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 Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more , systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more , mixed connective tissue disease Mixed Connective Tissue Disease (MCTD) Mixed connective tissue disease is an uncommon, specifically defined syndrome characterized by clinical features of systemic lupus erythematosus, systemic sclerosis, and polymyositis with very... read more , Hashimoto thyroiditis Hashimoto Thyroiditis Hashimoto thyroiditis is chronic autoimmune inflammation of the thyroid with lymphocytic infiltration. Findings include painless thyroid enlargement and symptoms of hypothyroidism. Diagnosis... read more , primary biliary cirrhosis Primary Biliary Cholangitis (PBC) Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more , or chronic autoimmune hepatitis Overview of Chronic Hepatitis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more , 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 Keratoconjunctivitis Sicca Keratoconjunctivitis sicca is chronic, bilateral desiccation of the conjunctiva and cornea due to an inadequate tear film. Symptoms include itching, burning, irritation, and photophobia. Diagnosis... read more ). 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
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 Xerostomia Xerostomia is dry mouth caused by reduced or absent flow of saliva. This condition can result in discomfort, interfere with speech and swallowing, make wearing dentures difficult, cause halitosis... read more ) 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.
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 Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more , interstitial lung involvement (which is common but infrequently serious), pancreatic insufficiency, and vasculitis Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more . Vasculitis can occasionally affect the peripheral nerves (causing sensory peripheral polyneuropathy Polyneuropathy A polyneuropathy is a diffuse peripheral nerve disorder that is not confined to the distribution of a single nerve or a single limb and typically is relatively symmetrical bilaterally. Electrodiagnostic... read more or multiple mononeuropathy Multiple Mononeuropathy Multiple mononeuropathies are characterized by sensory disturbances and weakness in the distribution of ≥ 2 affected peripheral nerves. (See also Overview of Peripheral Nervous System Disorders... read more ) or the central nervous system. It may cause rashes (including purpura) and glomerulonephritis. Kidney involvement can also cause renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is acidosis and electrolyte disturbances due to impaired renal hydrogen ion excretion (type 1), impaired bicarbonate resorption (type 2), or abnormal aldosterone... read more , 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
Eye and salivary gland testing
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 ; 1 Diagnosis references 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 ... read more ). 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)
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 Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more , HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more , bulimia Bulimia Nervosa Bulimia nervosa is characterized by recurrent episodes of binge eating followed by some form of inappropriate compensatory behavior such as purging (self-induced vomiting, laxative or diuretic... read more , and sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more should be differentiated from Sjögren syndrome. When submandibular glands are enlarged, particularly in patients with a history of pancreatitis, IgG4-related disease IgG4-Related Disease Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more (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 Diagnosis references 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 ... read more ). Slit-lamp examination showing a fluorescein tear breakup in < 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 Diagnosis references 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 ... read more ), 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) Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more ) 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.
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
Corticosteroids or rituximab for severe disease
Hydroxychloroquine and/or methotrexate for musculoskeletal manifestations
Sjögren syndrome should be initially managed by topical therapy of dry eyes and dry mouth. Other systemic manifestations of the disease should be treated depending on the severity and the involved organ. Recognition of therapies for other conditions that can exacerbate dryness complaints is crucial. Oral hydroxychloroquine 5 mg/kg of body weight once a day is often given to halt the progression of the disease and for the treatment of arthralgias, but supportive trial data are limited. Oral methotrexate 15 to 20 mg once a week can be given for musculoskeletal manifestations.
Dry eyes should be treated with lubricating eye preparations (initially drops such as hypromellose or methylcellulose and an over-the-counter 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. Oral pilocarpine 5 mg 3 times a day or oral cevimeline hydrochloride 30 mg 3 times a day 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, optic neuritis, or visceral involvement). Corticosteroids (eg, oral prednisone 1 mg/kg once a day), or rituximab may be needed in severe disease with cryoglobulinemic vasculitis, peripheral neuropathy/multiple mononeuropathy, severe parotid swelling, severe lung involvement, or inflammatory arthritis that does not respond to non-biologic therapy. (See also treatment guidelines for rheumatologic manifestations of Sjögren syndrome.)
Fatigue has no clearly effective treatment.
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.
If patients have severe disease (eg, severe vasculitis or visceral involvement), treat with corticosteroids and sometimes other immunosuppressants (eg, rituximab).
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