What is Sjögren's syndrome?

What is Sjögren's Syndrome

Sjögren's syndrome is a chronic systemic autoimmune disease characterized by lymphocytic infiltration and destruction of the lacrimal and salivary glands, resulting in severe dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), with potential for multi-organ involvement and increased lymphoma risk. 1

Core Pathophysiology

The disease fundamentally involves chronic inflammatory cellular infiltration of exocrine glands by lymphocytes, particularly targeting the lacrimal and salivary glands, which leads to progressive glandular dysfunction and the characteristic sicca (dryness) symptoms 2. This destruction occurs as a consequence of abnormal B cell and T cell responses to autoantigens, particularly Ro/SSA and La/SSB 3.

The mechanism is multifactorial, caused by the interplay of genetic susceptibility, environmental triggers (particularly viral infections like Epstein-Barr virus, hepatitis C, HTLV-1, and HIV), and hormonal factors 2.

Epidemiology and Demographics

• Prevalence: Affects approximately 0.4% of the general population, with an annual incidence of 3.9-5.3 per 100,000 people 1
• Gender distribution: Overwhelming female predominance with a 20:1 female-to-male ratio, suggesting strong hormonal influences 1, 2
• Clinical significance: Approximately 10% of patients with clinically significant aqueous deficient dry eye have underlying Sjögren's syndrome 1

Classification

Primary Sjögren's syndrome occurs alone as a distinct autoimmune entity 1.

Secondary Sjögren's syndrome occurs in association with other autoimmune diseases such as rheumatoid arthritis, scleroderma, or systemic lupus erythematosus 1.

Clinical Manifestations

Primary Sicca Symptoms

Dry eyes (keratoconjunctivitis sicca):

• Foreign body sensation, eye irritation, itchiness, or pain 1
• Light sensitivity and frequent need for eye drops 1
• Punctate epithelial erosions, filaments, and mucous plaques on examination 1

Dry mouth (xerostomia):

• Need for liquids to swallow dry foods and frequent water sipping 1
• Burning sensation in the mouth, angular cheilitis 1
• Frequent dental cavities and gingivitis 1
• The dryness is not just about water content—salivary mucin alterations affect the quality of saliva, reducing its ability to sequester water and lubricate the oral mucosa 4

Systemic Manifestations

• Musculoskeletal: Joint pain (arthralgias) and muscle pain (myalgias) 1
• Mucocutaneous: Vaginal dryness causing painful intercourse, dry skin with itchiness or flaking 1
• Neurological: Peripheral neuropathy with numbness, changed sensation, or burning pain in extremities 1
• Constitutional: Extreme fatigue 1
• Pulmonary: Dry nonproductive cough (xerotrachea) affecting 38% of patients, small airway disease, bronchiectasis, and interstitial lung disease (10% within first year, 20% after 5 years) 1

Serious Complications

• Lymphoma risk: Approximately 5% of patients develop lymphoproliferative disorders, particularly extranodal marginal zone B-cell lymphoma 1, 5
• Prognostic marker: Decreased C4 levels at diagnosis are associated with higher lymphoma risk 1, 5, 2
• Other immune manifestations: Scleritis, sterile keratitis, uveitis, and potentially life-threatening vasculitic disorders 1

Diagnostic Criteria

The latest classification criteria use a weighted scoring system where a total score of ≥4 meets criteria for primary Sjögren's syndrome in individuals with suggestive signs/symptoms 1:

• Anti-SSA/Ro antibody positivity: 3 points (most specific marker) 1, 2
• Focal lymphocytic sialadenitis with focus score ≥1 foci/4 mm² on minor salivary gland biopsy: 3 points 1, 2
• Abnormal ocular staining score ≥5 or van Bijsterveld score ≥4: 1 point 1
• Schirmer test result ≤5 mm/5 minutes without anesthesia: 1 point 1
• Unstimulated salivary flow rate ≤0.1 ml/minute: 1 point 1

Diagnostic Workup

Serological testing should include:

• Anti-SSA/Ro and anti-La/SSB antibodies 1
• Rheumatoid factor 1
• Inflammatory markers (ESR, CRP) 1
• Complement levels (C3, C4) for prognostic assessment 2

Objective ocular testing:

• Tear film osmolarity measurement using FDA-approved devices 1
• Point-of-care matrix metalloproteinase-9 testing for inflammatory dry eye 1
• Tear break-up time and meniscus height assessment 1
• Slit-lamp examination with vital dye staining (rose bengal, lissamine green, or fluorescein) 1

Salivary gland assessment:

• Minor salivary gland biopsy if clinical suspicion remains high, looking for focal lymphocytic sialadenitis 1
• Point-of-care testing for salivary protein 1, carbonic anhydrase 6, and parotid secretory protein may indicate early disease 1

Management Approach

First-Line Symptomatic Treatment

For dryness symptoms, topical therapies are first-line:

• Artificial tears and ointments for dry eyes 1
• Saliva substitutes for dry mouth 1

Mild Systemic Disease

For patients with mild systemic manifestations, consider antimalarials such as hydroxychloroquine and NSAIDs for joint pain and inflammation 1.

Severe Systemic Disease

For severe, refractory systemic disease, B-cell targeted therapies may be considered, with sequential use of glucocorticoids, immunosuppressive agents, and biologics following a systemic organ-specific therapeutic approach 1.

Critical Management Considerations

• Co-management with rheumatology is mandatory due to potential systemic complications and lymphoma risk 1, 5
• Regular monitoring for signs of lymphoma development is essential 1, 5
• Screening for other autoimmune conditions (thyroid dysfunction, primary biliary cholangitis) may be warranted 5
• Neurology consultation is mandatory if neurological symptoms develop, with rheumatology maintaining overall disease coordination 1
• Annual pulmonary function tests for patients with respiratory symptoms 1

Important Clinical Pitfalls

• Maintain high suspicion when dry eye occurs with systemic symptoms like fatigue, arthralgia, or recurrent parotid swelling 2
• Do not overlook Sjögren's syndrome in younger patients or men despite the strong female and postmenopausal predominance 2
• Unexplained chronic cough with dry eyes led to Sjögren's diagnosis in 36% of previously undiagnosed patients—consider this presentation 1
• Unstimulated salivary flow correlates poorly with symptoms of mouth dryness; the quality of saliva (particularly mucin alterations) is as important as quantity 4