Sjögren syndrome is a chronic, systemic, autoimmune, 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 some severe extraglandular organ involvement may be treated with corticosteroids and immunosuppressants.
Sjögren syndrome occurs most frequently among middle-aged women (1). It is classified as primary when there is no other associated disease. It is secondary in approximately 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.
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. Sicca symptoms (eg, dry eyes, dry mouth) are more common than autoantibody–positive Sjögren syndrome.
General reference
1. Ramos-Casals M, Brito-Zerón P, Kostov B, et al. Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun Rev. 2015;14(8):670-679. doi:10.1016/j.autrev.2015.03.008
Pathophysiology of Sjögren Syndrome
Salivary, lacrimal, and other exocrine glands become infiltrated with CD4+ T cells and with B cells. The T cells produce inflammatory cytokines (eg, interleukin [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
JAMES STEVENSON/SCIENCE PHOTO LIBRARY
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 and dysphonia.
Parotid glands enlarge in about one-third of patients and are usually firm, smooth, and mildly tender (1). Enlargement can be asymmetric, but highly disproportionate; persistent enlargement of one gland may indicate a tumor or other disorder 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 approximately 50% of patients. Arthritis occurs in approximately 20% 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 (eg, lymphocytic interstitial pneumonia), pancreatic insufficiency, and vasculitis. Vasculitis usually involves small vessels and can occasionally affect the skin and large-fiber nerves (causing sensory peripheral polyneuropathy or multiple mononeuropathy) or the central nervous system (eg, optic neuritis, transverse myelitis).
Sjögren syndrome may cause rashes (including purpura and petechiae) and glomerulonephritis. Kidney involvement can result in distal renal tubular acidosis, leading to hypokalemia, impaired concentrating ability, kidney stones, and interstitial nephritis.
Pseudolymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, diffuse large B-cell lymphoma, or Waldenström macroglobulinemia can develop; patients have an approximately 16-fold increased of developing non-Hodgkin lymphoma compared with the general population (2). Reported predictors of MALT lymphoma include a low C4 level, monoclonal gammopathy, cryoglobulinemic vasculitis, and persistently enlarged parotid glands.
Chronic hepatobiliary disease and pancreatitis (exocrine pancreatic tissue is similar to that of salivary glands) may also occur.
Photo courtesy of Kinanah Yaseen, MD.
Alopecia may occur.
Fatigue is often present but is not a specific feature of the disease.
Symptoms and signs references
1. Valim V, Secco A, Reis de Oliveira F, et al. Parotid gland swelling in primary Sjögren's syndrome: activity and other sialadenosis causes. Rheumatology (Oxford). 2022;61(7):2987-2992. doi:10.1093/rheumatology/keab816
2. Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjögren's syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796-803. doi:10.1136/ard.2005.041186
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 distal 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 have a score of ≥ 4 (see table EULAR/ACR Criteria for the Classification of Primary Sjögren Syndrome), 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)
Advanced HIV infection
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 healthy person normally moistens 15 mm of each paper strip. Most people with Sjögren syndrome moisten < 5 mm, although approximately 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). 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), 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 that may support the diagnosis include autoantibodies to Ro (SSA autoantibodies—see Systemic Lupus Erythematosus (SLE)) or to nuclear antigens (termed La or SSB autoantibodies), antinuclear antibodies (ANA), or an elevated level of antibodies against gamma-globulin. Rheumatoid factor is present in > 70% of patients (4). Erythrocyte sedimentation rate (ESR) is elevated in 70% of patients, 33% have anemia, and up to 25% have leukopenia. Only SSA (Ro) autoantibodies are included as part of the 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
4. Bournia VK, Vlachoyiannopoulos PG. Subgroups of Sjögren syndrome patients according to serological profiles. J Autoimmun. 2012;39(1-2):15-26. doi:10.1016/j.jaut.2012.03.001
Treatment of Sjögren Syndrome
Symptomatic treatment for sicca symptoms
Avoidance of aggravating factors
Sometimes corticosteroids or other immunosuppressants for severe extraglandular organ involvement
Hydroxychloroquine and/or methotrexate for concomitant arthritis or myositis
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 (1, 2). Recognition of therapies for other conditions that can exacerbate dryness is crucial. Oral hydroxychloroquine 5 mg/kg of body weight once a day is sometimes given for the treatment of arthralgias, but supportive trial data are limited (3). Oral methotrexate 15 to 20 mg once a week can be given for definite arthritis or myositis.
Dry eyes should be treated with preservative-free eye drops (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 and occasionally topical corticosteroids (under the care of ophthalmology). Skin and vaginal dryness can be treated with creams and 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. Medications that decrease salivary secretion (eg, antihistamines, antidepressants, other anticholinergics) should be avoided. Fastidious oral hygiene and regular dental visits are essential. Salivary gland stones (sialolithiasis) 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. Bacterial parotitis rarely occurs but if present requires treatment with antibiotics effective against staphylococcus.
Aggressive systemic treatment is rarely indicated; it is usually reserved for patients with extraglandular manifestations (eg, severe vasculitis, optic neuritis, interstitial lung disease). 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 lung involvement, or inflammatory arthritis that does not respond to other therapy. IV immune globulin may be considered for patients with severe small-fiber neuropathy related to Sjögren syndrome, but there are limited data to support this approach (4).
There is no clearly effective treatment for fatigue, but, if it is present, screening for thyroid disease, sleep apnea, and anemia is warranted.
Treatment references
1. Carsons SE, Vivino FB, Parke A, et al. Treatment Guidelines for Rheumatologic Manifestations of Sjögren's Syndrome: Use of Biologic Agents, Management of Fatigue, and Inflammatory Musculoskeletal Pain. Arthritis Care Res (Hoboken). 2017;69(4):517-527. doi:10.1002/acr.22968
2. Price EJ, Benjamin S, Bombardieri M, et al. British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease. Rheumatology (Oxford). Published online April 16, 2024. doi:10.1093/rheumatology/keae152
3. Gottenberg JE, Ravaud P, Puechal X, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA. 2014;312(3):249-258. doi:10.1001/jama.2014.7682
4. Rist S, Sellam J, Hachulla E, et al. Experience of intravenous immunoglobulin therapy in neuropathy associated with primary Sjögren's syndrome: a national multicentric retrospective study. Arthritis Care Res (Hoboken). 2011;63(9):1339-1344. doi:10.1002/acr.20495
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 involvement and, rarely, from renal failure or lymphoma. Associated systemic autoimmune disorders may dictate prognosis.
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 medications 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).
More Information
The following English-language resource may be useful. Please note that The Manual is not responsible for the content of this resource.
