A 55‑year‑old man with painless swelling of salivary and lacrimal glands and sicca symptoms (dry eyes and dry mouth) – what is the likely diagnosis and recommended work‑up and treatment?

IgG4-Related Disease vs. Sjögren's Syndrome in Painless Salivary and Lacrimal Gland Swelling with Sicca Symptoms

The most likely diagnosis in a 55-year-old man with painless bilateral swelling of salivary and lacrimal glands plus sicca symptoms is IgG4-related disease (IgG4-RD), not Sjögren's syndrome, given the male sex and bilateral gland enlargement pattern. While Sjögren's syndrome remains in the differential, the demographic profile strongly favors IgG4-RD.

Key Distinguishing Features

Demographic Considerations

• Sjögren's syndrome shows overwhelming female predominance with a 20:1 female-to-male ratio, making it statistically less likely in a male patient 1
• IgG4-RD affects predominantly males (57%) with average symptom onset at 50 years, matching this clinical scenario perfectly 2

Clinical Presentation Patterns

• IgG4-RD characteristically presents with subacute, painless submandibular and/or parotid swelling with bilateral involvement in most cases (71% bilateral disease) 3, 2
• Lacrimal gland involvement occurs in 62% of IgG4-related ophthalmic disease cases 2
• Sjögren's syndrome typically presents with sicca symptoms first, with gland enlargement being less prominent 4

Diagnostic Work-Up Algorithm

Initial Laboratory Testing

• Serum IgG4 concentration (elevated in IgG4-RD, particularly with bilateral and extra-orbital involvement) 2
• Anti-SSA/Ro and Anti-La/SSB antibodies (positive in Sjögren's, scores 3 points toward diagnosis) 4
• Rheumatoid factor, ANA, complement levels (C3, C4) 4
• Complete blood count, ESR, CRP 1

Objective Sicca Assessment

• Schirmer test without anesthesia (≤5 mm/5 minutes scores 1 point for Sjögren's) 4
• Ocular surface staining with lissamine green or fluorescein (≥5 Ocular Staining Score or ≥4 van Bijsterveld score scores 1 point) 4
• Unstimulated whole salivary flow rate (≤0.1 mL/minute scores 1 point for Sjögren's) 4

Tissue Diagnosis (Gold Standard)

• Biopsy of affected salivary gland remains the gold standard for definitive diagnosis 5
• IgG4-RD histopathology shows: dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis 6
• Sjögren's histopathology shows: focal lymphocytic sialadenitis with focus score ≥1 foci/4 mm² (scores 3 points) 4
• Minor labial salivary gland biopsy can be performed if major gland biopsy is not feasible 1

Imaging Studies

• Integration of different imaging techniques (ultrasound, CT, MRI) is often required for salivary gland swelling evaluation 5
• Assess for extra-orbital involvement, as 71% of IgG4-ROD patients have systemic disease 2

Treatment Approach

For IgG4-Related Disease

• First-line treatment: systemic glucocorticoids, which are usually highly efficacious and produce rapid response 6, 3
• Rituximab (B-cell depletion therapy) for steroid-resistant disease or as steroid-sparing agent for relapsing disease 6, 2
• Ten patients in one series improved following rituximab treatment 2

For Sjögren's Syndrome (If Confirmed)

• Topical lubricants and anti-inflammatory therapy (cyclosporine 0.05%) for moderate to severe dry eye 4
• Oral secretagogues (pilocarpine 5 mg three to four times daily or cevimeline) primarily effective for oral dryness 4
• Hydroxychloroquine for systemic manifestations (fatigue, arthralgias), though evidence for dry eye efficacy is weak 4
• Mandatory rheumatology co-management due to 5% lifetime lymphoma risk, particularly with low C4 levels 1, 7

Critical Diagnostic Pitfalls

Common Misdiagnosis Scenarios

• IgG4-RD frequently mimics Sjögren's syndrome, lymphoma, sarcoidosis, and granulomatosis with polyangiitis, making accurate biopsy diagnosis essential 2
• Do not rely solely on elevated serum IgG4, as this can occur in other conditions; histopathology is required 6, 5
• Sjögren's diagnosis requires ≥4 points on weighted scoring system; do not diagnose based on sicca symptoms alone 4

Key Monitoring Considerations

• Both conditions carry lymphoma risk: Sjögren's has ~5% lifetime risk, IgG4-RD can progress to lymphoproliferative disorders 1, 7
• Patients with decreased C4 levels at Sjögren's diagnosis have higher lymphoma risk 4
• Regular surveillance for systemic complications is mandatory in both conditions 1

Treatment Selection Errors

• Anti-TNF agents are not effective for Sjögren's-related dry eye 4
• Rituximab evidence for Sjögren's is not strong, but shows promise for IgG4-RD 4, 2
• Tear-conserving strategies (punctal plugs) should accompany topical therapy 4