Sjogren syndrome
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"Sjogren syndrome"[MeSH Terms]
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"Sjogren syndrome"[MeSH Terms] AND diagnosis
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Sjögren Syndrome
Definition and Epidemiology
Sjögren syndrome (SjS) is a chronic autoimmune inflammatory disorder of the exocrine glands - primarily the salivary and lacrimal glands - characterized by lymphoplasmacytic infiltration and resulting glandular hypofunction. The hallmark presentation is the sicca complex: xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes).
- Prevalence: 1-3% of the population
- Sex: >90% of patients are women (female-to-male ratio ~9:1)
- Age of onset: Most commonly in the 4th-5th decades of life
- Classification:
- Primary SjS: Sicca complex alone, not associated with another autoimmune disease
- Secondary SjS: Sicca complex occurring alongside another autoimmune disease (most commonly rheumatoid arthritis, SLE, scleroderma, polymyositis, or primary biliary cholangitis)
Pathogenesis
The etiology involves a three-way interaction of genetics, the immune system, and environment:
- Genetic predisposition: HLA alleles B8 and DR3 confer susceptibility
- Environmental trigger: Most likely a viral infection acts as the inciting event
- Aberrant autoimmune response:
- Dense lymphocytic infiltration of exocrine glands
- B-cell overstimulation producing excess immunoglobulins and autoantibodies
- Formation of germinal centers within salivary glands, allowing autoreactive B-cell clones to escape tolerance checkpoints
- Elevated follicular helper T-cell levels contribute to disease development
- Autoantibodies against M3-muscarinic acetylcholine receptors impair glandular secretion
Key autoantibodies:
- Anti-Ro/SS-A (60 kDa ribonucleoprotein, also associated with Ro52/TRIM21)
- Anti-La/SS-B (48 kDa protein, almost always accompanied by anti-SS-A)
- Also: ANA (homogeneous or speckled pattern), rheumatoid factor, cryoglobulins, hypergammaglobulinemia
Clinical Features
Glandular (Sicca Complex)
Oral (Xerostomia):
- Difficulty chewing, swallowing, and speaking
- Dental caries (often rampant)
- Adherence of food to buccal mucosa
- Intolerance to acidic/spicy foods
- Smooth, fissured tongue with papillary atrophy
- Oral candidiasis (Candida albicans overgrowth)
- Absence of pooled saliva in the floor of the mouth
- Scant or cloudy saliva from ducts
- Parotid gland enlargement in 25-66% of patients - may be unilateral initially, but typically bilateral; can be episodic or chronic
Ocular (Keratoconjunctivitis Sicca):
- "Gritty" or "sandy" foreign body sensation
- Dilated bulbar conjunctival vessels, periorneal injection
- Corneal epithelial irregularity
- Occasional lacrimal gland enlargement
Systemic (Extraglandular) Manifestations
Occur in approximately one-third of patients:
| System | Manifestations |
|---|---|
| Constitutional | Fatigue, generalized malaise, low-grade fever, myalgia, arthralgia |
| Pulmonary | Dryness of pharynx/trachea, bronchitis, pneumonia; NSIP (most common ILD pattern), lymphoid interstitial pneumonia (LIP), amyloidosis |
| Renal | Tubulointerstitial nephritis, distal renal tubular acidosis, impaired concentrating ability, hypercalciuria; rarely glomerulonephritis (mesangial, MPGN, membranous) |
| Vascular | Raynaud phenomenon, recurrent urticaria-like lesions; vasculitis in 20-30% |
| Neurologic | Peripheral sensory and motor polyneuropathies (10-30% of primary SjS); sensory ataxic neuronopathy; small-fiber neuropathy; trigeminal sensory neuropathy; autonomic neuropathy (cardiac parasympathetic dysfunction, anhidrosis, Adie pupil) |
| Skin | Cutaneous vasculitis, dry skin, vaginal dryness |
| GI/Endocrine | Dysphagia, esophageal dysmotility; associated with primary biliary cholangitis, chronic active hepatitis, Crohn disease, thyroid disease |
| Lymphoproliferative | Increased risk of B-cell lymphoma (esp. MALT type) - risk persists for >2 decades; also Waldenström macroglobulinemia |
Key risk: Persistent unilateral or bilateral parotid enlargement is a warning sign for lymphoma development.
Diagnosis
Objective Tests
Ocular evaluation:
- Schirmer test: <8 mm wetting per 5 minutes (or <5 mm in modified test) indicates reduced tear production
- Rose Bengal staining: Stains damaged corneal and conjunctival epithelia - positive in keratoconjunctivitis sicca
Salivary evaluation:
- Salivary flow rate (Lashley cups over Stensen duct)
- Sialography: Demonstrates sialectasis in 85-97% of SjS patients
Tissue biopsy:
- Minor salivary gland biopsy (labial) is the most consistent feature of primary SjS; should include several glandular lobes from areas with normal overlying mucosa
- Histopathology: Focal lymphocytic sialadenitis - multiple mononuclear aggregates adjacent to and replacing normal acini; focus score ≥1 (foci/4 mm²) is diagnostic
Serology:
- Anti-Ro/SS-A and anti-La/SS-B antibodies (ELISA)
- ANA (>1:320), RF (>1:320)
- Elevated ESR, hypergammaglobulinemia
Diagnostic Criteria
San Diego Criteria (Fox et al.) requires all three for definite SjS:
| Criterion | Details |
|---|---|
| A - Ocular | Schirmer test <8 mm/5 min AND positive Rose Bengal staining |
| B - Oral | Decreased parotid flow rate AND minor salivary gland biopsy (focus score ≥1) |
| C - Serologic | Elevated RF (>1:320), ANA (>1:320), or anti-SS-A/SS-B |
Probable SjS can be diagnosed without biopsy (criteria A, B-1 oral flow only, and C).
Exclusions: HIV infection, hepatitis B/C, sarcoidosis, preexisting lymphoma, primary fibromyalgia, keratitis sicca from other causes.
Note: Patients with HIV or hepatitis C virus can present with sicca complex that mimics SjS - these must be excluded before diagnosing SjS.
Pulmonary Radiology (HRCT Findings)
- NSIP is the most common ILD pattern
- LIP (lymphoid interstitial pneumonia): thin-walled cysts + ground-glass opacity
- Association of LIP with amyloidosis produces multiple irregular nodules with cysts
- Mild bronchiectasis is common
- Finding of LIP + nodules/consolidations should raise concern for pulmonary lymphoma
Neurology in Sjögren Syndrome
Peripheral nerve involvement occurs in 10-30% of primary SjS patients and may precede sicca symptoms:
- Most common: Distal symmetrical sensory neuropathy (mixed large/small fiber)
- Sensory ataxic neuronopathy (dorsal root ganglionopathy) - loss of kinesthesia/proprioception; may mimic spinocerebellar ataxia
- Small-fiber neuropathy, polyradiculoneuropathy, multiple mononeuropathies
- Trigeminal sensory neuropathy, autonomic neuropathy
- EMG/NCS: Reduced/absent SNAPs, normal or mildly abnormal motor conduction
- MRI cervical cord: T2 hyperintensity in posterior columns in sensory ganglionopathy
Treatment
Symptomatic Management
| Problem | Treatment |
|---|---|
| Xerostomia | Chew sugarless gum/candy (local stimulation); pilocarpine 5 mg TID-QID (muscarinic agonist sialagogue) - side effects: sweating, flushing, urinary frequency; saliva substitutes |
| Dental caries | Fluoride treatment, preventive dental care |
| Keratoconjunctivitis | Artificial tear lubricants; eye patching if corneal ulceration develops |
| Oral candidiasis | Antifungal agents |
Disease-Modifying / Systemic Treatment
| Indication | Treatment |
|---|---|
| Systemic disease / B-cell depletion | Rituximab (anti-CD20 monoclonal antibody) - reduces both peripheral and salivary gland B-cell subsets; improves xerostomia, fatigue, joint tenderness. Note: not beneficial for low disease activity |
| Severe extraglandular complications (glomerulonephritis, necrotizing vasculitis) | Systemic corticosteroids ± cytotoxic immunosuppressants |
| Emerging therapies | Belimumab (anti-BAFF), abatacept (CTLA4-Ig) - promising in preliminary trials |
Salivary Gland-Specific
- Sialendoscopy: Dilation and irrigation of affected ducts for recurrent sialadenitis - reduces intensity/frequency of episodes
- Gland excision: If all other treatments fail
- Unilateral enlargement despite known SjS should raise suspicion for tumor
Key Associations and Complications
- Lymphoma risk is elevated even after 2+ decades of benign disease - primary SjS is the autoimmune condition with the highest lymphoma risk (predominantly marginal zone / MALT lymphoma)
- Renal tubular acidosis can present with hypokalemic periodic paralysis
- Neonatal lupus/congenital heart block: anti-Ro/SS-A antibodies in pregnant women with SjS can cross the placenta
- Lab: Serum complement is generally normal in primary SjS (unlike SLE); low complement suggests associated cryoglobulinemia or secondary SjS-SLE overlap
Sources: Cummings Otolaryngology Head and Neck Surgery, p. 1497-1499 | Textbook of Family Medicine 9e, p. 698-700 | Brenner and Rector's The Kidney, p. 1487 | Bradley and Daroff's Neurology, p. 2699 | Grainger & Allison's Diagnostic Radiology, p. 238 | Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 1521-1528
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