Sjögren Syndrome
Chronic autoimmune exocrinopathy producing keratoconjunctivitis sicca and xerostomia.
Also known as: Sjogren syndrome, Sjögren syndrome, primary Sjögren, sicca syndrome
Overview
A chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, producing dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), with frequent extraglandular involvement. Primary Sjögren occurs in isolation; secondary Sjögren accompanies another autoimmune disease, most commonly rheumatoid arthritis, SLE, or systemic sclerosis.
Epidemiology
Estimated prevalence 0.5-1.0 percent. Female-to-male ratio approximately 9:1. Peak onset in the fifth and sixth decades.
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Risk factors
- Female sex
- Age 40-60
- Family history of autoimmune disease
- HLA-DR3, HLA-DQ2 associations
- Existing autoimmune disease (secondary Sjögren)
- Viral exposure has been implicated (Epstein-Barr virus, hepatitis C, HTLV-1) but not firmly established
Pathophysiology
Lymphocytic (predominantly CD4+ T-cell and B-cell) infiltration of exocrine glands disrupts secretion. B-cell hyperactivity produces hypergammaglobulinemia and characteristic autoantibodies (anti-SSA/Ro and anti-SSB/La). Chronic glandular inflammation may evolve into lymphoma, particularly mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid.
Clinical presentation
Symptoms
- Dry eyes — sandy, gritty sensation, foreign body feeling, photophobia, decreased tearing
- Dry mouth — difficulty swallowing dry foods, frequent water intake at meals, dental caries, oral candidiasis
- Parotid enlargement (recurrent or persistent)
- Vaginal dryness and dyspareunia
- Fatigue and arthralgia
- Symptoms of extraglandular disease: Raynaud, rash, lung disease, neuropathy
Signs / physical exam
- Decreased tear production (Schirmer test <5 mm wetting in 5 minutes is abnormal)
- Corneal staining with rose bengal, fluorescein, or lissamine green
- Dry, fissured tongue, salivary pooling absent
- Dental caries, particularly at the gum line
- Parotid enlargement
- Purpuric rash from hypergammaglobulinemic purpura on lower extremities
- Articular involvement — non-erosive inflammatory polyarthritis
Classic findings
Middle-aged woman with progressive ocular and oral dryness, bilateral parotid enlargement, positive anti-SSA/Ro and anti-SSB/La antibodies, and dental caries.
Differential diagnosis
- Age-related sicca — Mild dryness without systemic symptoms, normal labs, normal salivary gland biopsy
- Medication-induced dryness — Anticholinergics, antihistamines, antidepressants, antihypertensives; resolves with discontinuation
- IgG4-related disease (Mikulicz syndrome) — Symmetric salivary and lacrimal gland enlargement, elevated IgG4, characteristic histology
- Sarcoidosis — Bilateral hilar lymphadenopathy, elevated ACE, non-caseating granulomas; salivary involvement (Heerfordt syndrome)
- HIV-associated diffuse infiltrative lymphocytosis syndrome (DILS) — Salivary gland enlargement and CD8+ infiltrate in HIV; SSA/SSB negative
- Head and neck radiation history — Permanent xerostomia after radiation therapy
Diagnostic workup
Diagnostic criteria
ACR/EULAR 2016 classification criteria. Diagnosis requires a score ≥4 from the weighted items: anti-SSA positive (3), focus score ≥1 on labial biopsy (3), abnormal ocular staining score ≥5 (1), Schirmer test ≤5 mm/5 min (1), unstimulated salivary flow ≤0.1 mL/min (1). Patients must have symptoms of ocular or oral dryness or systemic features.
Labs
- Anti-SSA (Ro) — positive in 70-90 percent; anti-SSB (La) — positive in 40-60 percent
- ANA — positive in 70-80 percent
- Rheumatoid factor — positive in 50-70 percent
- CBC (cytopenias), CMP, ESR, CRP, immunoglobulins (hypergammaglobulinemia), complement (low C3/C4 in vasculitis)
- Cryoglobulins, urinalysis, and renal function in suspected glomerulonephritis or cryoglobulinemia
Imaging
- Schirmer test, tear breakup time, ocular staining score by ophthalmology
- Unstimulated whole salivary flow rate (<0.1 mL/min is abnormal)
- Salivary gland ultrasound — increasingly used to demonstrate characteristic glandular heterogeneity
- Minor salivary gland (labial) biopsy — focus score ≥1 (≥1 cluster of ≥50 lymphocytes per 4 mm² of glandular tissue) is the gold standard
Diagnostic algorithm
| Domain | Test | Abnormal Result |
|---|---|---|
| Ocular | Schirmer test | <5 mm wetting in 5 min |
| Ocular | Ocular staining score | ≥5 |
| Oral | Unstimulated salivary flow | ≤0.1 mL/min |
| Serology | Anti-SSA (Ro) | Positive |
| Histology | Labial salivary gland biopsy | Focus score ≥1 |
Treatment
First-line
- Symptom-directed therapy is the cornerstone
- Dry eyes: preservative-free artificial tears, lubricant gels at night, environmental humidification, avoidance of antihistamines and decongestants; topical cyclosporine (Restasis) or lifitegrast for moderate-severe disease
- Dry mouth: frequent sips of water, sugar-free lozenges and gum, saliva substitutes, meticulous dental hygiene with topical fluoride and routine cleanings
- Cholinergic agonists (pilocarpine, cevimeline) to stimulate residual salivary and lacrimal function
- Hydroxychloroquine for fatigue, arthralgia, and rash
- Methotrexate or azathioprine for inflammatory arthritis
Second-line / adjunct
- Systemic glucocorticoids for severe extraglandular disease (vasculitis, glomerulonephritis, severe inflammatory arthritis)
- Rituximab for systemic involvement, cryoglobulinemic vasculitis, refractory disease, and certain neurologic complications
- Immunosuppressive agents (mycophenolate, cyclophosphamide) for vasculitis, severe ILD, or glomerulonephritis
- Punctal plugs for refractory ocular dryness
Complications
- Severe dental caries, periodontal disease, oral candidiasis
- Corneal ulceration and visual loss from severe keratoconjunctivitis sicca
- Non-Hodgkin lymphoma — typically MALT lymphoma of the parotid; lifetime risk 5-10 percent, with persistent parotid enlargement, lymphadenopathy, low C4, and cryoglobulins as risk factors
- Interstitial lung disease (NSIP pattern, LIP, organizing pneumonia)
- Renal involvement (interstitial nephritis, renal tubular acidosis)
- Peripheral neuropathy (sensory, small fiber, sensorimotor) and CNS disease (rare)
- Cutaneous vasculitis
PANCE pearls
- Anti-SSA crosses the placenta and can cause congenital heart block in offspring — pregnancies require fetal echocardiographic monitoring between 16-26 weeks.
- Persistent unilateral parotid enlargement raises concern for lymphoma and warrants biopsy.
- Sjögren is the most common cause of distal renal tubular acidosis (type 1) — check for hypokalemic, non-anion-gap metabolic acidosis with inability to acidify urine.
- Sicca symptoms can also result from medications — review the medication list before pursuing extensive workup.
References
- ACR/EULAR 2016 — Shiboski CH et al., 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (Arthritis Rheumatol 2017)
- EULAR 2020 — Ramos-Casals M et al., EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies (Ann Rheum Dis 2020)
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