 \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 Schirmer \200\231s tear test: the standard bedside test is described in examination; other variants include Schirmer \200\231s test with topical anesthesia, Schirmer \200\231s test w ith nasal stimulation. Tear break-up time (see examination section). Lacrimal lysozyme and/ or lactoferrin levels: this provides some qualitative analysis of the lacrimal \202 uid. Slit-lamp examination (see examination features). Microscopy, culture and (antibiotic) sensitivities (MC&S) of conjunctival swab if a bacteri al conjunctivitis is suspected. MC&S of an mid-stream urine (MSU) will be needed in patient s with dysuria, urinary urgency or blood and/or protein on urinalysis. Viral serology is re quired to exclude HCV and, in appro- priate cases, HIV infection. \200 CHAPTER 8 Autoimmune connective tissue diseases 259 \200 Imaging \200 HIV can present with sicca symptoms or parotid swelling. Drug-related sicca syndrome, e.g. tricyclic antidepres- sants, diuretics. Sarcoidosis can cause sicca symptoms, arthritis, ra shes, and interstitial lung disease. Graft-versus-host disease. Alcohol abuse may cause par otid enlargement. Paraneoplastic disease may present with constitutional and sicca symptoms . Coeliac disease may also present with constitutional symptoms, oral in \202 ammation and rashes. Fibromyalgia: fatigue may be indistinguishable from constitutional symptoms of SS and patient may acquire sicca symptoms/signs secondary to medications (e.g. amitriptyline). Fybromyalgia has been reported in 22% of patients with SS. Ultrasound (US) and MR can detect in \201 ltrates in the major salivary glands of patients with SS, although such investigations are generally not required. Sialography using water- soluble contrast media is used in some centers to assess anatomical changes in the salivary gland ducts. Scintigraphy can be used to quantify salivary gland function. Following injec tion of 99mTc pertechnetate, the uptake of label by salivary glands can be imaged and the t ime taken for the label to appear in the mouth meas- ured; both are delayed or absent in pa tients with SS. MR sialography is a sensitive method of assessing changes in minor salivary glands (MSGs), but is not widely used. High resolution CT chest will reveal parenchymal ab nor- malities in 30% patient with SS, although lung disease is subclinical in the majority . Renal and urinary tract US is useful if renal stones are suspected. Plain radiographs of hands/feet (or MR or US) may be used to screen for erosive arthritis. \200 \200 Disease activity assessment SCAI SSDAI PROFAD Pro \201 le of fatigue and discomfort. SS Clinical Activity Index SS Disease Activity Index Treatment Objectives of management \200 \200 \200 \200 \200 Histology \200 MSG biopsy is frequently used to substantiate the diag- nosis. A focus score has largely re placed the less sensitive Chisholm classi \201 cation. (A focus is a cluster of \211 50 l ymphocytes; the focus score is the average number of foci in a 4 mm2 area, assessed from \211 4 salivary gland lobules). Parotid gland biopsy provides similar information to the MS G biopsy; lymphoma should be excluded Excision biopsies of lymph node(s) should be examined to exclude lymphoma. Bladder biopsy (if interstitial cystitis suspected). Symptomatic relief of mucosal dryness. Improvement of constitutional symptoms. Prompt treat ment of mucosal infections. Analgesia (where relevant). Arrest or retardation of underlying autoin \202 ammatory disease. Early detection and treatment of lymphoma. Reduction of car diovascular disease. Risk of CV disease is elevated in several chronic in \202 ammatory co nditions (e.g. RA and SLE), but it remains to be clari \201 ed whether this applies to SS. \200 Cytology Urinary cytology may occasionally be indicated in patients with sterile pyuria - ? interstitial cystitis. General measures See advice to patients. Cardiovascular Investigations \200 \200 Physical therapies \200 ECG. Cardiac ECHO, if clinical examination or ECG indicates new murmur or possible LVH. Arti \201 cial tears/ophthalmic lubricants. Short-acting prep- arations contain polyvinyl alcohol (SnoTears, Liqui \201 lm) or carboxycellulose (Hypromellose, Tears Naturale). Long er-acting preparations contain carbomer gels (e.g. Viscotears, Geltears) or paraf \201 n ( e.g. Lacrilube, Lubri- Tears); these are stickier and patients may prefer to use them at ni ght. Some patients are intolerant of preserva- tives in aqueous drops and preservative-free Liqui \201 lm may be tolerated. Mucolytic agents (e.g. acetylcysteine 10%) may be used sp aringly for sticky mucus in the eyes. Autologous serum (50% in normal saline) eye drops imp rove objective and subjective measure of ocular surface disease, but this treatment is not generally available. Arti \201 cial saliva is available as sprays (e.g Glandosane, Saliva Orththa, Luborant), lozenges (Saliva Orthana) or gels (e.g. Oralbalance, BioXtra). Note tha t Luborant is a neutral pH and contains \202 uoride, and therefore may reduce dental cari es. Vaginal lubricant (e.g. KY jelly). Skin emollients, e.g. E45 cream. Physiotherapy and g oal-setting can be helpful for manag- ing constitutional symptoms. Nordic walking for 45 mi n 3 times a week for 12 weeks has been shown to improve Other Investigations \200 Pulmonary function tests (spirometry and transfer factor) are abnormal in 25% patients. Mo st respiratory disease in SS remains subclinical. However, pulmonary function tests can be used to monitor for signi \201 cant progression and to determine, which patients require a HRCT chest. Nerve conduction studies may be performed on patients with suspected mononeuri tis (multiplex) MR or CT scanning of brain/spinal cord, along with other appropriate tests are indicated if patients have symp- toms suggesting CNS disease. Tests of autonomic functi on may be performed on patients with postural hypotension; these may include beat-to-beat v ariation or tilt-table tests. Differential diagnosis \200 \200 \200 \200 \200 Blepharitis secondary to Meibomian gland dysfunction. Allergic conjunctivitis. HCV: this is a common viral infection (prevalence 2% worldwide), which frequently causes sicca symptom s and cryoglobulinaemia. SJ \226GREN \200\231S SYNDROME 260 IFNA: Phase III studies in pSS of 150U IFNA lozenges tds revealed a signi \201 cantly incr ease in the unstimulated (but not stimulated) salivary \202 ow rate and a decrease in sic ca symptoms. Rituximab: given the prominence of B cells in the pathogenesis of SS, it is lo gical to consider B cell deple- tion therapy. Reports of small open-label studies of rituxi mab in SS are promising, suggesting that objective and subjective measures of disease activ ity may be improved; serial MSG biopsies in one study indicates that rituximab depletes B c ells from salivary tissue, as well as from peripheral blood. Rituximab has also been used t o successfully treat SS-associated MALT lymphoma. DBPCRCTs are currently being organized. aerobic capacity and to reduce fatigue and depression. Physiotherapy is also important in t he rehabilitation from neurological complications of SS. Gluten-free diet (only in SS patie nts with co-existing coeliac disease). Pharmacological stimulation of salivary \202 ow Muscarinic, cholinergic agonists can be u sed as secreta- gogues in patients with xerostomia. \200 Pilocarpine: data from a recent RDBPCT demonstrated that pilocarpine 5 mg qds improves subj ective and objec- tive measures of salivary \202 ow. Oral administration of 5% pilocarpin e solution is also effective. About 50% of SS patients respond to pilocarpine (the non-res ponders may be those with salivary acinar atrophy, but this requires clari \201 cation). T he main side effects are sweating, \202 ushing, diarrhea, and urinary urgency; these can be reduced by starting pilocarpine at 5 mg od and gradually increasing the dose. Cevelimine (licensed in USA and Japan) is a more selec- tive muscarininc agonist than pilocarpine; wi th greater ef \201 cacy at the M1 and M3 receptors, which are prevalent in exocrine glands . Two RDBPCT trials have shown ef \201 cacy for 20 or 30 mg tds. The main side-effects (pa r- ticularly at high doses) are nausea, sweating and head- ache. Theoretically, the selecti vity of cevelimine may result in fewer adverse effects than for pilopcarpine, but this is u nproven. Other pharmacological therapies/supplements \200 \200 \200 Thyroxine to correct hypothyroidism. Proton pump inhibitor for dyspepsia. Potassium bicarbo nate and citrate supplementation in patients with distal RTA. Thiazide diuretics may be use d to increase proximal tubule bicarbonate reabsorption in RTA. Vitamin D3 supplementation i f deficient. Note that chewable calcium/Vit D3 preparations are unlikely to be palatable in patients with dry mouth. Dispersible cacit D3 (2 sachets daily) is an alternative. Vitamin B12 injection in patients with co-existing pernicious anemia. Treatment of lymphoma. Outco me of patients with low- grade lymphomas in SS is not altered by chemotherapy and patients are managed by observation. High-grade lymphomas are treated with a variety of regimens, in cluding rituximab and cytotoxic agents. Pain relief \200 \200 Simple analgesia (e.g. paracetamol) is \201 rst-line. NSAIDs should be avoided wherever p ossible due to increased risk of gastrointestinal (and possibly tubu- lointerstitial) damag e in SS. When unavoidable, NSAIDs should be prescribed with a proton pump inhibitor in SS. Opiate analgesia is rarely required in SS. Surgery Lacrimal ducts may be plugged temporarily or cauterized for permanent occlusion. Conventional Immunosuppression \200 Hydroxychloroquine is widely used in Sj gren \200\231s. It has been assessed in one small double-blind, placebo- controlled randomized trial (DBPRCT) and a larger retrospective stud y; both provided some evidence for ef \201 cacy (subjective improvement, reduction in acut e phase markers and IgG levels). Azathioprine was not found to be effective in a single DBP RCT. Mycophenolate mofetil has not been subjected to clinical trial in SS. Methotrexate (MT X) \200\223 a pilot study indicated that MTX was safe, but revealed no objective improveme nt in sicca features. Le \202 unomide \200\223 a pilot study suggested some improve- ment in acute phase markers and vasculitis. Cyclophosphamide \200\223 case reports suggest imp rovement in myelopathy/neuropathy in SS. Other immunosuppressives, including ciclosporin or tacrolimus are used empirically. Glucocorticoids are used minimally in SS. There is no evi dence that they improve sicca features. Multidisciplinary approach \200 \200 \200 \200 \200 \200 \200 Ophthalmologist. Dentist. Chest physician (if signi \201 cant ILD). Maxillofacial/oral sur geon (MSG biopsy). Hematologist (if lymphoma). Histopathologist. Other specialists (renal p hysicians, dermatologists, radiologists, urologists). Patient advice \200 Avoid very dry environments. A humidi \201 er in the bedroom/ sitting room may be useful. Reduce evaporation from eyes by wearing tinted glasses with side panels in bright sunlight or tight \201 tting goggles during particularly dry/dusty tasks; avoid contact lenses. Us e lubricants and emollients, e.g. aqueous eye drops, eye ointment overnight, petroleum jell y on lips, skin emollients, vaginal lubricants, and moisturizing hair conditioner. Carry wa ter to sip. Stimulate salivary \202 ow using sugar-free pastilles and/or chewing gum. Avo id excess alcohol intake and do not smoke. Dental care must include careful twice-daily bru shing of teeth and regular dental check-ups. The patient should be advised to use acid and sugar-free drinks and sugar- free sweets/gum. Biologic drugs \200 \200 Anti-TNFA treatments appeared promising following an open-label pilot study of in \202 ixi mab in pSS, but neither a larger (n = 103) DBPCRCT of in \202 iximab 5 mg/kg nor a DBPCRCT of etanercept in 14 patients showed signi \201 - cant improvement in objective or subject ive measures. CHAPTER 8 Autoimmune connective tissue diseases 261 American College of Rheumatology patient information. Available at: www.rheumatology.org/pu blic/ factsheets/sjogrens_new.asp?aud=pat Seek medical advice if oral, conjunctival, or vaginal infection (including thrush) is suspe cted. Seek medical advice if salivary or lymph glands become swollen. An aerobic exercise p rogram (e.g. swimming lengths or Nordic walking 3 times weekly) should be recom- mended to patients with fatigue. ICD-10 codes M35.0 H19.3 J99.1 G73.7 N16.4 Sj gren \200\231s syndrome keratoconjunctivitis and keratitis Respiratory disorder in diff use CTD Myopathy in CTD Renal tubulo-interstitial disorders in CTD Prognosis and natural history SS is a chronic condition but the majority of cases are mild. Overall, the standardized mortality ratio for SS is 1.15. However, patients with risk fac tors for lymphoma (see above) have a less favorable prognosis. References Barendregt PJ, van Den Meiracker AH, et al. Parasympathetic failure does not con tribute to ocular dryness in primary Sj gren \200\231s syndrome. Ann Rheum Dis 1999; 58: 7 46 \200\22350. SS patients with non-gastric MALT lymphoma have a 5-year survival of 90%, despite the fact that 30% of these are disseminated at diagnosis. D \200\231Arbonneau F, Ansart S, et al. Thyroid dysfunction in primary Sj gren \200\231s s yndrome: a long-term follow-up study. Arthritis Rheum 2003; 49: 804 \200\2239. Monitoring disease activity This is rarely performed in routine clinical practice but score s of disease activity have recently been developed for research purposes (see assessment to ols). Dawson LJ, Smith PM, et al. Sj gren \200\231s syndrome \200\223 time for a new approach. Rheumatol 2000; 39: 234 \200\2237. Eriksson P, Denneberg T, et al. Urolithiasis and distal renal tubular acidosis preceding pr imary Sj gren \200\231s syndrome: a retrospective study 5 \200\22353 years after the prese ntation of urolithiasis. J Intern Med 1996; 239: 483 \200\2238. Follow-up \200 Annual follow-up is acceptable for patients with pSS, with \211 1 risk factor for lymphoma . Six-monthly follow-up is recommended for patients with >1 risk factor for developing lymp homa. More frequent follow up will also be required following complications such as progres sive interstitial lung disease, or vasculitis. Fox RI, Dixon R, et al. Treatment of primary Sj gren \200\231s syndrome with hydroxychloro quine: a retrospective, open-label study. Lupus 1996; 5: S31 \200\2236. Gottenberg JE, Busson M, et al. In primary Sjogren \200\231s syndrome, HLA class II is asso ciated exclusively with autoantibody production and spreading of the autoimmune response. A rthritis Rheum 2003; 48:2240 \200\2235. Hansen A, Lipsky PE, Dorner T. New concepts in the pathogenesis of Sjogren syndrome: many q uestions, fewer answers. Curr Opin Rheumatol 2003;15:563 \200\22370. Current controversies \200 \200 Role of various putative autoantigens in the pathogenesis. Role for T and B cell immunosupp ression in manage- ment of SS. Assessment of activity, including de \201 nition ofappropri ate biomarkers of disease activity. Extent of association of SS with cardiovascular disease . Jonsson MV, Delaleu N, et al. Impaired salivary gland function in NOD mice: association wit h changes in cytokine pro \201 le but not with histopathologica changes in the salivary gl and. Arthritis Rheum 2006; 54: 2300 \200\2235. Klaeger AJ, Cevallos V, et al. Clinical application of a homogeneous colorimetric assay for tear lysozyme. Ocul Immunol In \202 amm 1999; 7: 7 \200\22315. Kruize AA, HeneRJ, et al. Hydroxychloroquine treatment for primary Sj gren \200\231s syndr ome: a two year double blind crossover trial. Ann Rheum Dis 1993; 52: 360 \200\2234. Resources Nordic walking information. Available at: http://en. wikipedia.org/wiki/Nordic_wa lking Lodde BM, Sankar V, et al. Serum lipid levels in Sj gren \200\231s syndrome. Rheumatology 2006; 45: 481 \200\2234. Assessment tools VAS: Visual analog scales for fatigue, sicca symptoms and pain. SCAI: SS C linical Activity Index. SSDAI: SS Disease Activity Index. PROFAD: Pro \201 le of fatigue a nd discomfort. SF-36: Short form 36. Luft LM, Barr SG, et al. Autoantibodies to tissue transglutaminase in Sj gren \200\231s sy ndrome and related rheumatic diseases. J Rheumatol 2003; 30: 2613 \200\2239. Mackay F, Groom JR, Tangye SG. An important role for B-cell activa- tion factor and B cells in the pathogenesis of Sjogren \200\231s syndrome. Curr Opin Rheumatol 2007; 19: 406 \200 \22313. Manoussakis MN, Boiu S, et al. Rates of in \201 ltration by macrophages and dendritic cell s and expression of interleukin-18 and inter- leukin-12 in the chronic in \202 ammatory le sions of Sj gren \200\231s syn- drome: correlation with certain features of immune hyperac tivity and factors associated with high risk of lymphoma development. Arthritis Rheum 2007; 56: 3977 \200\22388. Patient organizations British Sj gren \200\231s Syndrome Association. PO Box 10867, Birmin gham B16 0ZW. Tel (UK): 0121 455 6532. Email: of \201 ce@bssa.uk.net Sj gren \200\231s Sy ndrome Foundation. 6707 Democracy Boule- vard, Suite 325, Bethesda, MD 20817, USA. Tel (USA ) (toll free): (800) 475-6473. Mariette X, Ravaud P, et al. Inef \201 cacy of in \202 iximab in primary Sj gren \200 \231s syndrome: results of the randomized, controlled Trial of Remicade in Primary Sj gren \200\231s Syndrome (TRIPSS). Arthritis Rheum 2004; 50: 1270 \200\2236. Mavragani CP, Moutsopoulos NM, Moutsopoulos HM. The manage- ment of Sj gren \200\231s synd rome. Nat Clin Pract Rheumatol 2006; 2: 252 \200\22361 Internet sites British Sj gren \200\231s Syndrome Association. Available at: www. bssa.uk. nt Sj gren \200\231s Syndrome Foundation. Available at: http://www. sjogrens.com; Arthriti s Research Campaign patient information. Available at: www.arc.org.uk/arthinfo/patpubs/6041 /6041.asp Montano-Loza AJ, Crispin-Acuna JC, et al. Abnormal hepatic biochemistries and clinical live r disease in patients with primary Sj gren \200\231s syndrome. Ann Hepatol 2007; 6: 150 \200\2235. Nordmark G, Alm GV, R nnblom l. Mechanisms of disease: primary Sj gren \200\231s syndrome and the type I interferon system. Nat Clin Pract Rheumatol 2006; 2: 262 \200\2239. SJ \226GREN \200\231S SYNDROME 262 Skopouli FN, Jagiello P, et al. Methotrexate in primary Sj gren \200\231s Ono M, Takamura E, et al. Therapeutic effect of cevimeline on dry eye in patients with Sj gren \200\231s syndrome: a randomized, double- blind clinical study. Am J Ophthalmol 2004; 138: 6 \200\22317. syndrome. Clin Exp Rheumatol 1996; 14: 555 \200\2238. Str mbeck BE, Theander E, Jacobsson LT. Effects of exercise on aerobic capacity and fatigu e in women with primary Sj gren \200\231s syndrome. Rheumatol 2007; 46: 868 \200\22371. Patel YI, McHugh NJ. Apoptosis-new clues to the pathogenesis of Sjogren \200\231s syndrome? Rheumatol 2000; 39:119 \200\22321. Teppo H and Revonta M. A follow-up study of minimally invasive lip biopsy in the diagnosis of Sj gren \200\231s syndrome. Clin Rheumatol 2007; 26: 1099 \200\223103. Petrone D, Condemi JJ, et al. A double-blind, randomized, placebo- controlled study of cevi meline in Sj gren \200\231s syndrome patients with xerostomia and keratoconjunctivitis sic ca. Arthritis Rheum 2002; 46: 748 \200\22354. Tsubota K, Kaido M, et al. Diseases associated with ocular surface abnormalities: the impor tance of re \202 ex tearing. Br J Ophthalmol 1999; 83: 89 \200\22391. Pijpe J, Kalk WW, et al. Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary Sj gren \200\231s syndrome. Rheumatol 2007; 46: 335 \200\22341. Tzioufas A. Update on Sjogren \200\231s syndrome autoimmune epithelitis: from classi \201 cation to increased neoplasias. Best Pract Res Clin Rheumatol 2007; 21: 989 \200\2231010. Price EJ, Rigby SP, et al. A double blind placebo controlled trial of azathioprine in the t reatment of primary Sj gren \200\231s syndrome. J Rheumatol 1998; 25: 896 \200\2239. Valtysdottir ST, Gudbj rnsson B, et al. Psychological well-being in patients with primary Sj gren \200\231s syndrome. Clin Exp Rheumatol 2000; 18: 597 \200\223600. Priori R. Medda E, et al. Risk factors for Sj gren \200\231s syndrome: a case-control study. Clin Exp Rheumatol. 2007: 25: 378 \200\22384. van Woerkom JM, Kruize AA, et al. Safety and ef \201 cacy of le \202 uno- mide in primary Sj gren \200\231s syndrome: a phase II pilot study. Ann Rheum Dis 2007; 66: 1026 \200\223 32. Rosas J, Ramos-Casals M, et al. Usefulness of basal and pilocarpine- stimulated salivary fl ow in primary Sj gren \200\231s syndrome. Correlation with clinical, immunological and his tological features. Rheumatol 2002; 41: 670 \200\2235. Venables PJ. Sjogren \200\231s syndrome. Best Pract Res Clin Rheumatol 2004; 18: 313 \200\22329. Sankar V, Brennan MT, et al. Etanercept in Sj gren \200\231s syndrome: a twelve-week rando mized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum 2004; 50: 224 0 \200\2235. Vitali C, Bombardieri S, et al. Classi \201 cation criteria for Sjogren \200\231s syndrome : a revised version of the European criteria proposed by the American-European Consensus Gr oup. Ann Rheum Dis 2002; 61: 554 \200\2238. Seror R, Sordet C, et al. Tolerance and ef \201 cacy of rituximab and changes in serum B c ell biomarkers in patients with systemic complications of primary Sj gren \200\231s syndro me. Ann Rheum Dis 2007; 66: 351 \200\2237. Wu Ch, Hsieh SC, et al. Pilocarpine hydrochloride for the treatment of xerostomia in patien ts with Sj gren \200\231s syndrome in Taiwan \200\223 a double-blind, placebo-controlled trial. J Formos Med Assoc 2006; 105: 796 \200\223803. Ship JA, Fox PC, et al. Treatment of primary Sj gren \200\231s syndrome with low-dose natu ral interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group. J Interferon and Cytok Res 1999; 19: 943 \200\22351. This page intentionally left blank SYSTEMIC SCLEROSIS 264 Systemic sclerosis De \201 nition Systemic sclerosis (SSc) is a multisystem autoimmune dis- ease characterize d by widespread microvascular disease, tissue in \201 ltration of mononuclear cells and ex cessive depo- sition of extracellular matrix material, particularly collagen. HLA associations are weak with SSc overall but anti- centromere antibodies are associated w ith HLA-DQB1 alleles, and anti-Scl70 antibodies with an HLA-DQB1 and an HLA-DRw11 allele. The 1988 LeRoy classi \201 cation of SSc Diffuse cutaneous systemic sclerosis (dcSSc) 33% \200 Classi \201 cation Several classi \201 cation criteria have been established through the years for SSc. In 1980 the American College of Rheu- matology (ACR) published consensus cri teria for the diag- nosis and classi \201 cation of SSc. This classi \201 cation is based on the presence one major criterion (sclerosis of the skin proximal to the metacarpophalan geal joints) and two of the three minor criteria (digital pitting scars, sclerodactyly and bilateral pulmonary \201 brosis) to establish the diagnosis. \200 These criteria requir e the presence of established disease and do not utilize serological information. The most widely used classification is the Le Roy classi \201 cation of 1988, which divides SSc int o limited and diffuse cutaneous systemic sclerosis \200\223 lcSSc and dcSSc respectively. Roy and Medsger have also proposed a limited SSc category; this will include patients with early SSc, but may also capture patients with autoimmune Raynaud \200\231s phenomenon, who do not progress to classical SSc. Skin sclerosis extending proximal to the elbow and truncal. Prominent pruritis and constitu tional symptoms. Renal, pulmonary (secondary pulmonary arterial hypertension), cardiac and GI involvement. Raynaud \200\231s often develops after other features. Tendon friction rubs . Disease activity stable over many years. \200 \200 \200 Limited cutaneous systemic sclerosis (lcSSc) 60% (previously CREST: Calcinosis, Raynaud \200\231s Esophageal dysmotility, Sclerodacytly and Telangectasias) \200 \200 Raynaud \200\231s precedes other features. Skin involvement restricted \200\223 hands, fac e, forearms and feet. Pulmonary arterial hypertension. Telangiectasiae. Calcinosis. Severe gut disease. Interstitial lung disease (association with anti-SScl-70). Disease progressive in \201 rst few years then often stabilizes. Associated with anti-centromere antibodies (ACA). \200 \200 \200 \200 \200 Epidemiology SSc occurs more frequently in women, with a female: male ratio of 3:1. Peak ag e of onset is between 30 and 50 years. The UK prevalence is 120 per million with an annual inci- dence 4 per million per year. Although there is no racial predilection, the disease may occur more often and most severely in young black women. \200 Limited systemic sclerosis \200 \200 \200 Many environmental agents have been associated with the occurrence of SSc including silica, organic chemicals, e.g. paraf \201 n, vinyl chloride, resin, and toxic oils and drugs, in cluding appetite suppressants, bleomycin, hydroxytryp- tophan, carbidopa, bleomycin, and co caine. It has been suggested that silicone breast implants may contribute to the developmen t of SSc, but a recent large case-control study and meta-analyzes do not support an associa tion. Familial clustering may occur and a positive family history is the strongest risk fac tor identi \201 ed for SSc and the recurrence rate for \201 rst-degree relatives ( r) i s 54. However, the absolute risk for each \201 rst degree relative is less than 1%. High titres of ANA were present in \201 rst- degree relatives of patients with SSc. The highes t prevalence of SSc has been demonstrated in a genetically isolated population of Choctaw A merican Indians. In this population, SSc is strongly associated with a polymorphism in the 5 \200\231-untranslated region of the FBN1 gene. Association studies in other populations h ave indicated that polymorphism in the genes encoding type I collagen A2 chain (COL1A2) and transforming growth factor (TGF)-B may predispose to SSc. Emerging genetic associations wi th interstitial lung disease (e.g. \201 bronectin) and with microvascular disease (e.g. b one morphogenetic protein receptor II with pri- mary pulmonary hypertension and activin-rec eptor-like kinase with hereditary haemorrhagic telangiectasiae) warrant further exploration in SSc. Raynaud \200\231s phenomenon (RP). Abnormal nail-fold capillaroscopy. SSc-selective antibod ies (ACA, anti-Scl-70, anti-RNA polymerase I/III). Diagnosis based on objective documentation of Raynaud \200\231s and one other criterion OR subjective documentation of Raynaud \200\231s and BOTH other criteria. Systemic sclerosis sine scleroderma <2% \200 \200 \200 Raynaud \200\231s phenomenon visceral manifestations. SSc-selective antibodies. No skin inv olvement. Etiology and pathophysiology SSc is a chronic auto-in \202 ammatory syndrome, in which abe rrant behavior of both innate and adaptive elements of the immune system is evident. Endoth elial cell dysfunc- tion and damage is prominent. Microvascular damage with vasospasm and v essel dropout, and excessive deposition of extracellular matrix tissue lead to the main cli nical manifes- tations of disease. Aberrant innate and adaptive immune responses An aberrant immune response in SSc is most ob vious in the \202 orid cutaneous in \202 ammatory in \201 ltrate, which often accompani es early dcSSc. \200 The mononuclear in \201 ltrate consists of T cells (mainly CD4+), macrophages, natural kil ler cells, mast cells and, rarely, B cells. CHAPTER 8 Autoimmune connective tissue diseases 265 Oligoclonal expansion of CD4+ T cells in SSc skin lesions has been shown, suggesting local antigen-dependent T cell activation. Activated CD4+ T cells produce IL-4, IL-17 and TGF-B, which stimulate endothelial cells to express HLA and adhesion molecules, promotes PDGF rele ase, \201 broblast proliferation, and CTGF secretion, which promotes synthesis of collage n. In \202 ammatory cells (neutrophils, eosinophils, and lym- phocytes) are also present i n the bronchoalveolar lavage \202 uid of SSc patients with interstitial lung disease. As cutaneous fibrosis progresses, the inflammatory in \201 ltrate recedes, and a similar tran sition may occur in other tissues. It has been noted that graft-versus-host disease often r esembles SSc and it has been hypothesized that microchimerism \200\223 persistence of allo reactive cells either from maternal blood at birth or from fetal blood at parturition \200 \223 may drive the chronic (allo)immune response which manifests as SSc. Although B cells a re scarce in skin in \201 ltrates, an abnormal humoural response is well recognized by vir tue of the characteristic autoantibodies associated with SSc (e.g. anti- centromere, anti-S cl70, and anti RNA polymerase I/III). The role of autoantibodies in pathophysiology is unce r- tain, but anti-endothelial antibodies may mediate endothelial damage and anti- \201 bro blast antibodies may contribute to synthesis of matrix constituents. vascular smooth muscle cells of the tunica media (Figure 8.5). Endocrine, paracrine, autocr ine, and neuronal stimuli enable the resistance vessels to respond both to local (ischaemia /in \202 ammation) and systemic (e.g. maintenance of blood pressure) needs. \200 Dysregulation of vasomotor tone in SSc may re \202 ect intrinsic abnormalities of endothel ial cells or vascular smooth muscle cells, aberrant production of local soluble mediators ( e.g. from endothelial cells, platelets, or leucocytes), or neuroendocrine abnormalities. Ab normalities suggested in SSc-associated RP include: \200 endothelial cell damage, e.g. by infection, anti-endothelial antibodies, cytotoxic T cells, free radicals; increased contractile response to sudden cooling and to A2-adrenergic agoni sts; this appears to be mediated by the A2c-adrenoceptors and is associated with increased activity of protein tyrosine kinase; increased levels of endothelin and/or increased densit y of endothelin receptors; reduction of calcitonin gene-related peptide (CGRP) release from sensory afferent nerve endings (possibly related to ischaemic tissue damage); aberrant act ivation of platelets and/or coagulation cascade; oxidative stress probably contributes to e ndothelial cell damage; release of vasomotor mediators from mononuclear cells (e.g. mast ce lls) in underlying tissue. Endothelial dysfunction and microvascular disease Vascular tone is determined by the balanc e between vasoconstrictive and vasodilatory stimuli received by the Abnormal vasomotor responses are evident early in the pathophysiology of SSc. Hypotension (sensed by juxtaglomerular) VSMCs in kidney) Inflammation Adrenal medulla Shear stress to endothelium Platelets Bradykinin Norepinephrine Angiotensin II Thromboxane A2 Blood Endothelin Serotonin Depletion of ATP in tissues Endothelium Endothelial damage or exposure to toxins eNOS Adenosine Prostacyclin Nitric Oxide Vascular Smooth Muscle Cell VASOCONSTRICTION VASODILATION Calcitonin Gene-Related Peptide Histamine Adenosine Acetylcholine Norepinephrine Mast Cells Parasympathetic nerves Sympathetic nerves Sensory Afferent Nerves Figure 8.5 Factors in \202 uencing vasomotor tone. SYSTEMIC SCLEROSIS 266 Clinical features Raynaud \200\231s phenomenon RP is the initial symptom in more than 90% o f SSc cases. Transient vasospasm leads to classic color changes in the digits: white (ischa emia), blue (cyanosis), and red (reperfu- sion). This is usually triggered by the cold, smo king, or emotional stress. RP usually affects digits, but it can also affect other areas in cluding the tip of the nose, ear lobes, tongue and patellae (see Plate 5). \200 