Sjögren syndrome 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 (sicca syndrome) due to lymphocytic infiltration of exocrine glands and secondary gland dysfunction. Sjögren syndrome 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, but visceral organ involvement is treated with corticosteroids and immunosuppressants.
Sjögren syndrome occurs most frequently among middle-aged women. The disease is classified as primary when there is no other associated disease. In about 30% of patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, Hashimoto thyroiditis, primary biliary cirrhosis, or chronic autoimmune hepatitis, Sjögren syndrome develops and, in such cases, is classified as secondary. Genetic associations have been found (eg, HLA-DR3 antigens in White people with primary Sjögren syndrome) but are not necessary for diagnosis or clinical management.
Pathophysiology of Sjögren Syndrome
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-gamma). 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). 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 gastrointestinal mucosal or submucosal atrophy and diffuse infiltration by plasma cells and lymphocytes may cause symptoms (eg, dysphagia).
Symptoms and Signs of Sjögren Syndrome
Glandular manifestations
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Sjögren syndrome often affects the eyes or mouth initially and sometimes exclusively (sicca syndrome). Dry eyes can cause a sandy, gritty sensation without pruritus. 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.
Parotid glands enlarge in 33% of patients and are usually firm, smooth, and mildly tender. Enlargement can be asymmetric, but highly disproportionate; persistent enlargement of one gland may indicate a tumor and should be evaluated. Chronic salivary gland enlargement is rarely painful unless there is obstruction or infection.
Extraglandular manifestations
Joint disease in Sjögren syndrome 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 rheumatoid arthritis but is not erosive.
Other extraglandular manifestations include generalized lymphadenopathy, Raynaud syndrome, interstitial lung involvement (which is common but infrequently serious), pancreatic insufficiency, and vasculitis. Vasculitis can occasionally affect the peripheral nerves (causing sensory peripheral polyneuropathy or multiple mononeuropathy) or the central nervous system. It may cause rashes (including purpura) and glomerulonephritis. Kidney involvement can also cause renal tubular acidosis, impaired concentrating ability, kidney stones, or interstitial nephritis. Pseudolymphoma, B-cell 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.
Alopecia may occur. Fatigue is often present.
Diagnosis of Sjögren Syndrome
Clinical criteria
Eye and salivary gland testing
Autoantibodies
Sometimes salivary gland biopsy
Sjögren syndrome 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 primary Sjögren syndrome. Modifications to the American-European classification criteria for primary Sjögren syndrome were proposed in 2016 (see table EULAR/ACR Criteria for the Classification of Primary Sjögren Syndrome; 1). Not every patient who receives a clinical diagnosis of Sjögren syndrome fulfills the proposed criteria, but the criteria provide useful guidance for evaluation and are applied to patients who have at least 1 symptom of eye or oral dryness:
Eye symptoms: ≥ 3 months of daily, persistent, troublesome dry eyes, recurrent sensation of sand or gravel in the eyes, or use of tear substitutes ≥ 3 times a day
Oral symptoms: > 3 months of daily dry mouth sensation or daily use of liquids to aid in swallowing dry food
To fulfill the criteria, patients must have at least 1 symptom of eye or oral dryness, must also have a score of ≥ 4, and must not have any of the following exclusion criteria:
History of radiation treatment to the head and neck
Active hepatitis C infection (confirmed by polymerase chain reaction)
AIDS
Sarcoidosis
Amyloidosis
Graft-vs-host disease
IgG4-related disease
EULAR/ACR Criteria for the Classification of Primary Sjögren Syndrome
Inclusion Criteria | Score* |
|---|---|
Labial salivary gland with focal lymphocytic sialadenitis and a focus score† of ≥ 1 | 3 |
Anti-SSA antibodies (anti-Ro) | 3 |
Ocular staining score‡ ≥ 5 (or van Bijsterveld score ≥ 4) in at least 1 eye | 1 |
Schirmer test ≤ 5 mm/5 min in at least 1 eye | 1 |
Unstimulated whole saliva flow rate ≤ 0.1 mL/min§ | 1 |
* To fulfill the inclusion criteria, patients must have a score of ≥ 4, at least 1 symptom of eye or oral dryness, and no exclusion criteria. Patients who fulfill the following exclusion criteria do not have primary Sjögren syndrome:
| |
† A focus score is the number of inflammatory infiltrates of at least 50 cells present in 4 mm2 of gland surface unit. | |
‡ As described in Whitcher JP, Shiboski CH, Shiboski SC, et al: A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's syndrome international registry. Am J Ophthalmol149(3):405–415, 2010. doi: 10.1016/j.ajo.2009.09.013 | |
§ As described in Navazesh M: Methods for collecting saliva. Ann N Y Acad Sci 694:72–77, 1993. doi: 10.1111/j.1749-6632.1993.tb18343.x | |
EULAR/ACR = European League Against Rheumatism/American College of Rheumatology | |
Modified from Shiboski CH, Shiboski SC, Seror R, et al: 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 69(1):35–45, 2017. doi: 10.1002/art.39859 | |
The most common causes of dry eyes and dry mouth (sicca symptoms) are aging and medications, but when parotid enlargement occurs in addition to sicca symptoms, diseases such as hepatitis C, HIV, bulimia, and sarcoidosis should be differentiated from Sjögren syndrome. When submandibular glands are enlarged, particularly in patients with a history of pancreatitis, IgG4-related disease (characterized by lymphoplasmacytic infiltration and fibrosis of various organs) should be considered.
Eye signs should be evaluated with the Schirmer test, which measures the quantity of tears secreted in 5 minutes 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 Sjögren syndrome 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. The total ocular staining score (OSS) for each eye is recorded (2< 10 seconds is also suggestive.
Salivary gland involvement can be confirmed by abnormally low saliva production (≤ 0.1 mL/minute) as measured by salivary flow, sialography, or salivary scintiscanning, although these tests are used infrequently. Saliva production can be qualitatively evaluated by several methods (3), including looking for normal pooling of saliva under the tongue. Alternatively, a tongue blade can be held against the buccal mucosa for 10 seconds. 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.
Autoantibodies have limited sensitivity and particularly low specificity. They include antibodies to Ro (SSA autoantibodies—see Systemic Lupus Erythematosus (SLE)) or to nuclear antigens (termed La or SSB autoantibodies), antinuclear antibodies, or an elevated level of antibodies against gamma-globulin. Rheumatoid factor is present in > 70% of patients. Erythrocyte sedimentation rate (ESR) is elevated in 70%, 33% have anemia, and up to 25% have leukopenia. However, only SSA autoantibodies are included as part of the new classification criteria.
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. Biopsy can be complicated by protracted dysesthesias.
Diagnosis references
1. Shiboski CH, Shiboski SC, Seror R, et al: 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 69(1):35–45, 2017. doi: 10.1002/art.39859
2. Whitcher JP, Shiboski CH, Shiboski SC, et al: A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's syndrome international registry. Am J Ophthalmol 149(3):405–415, 2010. doi: 10.1016/j.ajo.2009.09.013
3. Navazesh M: Methods for collecting saliva. Ann N Y Acad Sci 694:72–77, 1993. doi: 10.1111/j.1749-6632.1993.tb18343.x
Prognosis for Sjögren Syndrome
Sjögren syndrome is chronic. Overall health and life expectancy are mainly unaffected in patients whose only symptoms are dry eyes and mouth. However, prognosis is less favorable in those with systemic organ involvement. In those with severe disease, death may occasionally result from pulmonary infection and, rarely, from renal failure or lymphoma. Associated systemic autoimmune disorders may dictate prognosis.
Treatment of Sjögren Syndrome
Symptomatic treatment for sicca symptoms
Avoidance of aggravating factors
treatment guidelines for rheumatologic manifestations of Sjögren syndrome.)
Fatigue has no clearly effective treatment.
Key Points
Suspect Sjögren syndrome 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, particularly drugs that decrease salivary gland function.
More Information
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