Sjögren’s Syndrome
Last updated: November 16, 2014
Synonyms: Keratoconjunctivitis sicca, sicca complex.
ICD9 Code: Sjogrens (sicca) syndrome 710.2
ICD10 Code: Sjogrens with keratoconjunctivitis M35.01
Definition: Sjögren’s syndrome is a chronic autoimmune syndrome characterized by lymphocytic infiltration of exocrine glands, particularly the lacrimal glands and salivary glands, sometimes in association with other organ involvement and systemic symptoms. Infiltration of and damage to the lacrimal and salivary glands can result in the main symptoms of dry eyes (xerophthalmia) and dry mouth (xerostomia). When it occurs without another autoimmune disorder, it is considered primary Sjögren’s syndrome. Secondary Sjögren’s syndrome occurs in patients with preexisting autoimmune disease, most commonly RA and scleroderma.
Etiology: The causative trigger is not known, although various viruses including Epstein-Barr virus and human T-cell lymphotropic virus type 1 have been proposed as potential relevant agents. The high incidence in females suggests a possible facilitating role for sex steroid hormones. HLA associations (HLA-B8, -DR3, and -Dw52 in males) have been described, highlighting some genetic predisposition.
Pathology: Salivary gland biopsies show benign lymphoepithelial infiltration and proliferation in the exocrine (e.g., salivary, lacrimal, parotid) glands. Adjacent areas of the gland may appear normal. Helper (CD4+) T cells predominate and most likely activate antibody production by infiltrating B lymphocytes, resulting in hypergammaglobulinemia and circulating autoantibodies. Infiltrating lymphocytes mediate destruction and dysfunction of the adjacent glandular tissue.
Demographics: Onset is usually in middle age, with a predominance of females.
Cardinal Findings: Dry mouth and eyes are the predominant presentation. Xerostomia may be noticeable to the patient and may manifest as gingivitis and accelerated dental caries in some patients. Inadequate saliva production may result in pharyngeal dysphagia. Dry eyes may manifest as redness, conjunctival irritation, or the sensation of sand in the eye. Patients may blink or rub their eyes excessively. Gross parotid gland enlargement is found in a minority of patients. Musculoskeletal features include fatigue and fibromyalgia in nearly 50% of patients. Fewer patients complain of arthralgias, and frank arthritis is rare.
Uncommon Manifestations: Lymphocytic infiltration into the kidney may result in tubular dysfunction that is usually not clinically apparent. Rarely, such patients manifest a renal tubular acidosis with severe potassium wasting, hypokalemia and, eventually, even symptoms such as muscle weakness. CNS involvement (i.e., polyneuropathy, cranial nerve neuropathy, multiple sclerosis–like symptoms, headaches, or altered mentation) occurs but is rare. Pulmonary involvement is subclinical in most and rarely symptomatic. Pulmonary features include bronchitis, interstitial fibrosis, and lymphocytic alveolitis. GI features can include dysphagia, atrophic gastritis, primary biliary sclerosis, and sclerosing cholangitis. A small subset of patients with Sjögren’s syndrome may go on to develop malignant lymphoma. Hendytic anema, immune cytopenias, and vasculitis are rare.
Diagnostic Tests: Laboratory testing abnormalities may include an elevated ESR, polyclonal hypergammaglobulinemia, and an anemia of chronic disease. ANAs and RF are positive in 65% to 90% of patients, respectively. SSA antibodies are not specific for Sjögren’s syndrome and can be seen in other autoimmune disorders. SSB antibodies tend to have a greater association with Sjögren’s syndrome. Antibodies against SSA (anti-Ro) are seen in 70% to 80% of primary and in <10% of patients with secondary Sjögren’s syndrome. Antibodies against SSB (anti-La) are seen in 50% to 75% of primary and <5% of patients with secondary Sjögren’s syndrome.
The diagnosis of keratoconjunctivitis sicca can be further established with quantitative measures of tear production. The Schirmer test uses adsorbent paper strips inserted into the lower palpebral fold to measure the amount of wetting or tear production. Alternatively, the ophthalmologist can facilitate the diagnosis by performing a Rose bengal other similar staining test. Rose bengal is a vital stain that is taken up by dead or dying cells and is used to evaluate corneal abnormalities or suspected keratoconjunctivitis sicca. Biopsy of glandular tissue (i.e., minor salivary gland of the lip or parotid gland) may also reveal the characteristic lymphocytic infiltration diagnostic of Sjögren’s syndrome. Ultrasonography of the parotid and submandibular glands has been shown to be very sensitive and correlates with symptoms. It may well be incorporated into diagnostic criteria in the future, as it may avoid invasive or expensive testing.
Keys to Diagnosis: Xerostomia and xerophthalmia with or without parotid gland enlargement strongly suggests this diagnosis.
Differential Diagnosis: Infections (e.g., mumps) and infiltrative processes such as sarcoidosis may cause parotid gland enlargement. Parotid tumors are likely to be unilateral. Drugs (e.g., tricyclic antidepressants, antihistamines, etc.) and irradiation may cause dry eyes and mouth. A subset of HIV-positive patients develop xerostomia, parotid gland swelling, lymphadenopathy, and lymphocytic pulmonary infiltrates.
Diagnostic Criteria: Proposed 2012 ACR Criteria are shown in the Table below.
| Table 2012 ACR Criteria for the Classificiation of Sjogren’s Syndromeª | ||||
| The classification of SS, which applies to individuals with signs/symptoms that may be suggestive of SS, will be met in patients who have at least 2 of the following 3 objective features: 1. Positive serum anti-SSA/Ro and/or anti-SSB/La or (positive rheumatoid factor and ANA titer 1:320) 2. Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2† 3. Keratoconjunctivitis sicca with ocular staining score >3 (assuming that individual is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years)‡ Prior diagnosis of any of the following conditions would exclude participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: – History of head and neck radiation treatment – Hepatitis C infection – Acquired immunodeficiency syndrome – Sarcoidosis – Amyloidosis – Graft versus host disease – IgG4-related disease |
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| * Excluded participants with rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or other connective tissue disease from these analyses since there were only 87 (6%) such participants. SS Sjo¨gren’s syndrome; ANA antinuclear antibody. † Using histopathologic definitions and focus score assessment methods as previously described. ‡ Using ocular staining score as previously described |
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Therapy: Sicca symptoms are treated with lubricating eyedrops and avoidance of aggravating factors such as hair dryers or drying medications. Wearing glasses outdoors may protect from the drying effects of the wind. Ophthalmic consultation is recommended for patients with moderate to severe symptoms. Punctal occlusion, either temporarily with plugs or permanently with surgery, may improve tear retention and flow. Saliva substitutes are available and may be preferred by some patients. The use of sugar-free lemon hard candies may help stimulate salivary flow. Fastidious dental care is extremely important to avoid dental caries. The use of humidifiers at home or work may decrease symptoms significantly. There are two available medications that stimulate exocrine gland secretions, cevimilene and pilocarpine.NSAIDs and analgesic agents may improve the arthralgias and myalgias. Corticosteroids should not be used for most and are only indicated for vasculitis, pleuropericarditis, or hemolytic anemia. Numerous second-line and immunosuppressive agents (including MTX, penicillamine, and cyclosporine, hydroxychloroquine) appear to have minimal benefit in patients with Sjögren syndrome.
Surgery: Diagnostic minor salivary gland biopsy may be performed by an oral surgeon. Parotid biopsy via a posterior approach to the subauricular portion of the gland is preferred to reduce the risk of facial nerve injury.
Prognosis: Most patients do well. Sicca problems may require prolonged eye care. High-grade lymphoma that may be resistant to chemotherapy is rare.
BIBLIOGRAPHY
Silver RM. Variant forms of scleroderma. In: Koopman WJ, ed. Arthritis and allied conditions: a textbook of rheumatology. Baltimore: Williams & Wilkins, 1996:1465–1480.
Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res 2012; 64:475-87. PMID: 22563590
