Sjögren’s Syndrome

Stuart S. Kassan

KEY POINTS

Sjögren’s syndrome (SS) is a common autoimmune disease that may occur alone or in combination with any of the other autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and progressive systemic sclerosis (PSS).
Ninety percent of patients with SS are women.
The differential diagnosis includes conditions and medications that can produce dry eyes and mouth, including diabetes mellitus, amyloidosis, sarcoidosis, viral infections, trauma, irradiation, psychogenic conditions, certain vitamin deficiencies, and the use of certain antihypertensives, antihistamines, and psychotherapeutic agents.
Non-Hodgkin’s lymphoma has been found to occur more often in patients with SS, in whom the relative risk is 44 times greater than expected.
Patients of SS with parotid enlargement, splenomegaly, lymphadenopathy, palpable purpura, leg ulcers, low C4 levels and mixed cryoglobulin, and cross-reactive idiotypes of monoclonal rheumatoid factors may indicate the future development of lymphoma.

Sjögren’s syndrome (SS) is a common, slowly progressive, systemic autoimmune disease associated with exocrine gland dysfunction due to lymphocytic infiltration (epithelitis).

The most commonly accepted definition of SS has been the presence of two of the following findings: (a) keratoconjunctivitis sicca (dry eyes), (b) xerostomia (dry mouth), and (c) one of the connective tissue disease syndromes.
Primary SS includes patients with keratoconjunctivitis and xerostomia in the absence of any other definable connective tissue disease. They have certain clinical, serologic, and genetic differences from the secondary SS that are associated with connective tissue disorders. These differences suggest varying etiologies for similar clinical manifestations of disease.
Secondary SS is defined as keratoconjunctivitis and xerostomia in the setting of another connective tissue disease. Rheumatoid arthritis (RA) is the most common connective tissue disease seen in association with secondary SS, but other diseases have been well-documented and include systemic lupus erythematosus (SLE), scleroderma, polymyositis, mixed connective tissue disease, and juvenile idiopathic arthritis (JIA).
Pathologic evidence that differentiates between primary and secondary SS has also been developed and has been employed along with the clinical designations noted in the subsequent text.

ETIOPATHOGENESIS

I. ABNORMALITIES OF HUMORAL IMMUNITY

Anti-salivary duct antibody is present more frequently in secondary SS (70% positive) than in primary SS (10% positive). No differences in other organ-specific antibodies (e.g., antithyroid and antigastric parietal cell antibodies) have been found.
Non–organ-specific autoantibodies
- Immunoglobulin M (IgM) rheumatoid factor (RF) is the most common type of RF in all cases of SS and is present in nearly 100% of patients with SS.
- Levels of IgG and IgA rheumatoid factors seem to be elevated in primary SS more often than in secondary SS.
- Antinuclear antibody (ANA) positivity was found in 64% to 68% of all SS cases. ANA patterns tend to be speckled because of the anti–SS-B antibodies found in SS.
Antibodies to soluble acidic nuclear antigens (e.g., Ro and La) extracted from lymphoid cell lines.
- Anti–SS-A (or anti-Ro) antibodies are present in the following percentages:
  - Primary SS—70%.
  - SS with RA—1%.
  - SS with SLE—33%.
- Anti–SS-B (or anti-Ha, anti-La) antibodies are present in the following percentages:
  - Primary SS—50% to 70%.
  - SS with RA—3% to 5%.
  - SS with SLE—73%.

II. GENETICS

Histocompatibility testing of patients with SS has demonstrated a genetic dichotomy between patients with primary SS (SS alone) and those with secondary SS (SS associated with another connective tissue disease, generally RA).

Primary sicca syndrome has a significantly increased association with human leucocyte antigen-B8 (HLA-B8) and HLA-DR3.
HLA associations discussed in the preceding text are usually not found in patients with secondary sicca syndrome. In the case of patients with SS and RA, there is an increased incidence of the HLA-DR4 antigen (that antigen found most often in seropositive RA alone).
Family studies show that relatives of patients with SS may have an increased incidence of serum autoantibodies, positive results on Schirmer’s test, elevated γ globulin levels, and RA.

III. ABNORMALITIES OF CELLULAR IMMUNITY AND IMMUNE REGULATION IN SS

Evidence suggests the presence of a serum-blocking factor that may decrease the percentage of T cells. Natural cell-mediated cytotoxicity is depressed in both primary and secondary SS. Overall, it seems that B-cell activation is the most consistent immunoregulatory aberration in patients with SS. It may begin as a polyclonal activation, evolving to oligoclonal and monoclonal activation, and may end in a transformation to a malignant monoclonal proliferation. Elevated levels of immune
complexes and abnormal clearance of these complexes by the reticuloendothelial system have been demonstrated in active SS. Their role in the pathogenesis of disease is unclear, but they may be important in vasculitic states and glomerulonephritis.
Graft versus host disease (GVHD)-related SS resembles spontaneous SS, suggesting a possible pathophysiologic mechanism for the development of SS and other connective tissue diseases.
Viral studies. Tubuloreticular structures have been identified in labial salivary gland tissue and renal endothelium from patients with SS. No successful viral isolation from salivary gland tissues has been accomplished. Patients with human immunodeficiency virus (HIV) infection may manifest a clinical picture indistinguishable from that of SS. These patients usually do not demonstrate antibodies to Ro (SS-A) or La (SS-B) cellular antigens, and the intralesional T cells are CD8+, as opposed to CD4+ in autoimmune SS.

PREVALENCE

I. SEX

At least 90% of the patients with SS (primary or secondary) are women.

II. AGE

Most patients with the disease are older than 40 years, but the disease may be encountered in persons in their second and third decades of life.

III.

When various populations of patients with SS have been evaluated for the presence of other connective tissue diseases, the results are as follows:

RA—30% to 55%.
Scleroderma—5% to 8%.
SLE—5% to 10%.
Polymyositis—2% to 4%.
Hashimoto’s thyroiditis, mixed connective tissue disease, chronic active hepatitis, Raynaud’s disease—the incidences of these disorders in patients with SS is unknown.