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Sjögren Syndrome (SS)

by Rula A. Hajj-ali, MD

Sjögren syndrome (SS) is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes due to lymphocytic infiltration of the exocrine gland and secondary gland dysfunction. SS can affect various exocrine glands or other organs. Diagnosis is by specific criteria relating to eye, mouth, and salivary gland involvement, autoantibodies, and (occasionally) histopathology. Treatment is usually symptomatic.

SS occurs most frequently among middle-aged women. SS is classified as primary when there is no other associated disease. In about 30% of patients with autoimmune disorders such as RA, SLE, systemic sclerosis, mixed connective tissue disease, Hashimoto thyroiditis, primary biliary cirrhosis, or chronic autoimmune hepatitis, SS develops and, in such cases, is classified as secondary. Genetic associations have been found (eg, HLA-DR3 antigens in whites with primary SS).

Pathophysiology

Salivary, lacrimal, and other exocrine glands become infiltrated with CD4+ T cells and with some B cells. The T cells produce inflammatory cytokines (eg, IL-2, interferon-γ). Salivary duct cells also produce cytokines, eventually damaging the secretory ducts. Atrophy of the secretory epithelium of the lacrimal glands causes desiccation of the cornea and conjunctiva (keratoconjunctivitis sicca—see Keratoconjunctivitis Sicca). Lymphocytic infiltration and intraductal cellular proliferation in the parotid gland cause luminal narrowing and in some cases formation of compact cellular structures termed myoepithelial islands; atrophy of the gland can result. Dryness and GI mucosal or submucosal atrophy and diffuse infiltration by plasma cells and lymphocytes may cause symptoms (eg, dysphagia).

Symptoms and Signs

Glandular manifestations

SS often affects the eyes or mouth initially and sometimes exclusively. Dry eyes can cause a sandy, gritty sensation. In advanced cases, the cornea is severely damaged, epithelial strands hang from the corneal surface (keratitis filiformis), and vision can be impaired. Diminished saliva (xerostomia) results in difficulty chewing and swallowing, secondary Candida infection, tooth decay, and calculi in the salivary ducts. Taste and smell may be diminished. Dryness may also develop in the skin and in mucous membranes of the nose, throat, larynx, bronchi, vulva, and vagina. Dryness of the respiratory tract may cause cough. Alopecia may occur. Parotid glands enlarge in 33% of patients and are usually firm, smooth, and mildly tender. Enlargement can be asymmetric, but highly disproportionate enlargement of one gland may indicate a tumor. Chronic salivary gland enlargement is rarely painful unless there is obstruction or infection.

Extraglandular manifestations

Joint disease in SS is typically nonerosive and nondeforming. Arthralgias occur in about 50% of patients. Arthritis occurs in about 33% of patients and is similar in distribution to RA but is not erosive.

Other common extraglandular manifestations include generalized lymphadenopathy, Raynaud phenomenon, parenchymal lung involvement (which is common but infrequently serious), and vasculitis. Vasculitis can occasionally affect the peripheral nerves (causing peripheral polyneuropathy or mononeuritis multiplex) or CNS or cause rashes (including purpura) and glomerulonephritis. Kidney involvement can cause renal tubular acidosis, impaired concentrating ability, kidney stones, or interstitial nephritis. Pseudolymphoma, malignant lymphoma, or Waldenström macroglobulinemia can develop; patients develop non-Hodgkin lymphoma at 40 times the normal rate. Chronic hepatobiliary disease and pancreatitis (exocrine pancreatic tissue is similar to that of salivary glands) may also occur.

Diagnosis

  • Eye symptoms, oral symptoms, and eye and salivary gland testing

  • Autoantibodies

  • Sometimes salivary gland biopsy

SS should be suspected in patients with gritty or dry eyes or dry mouth, enlarged salivary glands, peripheral neuropathy, purpura, or unexplained renal tubular acidosis. Such patients should receive diagnostic tests that can include evaluation of the eyes and salivary glands and serologic tests. Different criteria have been proposed for classification of SS. The latest modifications to the American-European classification criteria for SS were proposed in 2002. These criteria were not developed for use in routine clinical practice, and not every patient who receives a clinical diagnosis of SS fulfills the proposed criteria (usually > 3 of 6 manifestations). The 6 manifestations are eye symptoms, oral symptoms, positive eye tests, salivary gland involvement, autoantibodies, and histopathology. The possibility of IgG4-associated disease (a newly recognized disease characterized by lymphoplasmacytic infiltration of various organs) should be considered if patients have submandibular gland enlargement, especially with a history of pancreatitis.

Eye symptoms are 3 mo of either dry eyes or use of tear substitutes 3 times/day; slit-lamp examination may also confirm dry eyes.

Oral symptoms are > 3 mo of daily dry mouth sensation, daily use of liquids to aid in swallowing, or swollen salivary glands.

Eye signs should be evaluated with the Schirmer test, which measures the quantity of tears secreted in 5 min after irritation from a filter paper strip placed under each lower eyelid. A young person normally moistens 15 mm of each paper strip. Most people with SS moisten < 5 mm, although about 15% of test results are false-positive and 15% are false-negative. Ocular staining with an eye drop of rose bengal or lissamine green solution is highly specific. Slit-lamp examination showing a fluorescein tear breakup in < 10 sec is also suggestive.

Salivary gland involvement can be confirmed by abnormally low saliva production ( 1.5 mL/15 min) as measured by salivary flow, sialography, or salivary scintiscanning, although these tests are used infrequently. Saliva production can be qualitatively evaluated by looking for normal pooling of saliva under the tongue. Alternatively, a tongue blade can be held against the buccal mucosa for 10 sec. If the tongue blade falls off immediately when released, salivary flow is considered normal. The more difficulty encountered removing the tongue blade, the more severe the dryness. In women, the lipstick sign, where lipstick adheres to the front teeth, may be a useful indicator of dry mouth. If a graduated container is available, the patient can expectorate once to empty the mouth and then expectorate all saliva into the container for several minutes. Normal production is 0.3 to 0.4 mL/min. Significant xerostomia is 0.1 mL/min.

Autoantibodies (serologic criteria) have limited sensitivity and specificity. They include antibodies to Ro (SS-A autoantibodies—see Systemic Lupus Erythematosus (SLE)) or to nuclear antigens (termed La or SS-B autoantibodies), antinuclear antibodies, or an elevated level of antibodies against γ-globulin. Rheumatoid factor is present in > 70% of patients. ESR is elevated in 70%, 33% have anemia, and up to 25% have leukopenia.

Histopathology is assessed by biopsy of minor salivary glands in the buccal mucosa. Salivary gland biopsy is usually reserved for patients in whom the diagnosis cannot be established by autoantibody testing or when a major organ is involved. Histopathologic involvement is confirmed if labial minor salivary glands show multiple large foci of lymphocytes with atrophy of acinar tissue.

Most common causes of dry eyes and dry mouth (sicca symptoms) are aging and drugs, but when parotid enlargement occurs in addition to sicca symptoms, diseases such as hepatitis C, HIV, bulimia, and sarcoidosis should be differentiated from SS.

Prognosis

SS is chronic, and death may occasionally result from pulmonary infection and, rarely, from renal failure or lymphoma. Associated systemic autoimmune disorders may dictate prognosis.

Treatment

  • Symptomatic treatment for sicca symptoms

  • Avoidance of aggravating factors

  • Occasionally oral corticosteroids, cyclophosphamide, or rituximab

SS should be initially managed by topical therapy of dry eyes and dry mouth. Other systemic manifestations of SS should be treated depending on the severity and the involved organ. Recognition of therapies for other conditions that can exacerbate dryness complaints is crucial. Hydroxychloroquine 200 to 400 mg po once/day is usually given to halt the progression of the disease and for the treatment of arthralgias.

Dry eyes should be treated with lubricating eye preparations (initially drops such as hypromellose or methylcellulose and an OTC ointment at bedtime). Other treatments include drainage (punctal) duct closure and topical cyclosporine. Skin and vaginal dryness can be treated with lubricants.

Mouth dryness may be avoided by sipping fluids throughout the day, chewing sugarless gum, and using a saliva substitute containing carboxymethylcellulose as a mouthwash. Drugs that decrease salivary secretion (eg, antihistamines, antidepressants, other anticholinergics) should be avoided. Fastidious oral hygiene and regular dental visits are essential. Stones must be promptly removed, preserving viable salivary tissue. The pain of suddenly enlarged salivary glands is generally best treated with warm compresses and analgesics. Pilocarpine 5 mg po tid to qid or cevimeline HCl 30 mg po tid can stimulate salivary production but should be avoided in patients with bronchospasm and closed-angle glaucoma.

Aggressive systemic treatment is occasionally indicated; it is usually reserved for patients with associated diseases (eg, severe vasculitis or visceral involvement). Corticosteroids (eg, prednisone 1 mg/kg po once/day), cyclophosphamide, or rituximab may be needed in severe disease, but there is concern regarding the increased baseline risk of lymphoma even without cytotoxic therapy.

Key Points

  • Suspect SS if patients have gritty or dry eyes or dry mouth, enlarged salivary glands, peripheral neuropathy, purpura, or unexplained renal tubular acidosis.

  • Confirm the diagnosis usually by specific clinical criteria.

  • Treat sicca symptoms symptomatically (eg, with topical lubricants) and avoid drying factors.

  • If patients have severe disease (eg, severe vasculitis or visceral involvement), treat with corticosteroids, cyclophosphamide, or rituximab.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CYTOXAN (LYOPHILIZED)
  • PLAQUENIL
  • NEORAL, SANDIMMUNE
  • EVOXAC
  • ISOPTO CARPINE, PILOPINE HS, SALAGEN
  • RITUXAN
  • RAYOS

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