Sjögren’s syndrome is an autoimmune connective tissue disease characterized by dryness of the eyes and mouth and lymphocytic infiltrates in the salivary, lachrymal, and other exocrine glands. Its cause is not known, but the condition may be primary, where the disease exists on its own, or secondary, where it is associated with other rheumatic diseases, most commonly rheumatoid arthritis. It affects women more than men (ratio 9:1) and is the second commonest autoimmune rheumatic disease (after rheumatoid arthritis), but in many patients remains undiagnosed because symptoms are usually mild.
Clinical features—presentation is typically with a gritty sensation in the eyes (or other ocular symptoms) and dryness of the mouth. Constitutional symptoms such as fatigue are common. Other systemic manifestations include Raynaud’s phenomenon, purpura, arthralgia/arthritis, pleurisy, peripheral neuropathy, myelopathy, interstitial nephritis, and lymphoma.
Investigation and diagnosis—laboratory testing reveals raised immunoglobulin levels, rheumatoid factors of all isotypes (70% of cases), and autoantibodies against the cellular ribonucleoprotein antigens Ro (50–90%) and La (30–50%). Diagnosis should be based on the American/European Consensus criteria, which require the presence of four of the following six criteria: (1) ocular symptoms, (2) oral symptoms, (3) ocular signs, (4) oral signs, (5) positive labial biopsy, and (6) antibodies to Ro- and/or La (one or other of conditions 5 or 6 must be present).
Management—for most patients treatment is topical and symptomatic, with tear and saliva substitutes. Fatigue and arthralgia respond to hydroxychloroquine. Serious systemic complications are treated with steroids and cytotoxic drugs. There is increasing interest in the use of immunodulatory drugs, which may have potential to improve long-term outcomes.
Sjögren’s syndrome was originally described in 1933 as a triad of dry eyes, dry mouth, and inflammatory arthritis. It gained prominence as a rheumatic disease in 1966 with classification of primary and secondary Sjögren’s syndrome. Its autoimmune nature was established in the 1970s when the autoantibodies to Ro and La were first described, although it was not until the 1990s that routine serological tests for these antibodies became widely available. A number of diagnostic criteria have been proposed over many years, but only the Consensus criteria of 2002 have attained widespread acceptance. Thus Sjögren’s syndrome is a relatively ‘new’ disease in rheumatology, and is only recently being appreciated as a common multisystem disease that may present to other specialties.
Aetiology and pathology
The aetiology of Sjögren’s syndrome is unknown, but is often considered to be an interaction between constitutional and environmental factors leading to autoimmunity. Primary Sjögren’s syndrome is strongly associated with HLA DR3, and the linked genes B8, DQ2, and the C4A null gene. Candidates for triggering autoimmunity in Sjögren’s syndrome are viruses that infect the salivary glands—including Epstein–Barr virus, cytomegalovirus, and human herpesvirus 6—all of which have been linked with the condition in some reports but not others. Retroviruses have also attracted interest because they infect and persist in cells of the immune system such as T cells and macrophages, and infect salivary gland epithelium, and Coxsackie viral sequences have been detected in salivary gland biopsies from Greek patients with Sjögren’s syndrome, but these findings were not confirmed in a study from France. Thus, although viruses remain attractive candidates for a pathogenic role in Sjögren’s syndrome, no particular agent has been consistently identified in independent studies.
The cardinal pathological features of Sjögren’s syndrome are inflammation and destruction of salivary gland tissue. The inflammatory infiltrates consist of focal aggregates of lymphocytes, mainly CD4+ T cells, localized around ducts and acini. Scattered interstitial plasma cells are commonly found, although these are not disease specific and are also found in glands from healthy individuals. The destructive changes are predominantly duct dilatation, acinal atrophy, and interstitial fibrosis. However, these last findings have also been described in biopsies from people without Sjögren’s syndrome, particularly in elderly people, and cannot be regarded as diagnostically specific. Furthermore, the fall in saliva production pre-dates glandular destruction in patients with Sjogren’s syndrome.
The most striking feature of the systemic autoimmune response in Sjögren’s syndrome is the marked activation of B cells which can lead to immunoglobulin levels of over three times the upper limit of the normal range. Rheumatoid factors of all isotypes are observed in blood in about 70% of patients, and their detection can lead to some patients with Sjögren’s syndrome being misdiagnosed as having rheumatoid arthritis. The typical autoantibodies are those against the cellular ribonucleoprotein antigens Ro and La, named after the patients in whom the antibodies were originally described. Anti-Ro antibodies are more frequently detectable (50–90% of cases) than anti-La antibodies (30–50% of cases), but the latter are more diagnostically specific for primary Sjögren’s syndrome. Two further potential autoantigens have also been described: fodrin, which is a cellular protein involved in apoptosis, and the muscarinic acetylcholine receptor M3, which is important in mediating parasympathetic stimulation of exocrine glands. A high degree of diagnostic sensitivity and specificity has been claimed for serum antibodies to both antigens in Sjögren’s syndrome, but neither autoantibody system has yet been adopted for routine clinical use. A subset of patients with Sjögren’s syndrome develop organized groups of cells known as ectopic lymphoid structures (ELS) or germinal centres (GC) in the salivary gland. Recent evidence suggests that this subset are at increased risk of development of B-cell lymphoma.
Sjögren’s syndrome is nine times more common in women than in men and can develop at any age from 15 to 65. Recent epidemiological studies based on the 2002 Consensus criteria suggest a prevalence of 0.1 to 0.7% of the population, indicating that it is the second most common autoimmune rheumatic disease after rheumatoid arthritis, which affects 0.8 to 1%.
Patients with Sjögren’s syndrome rarely complain of dry eyes, but rather a gritty sensation, soreness, photosensitivity, or intolerance of contact lenses. Excessive watering or deposits of dried mucus in the corner of the eye and recurrent attacks of conjunctivitis may occur in early disease. The dry mouth often manifests as inability to swallow dry food without fluid, or waking up in the night to take sips of water. About half of those affected with the condition complain of intermittent or persistent parotid swelling, which when excessively painful is sometimes due to secondary bacterial infection. On examination, xerostomia can be detected as a diminished salivary pool, a dried fissured tongue, often complicated by angular stomatitis, and chronic oral candidiasis. The eyes may be reddened and roughened due to shallow erosions in the conjunctivae. Very occasionally the front of the eye is eroded to reveal strands of underlying collagen, leading to the appearance of filamentary keratitis.
Other exocrine glands may be affected. Dry nasal passages and upper airways may lead to recurrent bouts of sinusitis, a dry cough, and (possibly) a higher than expected frequency of chest infections. Dry skin and dry hair are symptoms frequently elicited on direct questioning. About 70% of women with Sjögren’s syndrome have diminished vaginal secretions and may present with dyspareunia. Involvement of the gastrointestinal tract leads to reflux oesophagitis or gastritis due to lack of protective mucus secretion, and some patients complain of constipation, which may be attributed to defective mucus in the colon and rectum. Rarely, pancreatic failure leading to a malabsorption syndrome may occur.
Recent studies have highlighted yet another complication, namely interstitial cystitis. It has been suggested that this is due to an autoimmune response to the muscarinic acetylcholine receptor which is extensively expressed in the bladder wall. There is no doubt about the clinical association, but the serological link awaits confirmation.
There is a higher than expected frequency of thyroid autoimmunity in those with Sjögren’s syndrome; whether this is part of the same pathological process is debatable, but it is important to check thyroid function from time to time in patients with this condition.
Sjögren’s syndrome is a systemic disease: two-thirds of patients complain of fatigue, which can be both physical and mental, and according to several epidemiological studies is the single most important cause of disability. Occasionally weight loss and fever mimicking an occult malignancy may be the presenting symptoms, particularly in elderly people, in whom symptoms can be suggestive of polymyalgia rheumatica.
Raynaud’s phenomenon occurs in about 50% of patients. Hypergammaglobulinaemic purpura affecting the lower legs is found in patients with very high IgG levels, but true vasculitis is uncommon. Other features include an arthritis that resembles the Jaccoud-like arthritis of systemic lupus erythematosus (Fig. 220.127.116.11). Polymyositis is a rare presentation.
Pleurisy occurs in about 40% of patients; abnormalities of pulmonary function are frequently described, but are rarely clinically significant.
A wide range of neurological presentations is recognized. Peripheral neuropathies are relatively common, an important but unusual type being mononeuritis multiplex mediated by vasculitis. Central nervous system (CNS) involvement can resemble multiple sclerosis, with a myelopathy leading to paraparesis being particularly characteristic and often termed ‘Sjögren’s syndrome myelopathy’. Although rare, occurring in less than 1% cases of Sjögren’s syndrome, it is important to recognize the condition because it responds well to treatment with steroids and cyclophosphamide.
Interstitial nephritis leading to renal tubular acidosis or nephrogenic diabetes insipidus occurs in about 30% of patients; these are usually subclinical but may lead to hypokalaemia, causing muscular weakness or (occasionally) nephrocalcinosis.
Lymphoma, almost always of B-cell lineage, is a characteristic but unusual feature. This occurs in about 5% of patients referred to specialist centres and is particularly likely in patients with high levels of immunoglobulins, autoantibodies, and cryoglobulins.
Women of child-bearing age are at increased risk of giving birth to babies with congenital heart block. Although rare, about 1 in 20 000 births, this complication is of great immunopathogenic interest as it is thought that damage to the developing conduction system is mediated by transplacental transfer of anti-Ro and anti-La antibodies.
In secondary Sjögren’s syndrome the sicca symptoms are less severe than in primary disease. In rheumatoid arthritis with Sjögren’s syndrome the patient tends to have more frequent extra-articular disease manifested as digital infarcts and subcutaneous ulcers. There is a suggestion that secondary Sjögren’s is becoming less prevalent with earlier and more effective treatment of the underlying rheumatoid arthritis. In systemic lupus erythematosus, those with Sjögren’s syndrome have a lower frequency of renal disease and a relatively good prognosis.
Keratoconjunctivitis sicca can be detected by Schirmer’s test, tear break-up time, and rose Bengal staining, and xerostomia by a reduced parotid salivary flow rate and reduced uptake and clearance on isotope scans. There is increasing interest in the use of noninvasive ultrasound and MRI in the diagnosis of the condition. However, it is important to remember that both salivary and lacrimal function decline with age and may be impaired in conditions other than Sjögren’s syndrome. One cause of diagnostic confusion arises from treatment with drugs with anticholinergic side effects, the most frequent being the tricyclic antidepressants.
Biopsy and histology of the labial glands from behind the lower lip provides the most definitive diagnostic test. The area is anaesthetized with lidocaine containing adrenaline and an incision 1.5 cm long allows access to five to ten glands 2 to 4 mm in diameter that are removed by simple blunt dissection. A diagnosis of Sjögren’s syndrome depends on finding foci of periductular infiltrates of at least 50 lymphocytes and/or plasma cells at a density of more than one focus/4 mm2 (Fig. 18.104.22.168).
Most patients have a raised erythrocyte sedimentation rate (ESR) and a mild normocytic anaemia, with leucopenia in about 50% of cases. One of the most remarkable features of primary Sjögren’s syndrome is a high level of IgG, which can be up to 50 g/litre. Complement levels are usually normal, although C4 levels can sometimes be reduced because of the link between Sjögren’s syndrome and the C4A null gene. Anti-Ro and/or -La antibodies are found in 60% of patients with primary Sjögren’s syndrome and form part of the diagnostic criteria.
Rheumatoid factors, as measured by routine assays, occur in all forms of Sjögren’s syndrome and their detection in primary disease is a common reason for misdiagnosing such patients as having rheumatoid arthritis. Antinuclear antibodies can also occur. Both rheumatoid factors and antinuclear antibodies, although not diagnostically specific, can help in distinguishing Sjögren’s syndrome from nonautoimmune causes of sicca symptoms. Primary Sjögren’s syndrome can be mimicked very closely by infection with HTLV-I (human T-lymphocytic virus I), HIV-1, and hepatitis C virus. All three diseases cause dry eyes and mouth, swelling of salivary glands, and biopsy changes very similar to those of primary Sjögren’s syndrome. All are associated with hypergammaglobuli naemia, a raised ESR, and autoantibodies, although anti-Ro and anti-La are unusual. The only way to differentiate them with certainty is by specific serological testing. The Sjögren-like syndrome associated with HIV infection has been termed ‘diffuse infiltrative lymphocytosis syndrome’ and occurs in about 5% of HIV-positive individuals. Chronic fatigue syndrome is frequently mistaken for Sjögren’s syndrome and vice versa (less frequently); a salivary gland biopsy usually clarifies the situation.
Diagnostic criteria are essential for the standardization of any research involving patient groups, particularly with a disease, or group of diseases, as heterogeneous as Sjögren’s syndrome. In the case of Sjögren’s syndrome such criteria are also useful in clinical practice. Currently used criteria depend on the demonstration of keratoconjunctivitis sicca, xerostomia, and a positive labial gland biopsy. The previously widely used 1993 ‘European’ criteria, based on the results of a multicentre European study, have now been supplanted by the 2002 American/European Consensus criteria (Box 22.214.171.124). These are based on a short questionnaire about ocular and oral symptoms, with other criteria being ocular signs (by Schirmer’s test or rose Bengal staining), lymphocytic infiltrates on lip biopsy, salivary gland involvement (decreased salivary flow rate), and demonstration of serum Ro or La antibodies. Importantly, unlike the previous European criteria, these Consensus criteria must include either a positive biopsy or the presence of anti-Ro and/or anti-La antibodies.
Annals of Rheumatic diseases (2002) 61, 554–8. Reproduced with permission from the BMJ Publishing Group.
Most treatment in Sjögren’s syndrome is topical and symptomatic. Simple measures can help preserve the integrity of the cornea as well as the gums and teeth, and are worth pursuing with enthusiasm. Tear substitutes are the mainstay of treatment for dry eyes. In general, patients are advised to start with simple, less viscous preparations such as hypromellose, before moving on to more viscous drops such as carbomers, carmellos, and the newer sodium hyaluronate based preparations. They should be advised to use preservative-free preparations. Where thick mucus strands are a particular problem, topical acetylcysteine eye drops may help. Eye ointments, particularly at night, can help lubricate sticky eyes. Blepharitis is a common problem and can be treated with warm compresses and lid hygiene using a weak solution of baby shampoo. Bacterial infection should be treated immediately with chloramphenicol ointment or drops. The use of ciclosporin-containing eye drops has been shown to be helpful in those with ongoing corneal inflammation. Wearing spectacles reduces tear evaporation by up to 30%, and further benefit can be achieved by adding side panels to the frames. Temporary or permanent occlusion of the canaliculi or (rarely) tarsorrhaphy may help to retain tears within the conjunctival sac.
The dry mouth is best managed by drinking water regularly, and saliva substitutes—especially the gels—may provide symptomatic relief. Oral pilocarpine has been shown to improve salivary flow rates in those with residual glandular function and reduce rates of dental decay and candidal infection, but cholinergic side effects such as palpitations, sweating, and abdominal cramps may limit its use. Candidal infections are extremely common in Sjögren’s syndrome and are often missed: they are best treated with prolonged courses of drugs such as fluconazole 50 mg daily for 10 days. Attention to dental hygiene may help to prevent the premature caries that is a common problem.
Hydroxychloroquine modifies antigen presentation and studies confirm that it lowers the ESR and immunoglobulin levels, which may prevent bouts of purpura. Clinical observation suggests it improves fatigue, arthralgia, and arthritis. Fever, weight loss, parotid swelling, and interstitial cystitis often respond well to a low dose of steroids, although steroids are not recommended for longer-term use because of the potential for side effects. There is no convincing evidence that methotrexate has any useful role in management, and it is generally agreed that other second-line agents for rheumatoid arthritis such as gold or sulfasalazine are associated with a high frequency of side effects, which is one of the most important reasons for distinguishing between the arthritis of primary Sjögren’s syndrome and that of rheumatoid arthritis. Two published controlled trials of tumour necrosis factor (TNF)-α inhibitors have not shown benefit, which is perhaps not surprising because there is little evidence that TNFα is involved in the pathogenesis of glandular inflammation. Serious systemic complications such as polymyositis, mononeuritis multiplex, or fibrosing alveolitis are treated with steroids and cytotoxic drugs. There is increasing interest in the use of immunomodulation and its potential benefit in early disease, with anecdotal reports of the benefits of rituximab (anti-B-cell therapy) such that the results of current placebo-controlled studies are awaited with interest.
Sjögren’s syndrome causes morbidity rather than mortality, with a few epidemiological studies suggesting that life expectancy is normal. Clinical experience suggests that the disease tends to remain relatively stable, unlike the catastrophic and unpredictable flares that characterize (for example) systemic lupus erythematosus. The main long-term complication that needs to be anticipated is lymphoma: several studies have shown that those with anti-Ro and anti-La antibodies, hypergammaglobulinaemia, hypocomplementaemia, and vasculitis are at highest risk, so such patients should be followed up on an annual basis in a specialized clinic. However, the relatively rare and potentially life-threatening complications such as lymphoma or CNS involvement appear to respond well to treatment.
Likely future developments
Polyclonal B-cell activation is a prominent feature of the disease. Trials of anti-CD20 (rituximab) are currently in progress, and trials involving monoclonal antibodies directed to other B-cell markers are now in the planning phase. Type 1 interferons are also thought to be important in Sjögren’s syndrome and it has been suggested that inhibition of interferon-α might suppress exocrine inflammation, although paradoxically the use of low-dose interferon-α pastilles has been reported to increase salivary flow rate. One problem to be anticipated with such therapies is whether the cost of biologic agents can be justified for the treatment of what is usually a relatively mild disease.
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