What are the clinical presentation, diagnostic criteria, and management strategies for Sjögren’s syndrome?

Sjögren's Syndrome: Clinical Overview

Definition and Epidemiology

Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, primarily affecting the lacrimal and salivary glands, resulting in severe mucosal dryness (sicca syndrome), with a prevalence of approximately 0.4% and a striking female predominance (20:1 female-to-male ratio). 1, 2

• Annual incidence ranges from 3.9-5.3 per 100,000 people 1, 2
• Predominantly affects middle-aged women but can occur in children, men, and elderly 3
• Approximately 10% of patients with clinically significant aqueous deficient dry eye have underlying primary Sjögren's syndrome 2

Clinical Presentation

Core Sicca Symptoms

The clinical hallmark is the "sicca complex" of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), which dominates the clinical picture. 1

Ocular manifestations include: 2

• Foreign body sensation in the eyes
• Eye irritation, itchiness, or pain
• Light sensitivity (photophobia)
• Frequent need for artificial tears

Oral manifestations include: 2

• Need for liquids to swallow dry foods
• Frequent sipping/drinking of water
• Burning sensation in the mouth
• Angular cheilitis (painful sores at mouth corners)
• Frequent dental cavities and gingivitis

Systemic Manifestations

Beyond sicca symptoms, Sjögren's syndrome presents with a wide spectrum of systemic features that significantly impact morbidity and quality of life. 1

Musculoskeletal involvement: 2

• Joint pain (arthralgias) and muscle pain (myalgias)

Mucocutaneous manifestations: 2, 4

• Vaginal dryness causing dyspareunia
• Dry skin (xeroderma) with itchiness or flaking
• Eyelid dermatitis, annular erythema, cutaneous vasculitis

Neurological complications: 2

• Peripheral neuropathy with numbness, altered sensation, or burning pain in extremities

Constitutional symptoms: 2

• Extreme fatigue (markedly impairs quality of life)

Pulmonary involvement (affects up to 38% of patients): 2

• Chronic dry cough (xerotrachea) lasting >8 weeks
• Small airway disease (bronchiolitis)
• Bronchiectasis with chronic sputum production
• Interstitial lung disease (ILD) - prevalence increases to 20% after 5 years
• Progressive dyspnea ranging from minimal exertional to severe respiratory compromise

Renal manifestations: 5

• Distal renal tubular acidosis (dRTA) - classified as potentially life-threatening
• Nephrocalcinosis

Critical Complications

Approximately 5% of patients develop lymphoid malignancy, representing the most serious complication with significant mortality implications. 1, 2

• Primary Sjögren's syndrome is the rheumatic disease most strongly associated with lymphoma development 6
• Decreased C4 complement levels at diagnosis predict higher lymphoma risk 1, 2
• Other life-threatening complications include vasculitic disorders 1
• Additional ocular immune manifestations: scleritis, sterile keratitis, uveitis 1

Diagnostic Criteria

The 2016 American-European consensus classification criteria use a weighted scoring system where a total score ≥4 points establishes the diagnosis of primary Sjögren's syndrome. 1, 2

Scoring System

High-value criteria (3 points each): 1, 2

• Anti-SSA/Ro antibody positivity
• Focal lymphocytic sialadenitis with focus score ≥1 foci/4 mm² on minor salivary gland biopsy

Standard criteria (1 point each): 1, 2

• Abnormal ocular staining score ≥5 (or van Bijsterveld score ≥4)
• Schirmer test ≤5 mm/5 minutes without anesthesia
• Unstimulated salivary flow rate ≤0.1 ml/minute

Diagnostic Workup

Serological testing should include: 1, 2

• Anti-SSA/Ro and anti-SSB/La antibodies (most specific)
• Antinuclear antibodies (ANA) - most frequently detected
• Rheumatoid factor (RF)
• Complement levels (C3, C4) - prognostic markers
• Cryoglobulins - prognostic markers

Objective ocular surface testing: 2

• Slit-lamp biomicroscopy evaluating tear meniscus height, tear break-up time, punctate staining patterns
• Tear film osmolarity measurement using FDA-approved devices
• Point-of-care matrix metalloproteinase-9 testing for inflammatory dry eye
• Ocular surface staining with lissamine green or fluorescein

Salivary gland assessment: 2

• Unstimulated whole salivary flow rate measurement
• Minor salivary gland biopsy (if clinical suspicion remains high despite negative serology)
• Point-of-care testing including salivary protein 1 (SP1), carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP) may indicate early disease

Pulmonary evaluation (if respiratory symptoms present): 2

• High-resolution CT chest with expiratory views
• Baseline pulmonary function tests
• Oximetry testing at rest and with exercise

Diagnostic Pitfalls to Avoid

Do not dismiss Sjögren's syndrome based solely on negative anti-SSA/Ro antibodies - diagnosis can still be established with ≥4 points from other objective criteria. 2

• Medication-induced sicca symptoms (antihistamines, diuretics, antidepressants, anticholinergics) must be excluded 2
• Diabetes increases dry eye prevalence (17.5% in diabetics) but does not exclude concurrent Sjögren's syndrome 2
• Maintain high suspicion in nonelderly women with rapid-onset or severe tear deficiency 1
• Unexplained chronic cough with dry eyes led to Sjögren's diagnosis in 36% of previously undiagnosed patients 2

Management Strategies

Overarching Principles

Management follows a logical sequence: first address the central triplet of symptoms (dryness, fatigue, pain), then manage systemic disease manifestations. 1

Mandatory rheumatology co-management is essential due to systemic complications, lymphoma risk, and need for immunosuppressive therapy coordination. 1, 2

Symptomatic Management of Sicca Features

First-line treatment for dryness should be symptomatic relief using topical therapies. 1, 2

Ocular dryness management: 1

• Artificial tears and lubricating ointments (primary therapy)
• Topical cyclosporine 0.05% for moderate to severe dry eye with inflammatory component
• Topical corticosteroids (short-term use)
• Serum tear drops for severe cases
• Topical NSAIDs (limited role)

Oral dryness management: 1, 2

• Saliva substitutes as first-line symptomatic relief
• Oral muscarinic agonists if inadequate response to topical measures:
  • Pilocarpine 5 mg orally three to four times daily
  • Cevimeline (alternative muscarinic agonist)
• Note: Oral secretagogues show greater efficacy for oral dryness than ocular dryness 1

Patient education is critical: 1, 2

• Avoid alcohol and tobacco smoking
• Pursue meticulous dental hygiene
• Understand aggravating factors and treatment goals

Systemic Disease Management

For mild systemic manifestations (arthralgias, fatigue): 1, 2

• Hydroxychloroquine 200-400 mg daily may be considered
• NSAIDs for joint pain and inflammation
• Note: Evidence for hydroxychloroquine improving dry eye is weak 1

For severe, refractory systemic disease, follow sequential escalation: 1, 2

1. Oral glucocorticoids:

   • Pulse methylprednisolone 1-2 mg/kg IV for acute severe involvement
   • Oral prednisone 0.5-1 mg/kg/day for moderate involvement

2. Synthetic immunosuppressive agents: 1

   • Cyclophosphamide
   • Azathioprine
   • Methotrexate
   • Leflunomide
   • Mycophenolate

3. Biological therapies: 1

   • Rituximab (B-cell targeted therapy for severe disease)
   • Abatacept
   • Belimumab
   • Note: Anti-TNF agents were not found effective 1

Organ-Specific Management

Neurological complications require immediate neurology consultation: 2

• Mandatory co-management with neurology when neurological symptoms develop
• EMG/nerve conduction studies and MRI imaging as indicated
• Plasmapheresis for acute or severe disease

Pulmonary involvement requires: 2

• Annual pulmonary function tests for patients with respiratory symptoms
• Aggressive management of interstitial lung disease with immunosuppression

Monitoring and Surveillance

Regular monitoring for lymphoma development is essential: 2, 6

• Screen for unexplained weight loss, fevers, night sweats
• Evaluate new lymphadenopathy, particularly head and neck region
• Monitor complement levels (low C4 indicates higher risk)
• Complete blood count monitoring for cytopenias or abnormal lymphocyte counts

Avoid these critical pitfalls: 2, 6

• Overlooking medication-induced hematologic abnormalities in patients on immunosuppressive therapy
• Neglecting lymphoma screening in patients with unexplained hematologic abnormalities
• Failing to recognize pulmonary involvement early (chronic cough is a key diagnostic clue)

Evidence Quality Note

The EULAR recommendations acknowledge that levels of evidence are mostly modest, though task force agreement is very high. 1 Treatment decisions remain challenging without specific therapeutic targets beyond symptom relief, emphasizing the importance of individualized approaches within the framework provided.