurement may be made if a generalized proximal tubular leak is suspected. \200 \200 \200 \200 \200 Other co-morbidities \200 \200 Thyroid disease occurs in 30% of pSS patients. Coeliac disease 15% patients reported to h ave SS and 12% of SS patients have anti-tissue transglutaminase antibodies, a robust marker for CD. Fibromyalgia has been reported in 22% patients with pSS. Distal (type 1) renal tub ular acidosis. In distal RTA, the distal renal tubules fail to excrete H+ ions and the urin e fails to acidify (pH > 5.3, even when the patient become acidotic). Hypokalaemia may mani fest as muscle weak- ness and may predispose to cardiac arrhythmias. Calcium derived from b ones buffers the excess H+ ions. This causes osteomalacia. Renal stone formation may occur as a result of hypercalcuria, hypocitraturia (citrate inhib- its precipitation of calcium p hosphate), and alkaline urine (which favors calcium phosphate deposition). Urolithiasis its elf predisposes the patient to recurrent UTI. Subclinical tubular disease occurs in 30% of pSS patients. Proximal (type 2) renal tubular acidosis has been reported in rarely in SS. It results from failure to reab- sorb bicarbonate from the proximal tubule. Hypokalaemia oc curs and the urine pH > 5.3, despite systemic acidosis. There may be a generalized proximal tubular leak (glycosuria, aminoaciduria, B2 microglobulin in urine). Primary biliary cir rhosis (PBC) has been reported to occur in 5% of pSS patients. Vasculitis may manifest as palpable purpura, glomeru- lonephritis (usually associated with cryoglobulinaemia) or monon euritis. Depression. The coexistence of pernicious anemia and SS has been reported. The ext ent of association is unknown. \200 Immunology \200 \200 \200 ANA, ENA, and RF. Complement C3 and C4. Immunoglobulins and protein electrophoresis, Bence- Jones protein estimation. Cryoglobulins. A positive ANA, RF with anti-Ro (in 50 \200\22370 %) anti-La (in 20 \200\22350%) antibodies are commonly found. Hypergammaglobulinaemia oc curs 80% pSS patients. A monoclonal band and/or low complement C4/C3 are risk factors for developing lymphoma. Anti-mitochondrial antibodies \200\223 if the clinical features sugge st PBC. Anti-tissue transglutaminase or anti-endomysial antibod- ies \200\223 if the clini cal features suggest coeliac disease. (note: ensure that the patient has normal IgA levels in order to avoid a false negative test). \200 \200 Investigations Ocular \200 Microbiology \200 