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| CECIL |
| TEXT BOOK of MEDICINE |
Section XXII Rheumatic Disease
| 289 SJÖGREN'S SYNDROME Stanley Naguwa • M. Eric Gershwin • |
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Definition
Sjögren's syndrome (SS) is an autoimmune disease characterized by immune-mediated destruction of exocrine glands, particularly salivary and lacrimal glands, with secondary development of keratoconjunctivitis and xerostomia. Primary and secondary forms of SS have been defined. Primary SS occurs in the absence of a connective tissue disease; secondary SS occurs most commonly in association with a systemic connective tissue disorder, particularly rheumatoid arthritis but also systemic sclerosis, systemic lupus erythematosus, and polymyositis.
Epidemiology
SS was first described in detail in 1933, but in fact there is an earlier description in 1892, termed Mikulicz's syndrome. For more than three decades after the 1933 description, SS was considered a relatively uncommon diagnosis of older women. However, more recent data, obtained by use of standardized criteria, suggest that SS may affect 0.5 to 2% of women. The incidence of SS increases with age, and SS is virtually absent in children. Nearly 2% of women older than 60 years have features of primary SS, particularly dry eyes and dry mouth. Other exocrine glands also can be affected with subsequent development of pancreatic dysfunction, vaginal dryness, and dry cough. SS occurs in 10 to 25% of patients with systemic lupus erythematosus (Chapter 287) and 30 to 50% of patients with rheumatoid arthritis (Chapter 285).
Pathobiology
Multiple viral agents have been incriminated as etiologic factors for either the development or modulation of SS; these include Epstein-Barr virus, retroviruses, and coxsackieviruses, but in all cases, the data remain controversial. SS does have a strong immunogenetic basis, however, and it was one of the first autoimmune diseases associated with specific major histocompatibility complex genes. Several genetic alleles have been described to occur more commonly in patients with SS, particularly human leukocyte antigen (HLA) class II antigens. As with other autoimmune diseases, the specific HLA gene association varies according to the ethnic background of the individual. The responsible mechanisms are unknown, and more extensive studies are required to map class II genes precisely, particularly in the DQB1 first hypervariable region.
The significance of anti-Ro and -La antibodies in SS is speculative. These antibodies are found deposited in the salivary glands of affected patients. The Ro proteins colocalize to the blebs of apoptotic cells and may become an immune target or function as a primary immunogen. Nonetheless, serum levels of antibodies to Ro and La do not correlate with disease activity. A pathologic role of anti-Ro antibodies has been described because their passive transfer in pregnancy leads to neonatal congenital heart block. In fetuses of mothers with anti-Ro antibodies and heart block, therapy with dexamethasone, which readily passes the placenta, is preferred to prednisone.
Clinical Manifestations
The differential diagnosis of xerophthalmia (dry eyes) and xerostomia (dry mouth) is noted in Table 289-1; presentation is most common in women in their 30s to 50s. Dry mouth leads to difficulty in swallowing, recurrent dental infections, pain on eating salty or spicy foods, and difficulty in talking. In many patients, impairment of fluid secretion within the nasal and throat passage predisposes to oral thrush. Dry eyes result in complaints of ocular itching, a sense of grittiness, and an exaggerated sensitivity to ocular insults such as smoke. Other upper and lower respiratory symptoms also are secondary to dryness and include a nonproductive cough and occasionally tracheobronchitis.
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Classically, SS is manifested by a painless enlargement of salivary glands, generally beginning unilaterally. This enlargement may be dramatic and cyclic in nature and is generally absent in patients with coincidental rheumatoid arthritis. The symptoms of SS develop insidiously, and often the diagnosis is not considered for several years because the complaints of sicca are attributed to medications (e.g., antihistamines, antidepressants), a dry environment, or aging. The neurologic components of SS include peripheral and cranial neuropathies and a multiple sclerosis “look-alike” central nervous system disease. Skin manifestations include palpable or nonpalpable purpura, papules, urticarial lesions, and annular lesions. Xerosis is frequently found on examination. A nonerosive arthritis, polyarthralgia, and Raynaud's phenomena are typically seen in SS. In addition to tracheobronchitis, lung involvement in SS may include bronchiectasis, interstitial pneumonitis, and fibrosis. Smoking is an additional major risk factor for pulmonary disease in patients with SS. Renal involvement may include interstitial nephritis, renal tubular acidosis, and hyposthenuria with glomerulonephritis, a more recently recognized problem. Autoimmune liver disease and pancreatitis are seen occasionally.
The classic exocrine symptoms of SS are listed in Table 289-2, but SS theoretically can affect all major organ systems (Table 289-3). Patients initially may present only with extraglandular symptoms, especially a nonerosive rheumatoid factor–positive arthritis. In addition, as a component of the inflammatory process and proinflammatory cytokine release, patients may manifest chronic fatigue and low-grade fevers. Finally, B-cell lymphoma has been described as a secondary event in SS. The incidence of lymphoma in SS varies among studies and may depend on local referral patterns (selection bias); lymphoma develops in approximately 5% of patients.
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Laboratory Findings
The most commonly used test for the diagnosis of SS is Schirmer's test, performed without anesthetic eye drops, measuring the wetting of standardized tear test strips that are applied between the eyeball and the lateral inferior lid. Salivary flow and labial salivary biopsy are also commonly used for diagnosis. Patients with SS have antinuclear antibodies of either homogeneous or speckled patterns (80 to 90% frequency), antibodies to Ro (SSA; 60 to 75% frequency) and La (SSB; 40% frequency), presence of rheumatoid factor (70 to 90% frequency), mixed cryoglobulin with rheumatoid factor activity (type II; <5%), and antibodies to centromere (<5%). The presence of mixed cryoglobulinemia suggests hepatitis C infection; these complexes contain rheumatoid factor, hepatitis C antigen, and complement. Antibodies to mitochondria likewise have been described in SS but are found reliably only in patients with coexistent primary biliary cirrhosis. It has been reported that patients with SS develop antibodies to three new autoantigens called IFI16, KLHL12, and KLHL7. These autoantigens represent a family of transcription regulators; KLHL12 and KLHL7 are kelch-like proteins of unknown physiologic function. Although diagnostic tests for these autoantigens are not widely available, we believe they will become important biomarkers for the clinical diagnosis of SS.
Patients with SS exhibit a dramatic polyclonal B-cell activation. Several other autoantibodies have been described with variable frequencies, including antibodies to carbonic anhydrase, α-fodrin, proteosomal subunits, and the muscarinic M3 receptor; the last-mentioned protein is found on salivary glands and may explain glandular dysfunction in SS. There also is evidence for altered B-cell differentiation. An SS-like disorder develops in mice transgenic for BAFF (a member of the tumor necrosis factor-α superfamily that regulates B-cell proliferation). Anemia (including autoimmune hemolytic anemia), leukopenia, and thrombocytopenia occur in SS and are most commonly found in patients with chronic disease.
The serious immune system abnormalities in SS include lymphadenopathy, pseudolymphoma, and lymphoma. The transition from a rheumatoid factor–positive, polyclonal gammopathy to a rheumatoid factor–negative, oligoclonal or monoclonal gammopathy augurs a change from a benign to a malignant process. This process can be enhanced if the VK3b-related and the G6 (VH1-related) idiotypes are present. On histologic examination, the intense lymphoid infiltration includes germinal centers in the exocrine glands; the intense lymphocytic infiltrate is predominantly CD4+ T-cell TCRαβ CD45RO cells. Finally, the degree of inflammation seems to be associated with a TH1 response with striking production of interferon-γ, interleukin-2, and interleukin-10. The development of severe histologic changes may be a prodrome of lymphoma. The migration of mononuclear cells to exocrine glands is mediated by chemokines and their cognate receptors, particularly macrophage inflammatory protein 1 (MIP-1) and RANTES.
Diagnosis
Diagnostic Criteria
The diagnostic criteria of SS continue to evolve, but revised American-European classification criteria are currently employed (Table 289-4 and Fig. 289-1). These criteria cannot be employed if the patient has compounding medical problems including preexisting lymphoma, acquired immunodeficiency syndrome, sarcoidosis, graft-versus-host disease, past head and neck irradiation, use of anticholinergic drugs, and hepatitis C, diseases commonly included in the differential diagnosis. A Sjögren's-like disorder is associated with graft-versus-host disease and diffuse infiltrative lymphocytosis syndrome. The diagnosis of graft-versus-host disease is clinically obvious on the basis of the history. Diffuse infiltrative lymphocytosis syndrome occurs more commonly in males in the absence of the unique autoantibody profile of SS. The classification criteria are helpful in distinguishing between SS and sicca syndrome secondary to medications. An abnormal finding on lip biopsy and the presence of autoantibodies suggest a systemic autoimmune disease. SS is more commonly associated with several other autoimmune diseases including Hashimoto's thyroiditis, primary biliary cirrhosis, chronic active hepatitis, celiac sprue, myasthenia gravis, and pernicious anemia.
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| FIGURE 289-1 Algorithm for the diagnosis of Sjögren's syndrome. (From Tzioufas AG, Moutsopoulos HM: Sjögren's syndromes. In Klippel JH, Dieppe, PA [eds]: Rheumatology, 2nd ed. London, Mosby, 1998, with permission.) |
Treatment
The primary treatment of SS is to minimize discomfort by use of substitutes for the dysfunctional exocrine secretions (e.g., artificial tears, artificial saliva, increased oral fluids, ocular lubricants, vaginal lubricants). Ocular steroids are not recommended because they predispose to serious secondary infections. Goggles and punctal occlusion also are used to slow the loss of tears. Oral pilocarpine and cevimeline may stimulate functional exocrine glands and improve symptoms, but the response varies greatly among patients. The appearance of thrush warrants prompt treatment because it severely aggravates oral symptoms; nystatin is generally effective for this complication. Finally, regular dental examinations and oral hygiene are crucial for reducing subsequent oral health issues (i.e., caries and periodontal disease associated with xerostomia). Tumor necrosis factor-α inhibitors have proved largely disappointing. The use of rituximab has been reported to be beneficial in SS-associated lymphoma. Multiple other biologic agents are under development.
Extraglandular manifestations of SS also are managed in a symptomatic fashion. Treatment of arthritis includes nonste-roidal anti-inflammatory drugs, prednisone, hydroxychloroquine, methotrexate, and tumor necrosis factor-α inhibitors. Constitutional symptoms are treated with hydroxychloroquine or prednisone. Inflammatory organ system disease (involving the lung, liver, neurologic system, hematologic system, and kidney) is treated individually with prednisone, methotrexate, azathioprine, or tumor necrosis factor-α inhibitors. Careful surveillance for infectious complications and neoplasia is crucial because the risk of both is increased in SS. Intravenous immunoglobulin has been suggested as a treatment of SS, but there is no evidence to support its use. The mortality of patients with SS has been estimated to be 2.7-fold greater than that of a control population.
Future Directions
It is ironic that although much has been learned about the effector mechanisms of SS, little is known about the inductive mechanisms. It is likely that future therapy will focus on interrupting the inflammatory pathways without ever understanding how the disease begins. If the latency time for development of an autoimmune disease is measured in years, it will be extremely difficult to identify the etiologic agents involved. Future work will focus on specific cytokines, chemokines, and their cognate receptor interactions in efforts to block the exocrine gland destruction. It is also likely that more specific therapy for the anti-Ro–mediated complete heart block of newborns will be developed, again focusing on abrogation of effector inflammatory pathways. Finally, it is anticipated that newer biologic agents will directly influence effector mechanisms, but they will probably be effective only if they are given to patients early in the disease course.
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