Sjogrens Syndrome

PJW Venables and RN Maini, The Mathilda and Terence Kennedy Institute of Rheumatology, Kennedy Building, London, UK

Clinical descriptions of patients with dry eyes and a dry mouth associated with swellings of lacrimal and salivary glands began to appear in the medical literature towards the end of the nineteenth century. In all probability a heterogeneous group of disorders such as sarcoidosis and lymphoma was included in these early descriptions, but in 1888 Mikulicz gave a histo-

pathological account of the glands from a patient with the characteristic histological picture of Sjogren's syndrome (SS). In 1933, Sjögren, a Swedish ophthalmologist, published a thesis on patients with dry eyes, dry mouth and a deforming arthritis, mostly without swollen lacrimal or salivary glands. Correlations between dry eyes, a dry mouth and abundance of round cell infiltration in lacrimal and salivary tissue were noted, as was the association with rheumatoid arthritis in some patients.

Sjogren's syndrome has been defined by a workshop on diagnostic criteria held in Pisa in 1988 under the egis of the Commission of the European Community as a 'chronic inflammatory disorder of tear and salivary glands, reflecting general involvement of exocrine tissues, leading to dry eyes and a dry mouth and its sequelae. It may or may not be associated with systemic features and/or a defined autoimmune disease and connective tissue disease.' The same group subsequently developed diagnostic criteria (the Vitali criteria) which are currently considered to be the best evaluated. They are based on a short questionnaire of 1) ocular symptoms and 2) oral symptoms. Other essential criteria are 3) ocular signs (by Schirmer's test or Rose Bengal staining; 4) lymphocytic infiltrates on lip biopsy; 5) salivary gland involvement (scintigraphy, sialography or decreased salivary flow rate); and 6) demonstration of serum autoantibodies (rheumatoid factors, antinuclear antibodies and/or Ro or La antibodies).

Primary SS can exist with dry eyes and dry mouth as the sole disorder. However, many such patients exhibit extraglandular clinical features which do not in themselves constitute a distinct connective tissue disease and are included in the spectrum of primary SS. These include fatigue, fever, Raynaud's phenomenon, arthralgia, intermittent or chronic synovitis, myalgia, myositis, interstitial pneumonitis, purpuric vasculitis, renal tubular acidosis, chronic liver disease and peripheral neuropathy.

Bunim and Talal in 1963 first reported an increased incidence of lymphoma in SS, and subsequent follow-up at the National Institutes of Health, USA, of a cohort of patients over 8 years led to the conclusion that the risk of lymphoma in SS was about 6.4 cases per thousand patients per year, and represented a 40-fold higher incidence over a control population. Malignant lymphoma needs to be distinguished from pseudolymphoma, which also occurs in SS and is characterized by lymphoprolifer-ation in exocrine tissues and peripheral lymphoid organs, giving rise to lymphadenopathy and splenomegaly but which clinically behaves as a benign disorder. Monoclonal immunoglobulins are detectable in many patients with SS, including those with pseudolymphoma and malignant lymphoma, emphasizing that hidden in the polyclonal B cell response are individual expanded clones which occasionally undergo oncogenic transformation.

The basis of classification into 'primary' and 'secondary' SS has received support from clinical, serological, and immunogenetic studies. For example, in patients with primary SS, the occurrence of arthritis and immunoglobulin M (IgM) rheumatoid factor simulates diagnostic features of rheumatoid arthritis (RA), but such patients do not develop deforming arthritis with cartilagc and bone erosions of the type seen in rheumatoid arthritis. Furthermore, in primary SS antibodies to Ro and La occur in about 50%. of patients whereas these antibodies arc rare in RA. In Caucasians with primary SS, the human leukocyte antigen (HLA) phenotype is usually HLA-B8, DR3, DRw52, whereas in Caucasian patients with secondary SS and RA, HLA phenotyping usually reveals either HLA-DR4 and/or DRw53.

Patients with primary SS and extraglandular features may, however, be more difficult to distinguish from secondary Sjogren's syndrome associated with systemic lupus erythematosus (SLE) since clinical, serological, and immunogenetic markers overlap considerably. Similarities include the presence of Raynaud's phenomenon, purpura, leukopenia, anti-La and anti-Ro antibodies, hyperglobulinemia, hypo-complementemia, and the presence of HLA-B8, DR3, DRw52 and C4 null genes. However, anti-double-stranded DNA in high titers and anti-Sm antibodies are markers of SLE and are not normally found in the serum of patients with primary Sjogren's syndrome. Features which distinguish SLE from primary SS include an immune complex-mediated diffuse glomerulonephritis, photosensitive rashes, alopecia, pleurisy, pericarditis, hemolytic anemia and thrombocytopenia.

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