Sjogren Syndrome

Etiology

The precise etiology of Sjögren syndrome remains unknown, as with most autoimmune disorders. A complex interplay of genetic, hormonal, and environmental factors likely contributes to disease onset. A genome-wide association study identified a strong correlation between Sjögren syndrome and the HLA-DQB1 haplotype.[1] These major histocompatibility complex variants appear to promote an abnormal immune response when combined with specific environmental triggers. Laboratory findings and indirect epidemiological data implicate viral infections, particularly Epstein-Barr virus (EBV), in disease development.[2][3] Exposure to solvents and inorganic chemicals has also been associated with the etiopathogenesis of Sjögren syndrome.[4]

The leading “pathogenic model” suggests that environmental insults in genetically predisposed individuals injure the salivary gland epithelium. This epithelial damage initiates inflammation and triggers an aberrant immune response, driving the chronic autoimmune process that defines the disease.[5]

Epidemiology

Sjögren syndrome affects approximately 0.5% to 1.0% of the population, with an incidence approaching half that of rheumatoid arthritis. Estimates suggest that between 400,000 and 3.1 million adults live with the condition. Although Sjögren syndrome can develop at any age, symptoms most commonly begin between the ages of 45 and 55. Approximately half of those diagnosed also have rheumatoid arthritis or another connective tissue disease (eg, lupus).

Sjögren syndrome occurs globally in adults and, less commonly, in children, without evidence of racial or geographic bias in incidence. The disorder shows a strong predilection for women, with a female-to-male ratio of approximately 9:1, similar to the pattern seen in SLE.[6][7] 

The lack of an evidence-based, standardized screening tool to identify which dry eye patients require evaluation for Sjögren syndrome contributes to the underreferral of these individuals. As a result, many cases of Sjögren syndrome remain undiagnosed, perpetuating a pattern of underrecognition and delayed diagnosis.[8]

Pathophysiology

The characteristic lesion of Sjögren syndrome, focal lymphocytic sialadenitis (FLS), affects exocrine glands. In FLS, lymphocyte-rich mononuclear cell foci infiltrate glandular tissue near blood vessels and excretory ducts. These foci consist primarily of T lymphocytes, although B lymphocytes, plasma cells, and other immune cells are also present. As disease severity increases, foci may coalesce.

LAMP3 (lysosome-associated membrane protein 3) becomes overexpressed in Sjögren syndrome, driven by elevated type I interferon levels. LAMP3 promotes salivary gland epithelial damage and triggers innate immune responses. Persistent epithelial activation leads to apoptosis and escalating inflammation. Plasmacytoid dendritic cells—key producers of type I interferon—play a central role in early disease development. Monocytes and macrophages, frequently found in salivary gland biopsies, sustain inflammation by interacting with B and T lymphocytes.[5]

B cells generate autoantibodies characteristic of Sjögren syndrome, including rheumatoid factor, SSA/Ro, and SSB/La. These cells appear in salivary glands and may form ectopic lymphoid structures. B cells, capable of transforming into malignant clones, contribute to the heightened risk of mucosa-associated lymphoid tissue (MALT) B-cell lymphoma in affected patients. Alongside antigen-presenting cells, B cells also activate T lymphocytes.[5]

Exocrine gland dysfunction results from mononuclear cell infiltration, humoral factors such as cytokines and antibodies, or both. This dysfunction reduces tear and saliva production by the lacrimal and salivary glands, respectively. Other exocrine glands may also become involved, leading to dryness of the skin, tracheobronchial tree, and vagina, and contributing to impairment of the lungs and kidneys. In rare cases, B lymphocyte malignancy may give rise to non-Hodgkin lymphoma. Additionally, immune complex deposition in the skin, joints, and organs can cause systemic vasculitis.[9]

Histopathology

Tissues involved in Sjögren syndrome—including the minor and major salivary glands and lacrimal glands—undergo infiltration by both T and B lymphocytes. While a tissue diagnosis remains nonessential, it may support diagnostic confirmation when other objective criteria are absent. Minor salivary glands (MSGs) are the preferred biopsy site due to their lower risk of complications. Access requires a small incision on the inner lip to excise 4 to 5 MSGs.

Biopsy typically reveals lymphocytic aggregates exceeding 50 cells within a 4 mm² area, known as the "focus score" [10], along with macrophages and plasma cells. CD4+ T cells dominate the infiltrate, and approximately 10% of lymphocytes are CD5-positive B cells that produce IgG and IgM antibodies. Up to 25% of patients with primary Sjögren syndrome also exhibit germinal center-like structures in biopsy samples, a finding associated with more severe disease.[11]

History and Physical

Clinical History

Dryness of the eyes (xerophthalmia) and mouth (xerostomia) almost always occurs in patients with Sjögren syndrome, though symptom severity ranges from very mild to debilitating. Diagnosing Sjögren syndrome can be challenging due to the high prevalence of dry eyes and mouth, especially in older adults, among whom only a small subset actually has the disease. Clinicians should suspect Sjögren syndrome in patients with persistent dryness, abnormal serologic findings, or signs suggestive of organ involvement.

Extraglandular manifestations may include Raynaud syndrome, synovitis, interstitial lung disease, autoimmune cytopenias, hypergammaglobulinemia, cutaneous vasculitis, renal disease, myositis, lymphadenopathy, neuropathy, and central nervous system (CNS) disease. Many patients also experience systemic symptoms, eg, fatigue, arthralgia, and cognitive difficulties commonly described as brain fog. Additionally, non-Hodgkin lymphoma risk increases significantly in individuals diagnosed with Sjögren syndrome.

Physical Examination

An eye examination may reveal absent tear pooling in the inferior conjunctival sac and injected (reddened) eyes. Referral to an ophthalmologist remains essential for a slit-lamp evaluation. When performed with vital dye staining, this exam can confirm keratoconjunctivitis sicca, the hallmark ophthalmologic finding in Sjögren syndrome. A Schirmer test can further support the diagnosis by quantifying ocular dryness.

Oral findings often include a dry mouth, smooth tongue, and thinned mucosa. Around 50% of patients experience parotid or submandibular gland enlargement at some stage (see Image. Sjogrens Parotid). Extraglandular involvement frequently presents with polyarthritis, pulmonary abnormalities, lower extremity purpura, or signs of peripheral neuropathy.

Diagnostic Considerations

Diagnosis has evolved alongside updates to classification criteria from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). The most recent classification criteria, published in 2016, should not be used as a stand-alone diagnostic tool, but rather may provide a structured framework for evaluating patients.

These criteria apply to individuals reporting at least 1 symptom of ocular or oral dryness, defined by a positive response to at least 1 of the following:

• Daily, persistent, troublesome dry eyes

• Recurrent sensation of sand or gravel in the eyes

• Regular use of tear substitutes

• Daily feeling of dry mouth

• Frequent need to drink liquids to help swallow dry food [12]

Patients may also qualify based on a positive domain from the EULAR Sjögren Syndrome Disease Activity Index (ESSDAI).[13] This index assesses systemic involvement, including systemic symptoms (eg, fever and weight loss), lymphadenopathy, salivary or lacrimal gland swelling, inflammatory arthritis, cutaneous findings (eg, urticarial vasculitis and palpable purpura), interstitial lung disease, renal disease (eg, proteinuria, renal tubular acidosis, and glomerulonephritis), myositis, peripheral neuropathy, central nervous system syndromes (eg, optic neuritis, multiple sclerosis-like syndromes, vasculitis), and autoimmune cytopenias.[14]

Objective findings used for classification include:

• Labial salivary gland biopsy showing focal lymphocytic sialadenitis with a focus score ≥1 focus per 4 mm² (3 points)

• Positive anti-Ro/SSA or anti-La/SSB antibodies (3 points)

• Ocular staining score ≥5 or van Bijsterveld score ≥4 in at least 1 eye (1 point)

• Schirmer’s test result ≤5 mm/5 minutes in at least 1 eye (1 point)

• Unstimulated whole salivary flow rate ≤0.1 mL/minute (1 point) [15]

A total score of ≥4 based on objective criteria confirms classification as Sjögren syndrome in patients meeting inclusion criteria.

Exclusion criteria include a history of head and neck irradiation, active hepatitis C infection, HIV/AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related disease.

Evaluation

Sjögren Syndrome Diagnostic Tools

Evaluation of a patient suspected of Sjögren syndrome should include a thorough assessment of oral and ocular dryness and glandular function.

In addition to clinical history, diagnostic tools may involve the Schirmer test, slit-lamp examination with vital dye staining, measurement of salivary flow rate, and evaluation of salivary gland function.

Schirmer test

This standard method measures aqueous tear production by placing a sterile strip inside the lower eyelid and recording the amount of tear wetting in millimeters over a 5-minute period. The test offers an inexpensive and simple approach, though it can cause discomfort and demonstrates some variability on repeat testing. Wetting of ≤5 mm indicates abnormal tear production.

Lissamine green and fluorescein staining

These dyes detect areas of dryness or damage on the conjunctiva and cornea. Fluorescein also measures tear film break-up time, with ≤10 seconds considered abnormal, suggesting Meibomian gland dysfunction.

Salivary scintigraphy

This nuclear medicine technique assesses salivary gland dysfunction by measuring the uptake of radiolabeled technetium by the major salivary glands. While specific, the test shows limited sensitivity.

Sialometry

This test quantifies unstimulated salivary flow by collecting saliva over 5 to 15 minutes into a preweighed cup. The flow rate in grams per minute is calculated by reweighing the cup, with a rate of ≤0.1 mL/minute considered abnormal.

Laboratory Studies

Autoantibody testing, including ANA, rheumatoid factor, SSA, and SSB, plays an important role. SSA antibodies demonstrate the highest sensitivity and specificity for Sjögren syndrome, but they do not alone confirm a diagnosis, as they may also appear in other autoimmune diseases or be absent in up to one-third of Sjögren cases. 

Baseline laboratory tests for patients suspected of having Sjögren syndrome should also include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), a chemistry panel, and urinalysis to identify disease complications or concurrent conditions. For ongoing disease activity monitoring in established Sjögren syndrome, routine bloodwork may include complement levels (C3 and C4), rheumatoid factor (RF), serum protein electrophoresis (SPEP), and cryoglobulin testing. Abnormal results often correlate with more severe disease and increased lymphoma risk.

Sjögren Syndrome Histologic and Imaging Studies

The minor salivary gland (lip) biopsy remains the most specific single test, demonstrating focal lymphocytic sialadenitis (FLS) in positive cases.[16][17][18]  Debate continues regarding the added diagnostic value of this biopsy in seropositive patients.[19] However, biopsy findings provide important prognostic information, helping to stratify disease severity and predict systemic manifestations, including the risk of lymphoma.[20]

Salivary gland ultrasonography (SGUS) has emerged as a promising, noninvasive, safe, and cost-effective tool for assessing structural changes in salivary glands. B-mode SGUS can distinguish primary Sjögren syndrome changes from non-Sjögren alterations.[21] Incorporating SGUS into ACR/EULAR classification criteria causes a moderate sensitivity decrease when substituting for minor salivary gland biopsy or SSA antibody testing, with a mild specificity decrease. Sensitivity and specificity remain comparable when SGUS replaces ocular staining score, Schirmer test, or unstimulated whole saliva flow rate.[22]

Treatment / Management

Treatment of Sjögren-Associated Dry Eye and Dry Mouth

First-line therapies

Management of Sjögren-associated dry eye typically begins with tear substitutes, followed by anti-inflammatory eye drops when needed. Preservative-free artificial tears are preferred due to lower ocular toxicity. These may include hydroxypropyl methylcellulose, carboxymethylcellulose, polyvinyl alcohol, hyaluronic acid, or liquid polyols. At night, preservative-free gels or ointments can offer additional relief.

Autologous serum eye drops, prepared from the patient’s blood, may improve symptoms and protect the ocular surface in some cases. However, further research is necessary to confirm its efficacy.[23] Use may be limited by access to approved kits and the need for safe preparation.(A1)

Anti-inflammatory drops and topical corticosteroids can help reduce inflammation; however, infrequent use is recommended due to the unclear long-term benefits and potential risks, including glaucoma, cataracts, and infections. Immunosuppressive eye drops such as cyclosporine or tacrolimus inhibit T-cell activity in the lacrimal glands. These agents require several weeks of consistent use to achieve effects and may be limited by cost or tolerability.

Additional supportive therapies

Punctal occlusion using plugs or cauterization is often needed in more severe cases. Cauterization should follow a successful trial of plugs to avoid excessive tearing.

For dry mouth, drinking water, chewing sugar-free gum, and using saliva substitutes may provide symptom relief. Prescription medications like pilocarpine (Salagen) or cevimeline (Evoxac) stimulate salivary flow. A meta-analysis of 383 patients across 8 randomized controlled trials showed that pilocarpine improved certain measures of saliva production and dry eye symptoms.[24](A1)

Antifungal therapies may be required when yeast infections develop. Additional measures, eg, humidifiers and nasal saline irrigation, may alleviate nasal dryness. Medications that reduce gastric acid, including proton-pump inhibitors and H2 blockers, can ease reflux-related symptoms.

Systemic treatment

Systemic treatment is generally unnecessary for isolated dry eye (xerophthalmia) or dry mouth (xerostomia). However, moderate to severe extraglandular manifestations call for systemic therapy. In such cases, glucocorticoids, antimalarial medication (eg, hydroxychloroquine), and steroid-sparing immunosuppressants, including methotrexate, azathioprine, mycophenolate mofetil, or leflunomide, may be used. Rituximab or cyclophosphamide may be considered occasionally. No clear consensus exists regarding the superiority of one therapeutic approach over another.[25][26][27](A1)

Differential Diagnosis

Differential diagnoses that should also be considered in the evaluation of Sjögren syndrome include:

• Sarcoidosis
• Hashimoto thyroiditis
• Celiac disease
• Rosacea
• Mumps
• Dehydration
• Medications (eg, antidepressants and anticholinergics)
• Mouth breathing
• Lymphoma
• Advanced age with atrophy of exocrine tissues
• sclerosing sialadenitis
• Parkinson disease
• Scleroderma
• Rheumatoid arthritis
• AIDS
• Lupus
• IgG4-related disease
• Sjögren syndrome/sicca syndrome associated with cancer immunotherapy

Prognosis

Mild Sjögren syndrome generally carries a favorable prognosis, while moderate to severe disease often results in diminished quality of life. Persistent symptoms such as dry mouth and dry eyes commonly lead to chronic pain, dental decay, and tooth loss.

Among patients with seropositive disease (positive SSA or SSB antibodies), approximately 7% developed ANA-associated rheumatologic conditions, eg, systemic lupus erythematosus, polymyositis, and systemic sclerosis, over a follow-up period of 5 to 6 years.[28] Constitutional symptoms, cutaneous manifestations, renal abnormalities, and hematological findings occur more frequently in patients with positive ANA or SSA serologies.[29] 

Ongoing long-term studies aim to identify which patients face the greatest risk of complications. A recent French study revealed three distinct clinical subsets based on disease activity scores (ESSDAI), patient-reported symptom burden (ESSPRI), and markers of B-cell activation.[30] 

One group consists of younger individuals with low systemic disease activity but a high symptom burden, typically including fatigue, dryness, and pain. These patients often exhibit increased B-cell activation, eg, hypergammaglobulinemia, reduced C4 levels, and higher seropositivity for SSA or SSB.[30]  A second group presents with both high systemic disease activity and a high symptom burden. These individuals frequently possess additional autoantibodies, including anti-RNP or anti-centromere antibodies.

The third subset includes patients with a high symptom burden but low systemic disease activity. This cohort demonstrated minimal disease progression over a 5-year period and no lymphoma development during a 15-year follow-up. Patients with both high symptom burden and high systemic disease activity demonstrated the greatest risk for developing lymphoma.[30] 

Complications

Complications from Sjögren syndrome may be glandular or extraglandular.[31]

Glandular complications include:

• Keratoconjuntivitis sicca: corneal erosions, vision loss
• Xerostomia: accelerated dental caries, dental decay, and tooth loss

Extraglandular complications include:

• Musculoskeletal: Arthritis, arthralgia, and myalgias occur in most patients with Sjögren syndrome. The estimated prevalence of arthralgia is 96%, while arthritis is about 16%, and myalgia is approximately 70%.[32] Patients may also develop myositis, though low in incidence.

• Dermatologic: The skin is affected in up to 72% of patients with Sjögren syndrome. Complications range from the more common, eg, xeroderma, eyelid dermatitis, and Raynaud phenomenon, to the less common, including cutaneous vasculitis (palpable purpura), cutaneous amyloidosis, and annular erythema.[32]

• Neurologic: Both the central and peripheral nervous systems may be involved in Sjögren syndrome. CNS complications occur in approximately 5% of patients and can vary from mild cognitive dysfunction to transverse myelitis, demyelinating diseases such as neuromyelitis optica, lymphocytic meningitis, or cerebral vasculitis. Cranial neuropathies are uncommon but tend to affect the trigeminal, facial, or cochlear nerves.[32] Peripheral nervous system complications occur in up to 16% of patients with Sjögren syndrome and can involve sensory and sensorimotor neuropathies, small fiber neuropathy, sensory ataxic neuronopathy, and mononeuritis multiplex. Autonomic dysfunction is also reported in patients with Sjögren syndrome.

• Renal: Disorders of the kidney are rare in Sjögren syndrome and are estimated to occur in up to 5% of patients.[32] These complications may include tubulointerstitial nephritis, distal renal tubular acidosis (RTA), and rarely, membranoproliferative glomerulonephritis.

• Hematologic: Cytopenias, hypergammaglobulinemia, hypogammaglobulinemia, monoclonal gammopathy, and cryoglobulins are the most common manifestations. Leukopenia can occur in up to 20% of patients with Sjögren syndrome, anemia in up to 24%, and thrombocytopenia in up to 30% of patients.[32] Hypergammaglobulinemia may occur in up to 40% of patients. 

• Pulmonary: Lung involvement has a wide range of prevalence from 9% to 75%.[33] Manifestations can include respiratory symptoms, eg, cough and dyspnea related to dryness, airway disease (eg, bronchiectasis and bronchiolitis), interstitial lung disease (including nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, organizing pneumonia), cystic lung disease, pulmonary hypertension, and more rare complications.[33]

• Non-Hodgkin lymphoma: A higher risk for lymphoma has been noted compared to the general population. A 2024 meta-analysis of studies examining the relationship between Sjögren syndrome and lymphoma showed an 8.7-fold increased risk in patients with Sjögren syndrome.[34] The risk was also highest in the 40 to 49 age range and for females compared to males.