Sjögren syndrome
Description
- Chronic autoimmune exocrinopathy: progressive lymphocytic infiltration of salivary and lacrimal glands
- Classic triad: sicca (dry eyes + dry mouth), fatigue, pain
- Primary - isolated
- Secondary - alongside another CTD
- RA > SLE > systemic sclerosis (also dermatomyositis, PBC, autoimmune thyroid disease)
Two disease axes - they do not track together
- Glandular (sicca) - burdensome, rarely dangerous
- Extra-glandular / systemic - drives morbidity and mortality
- Sicca severity does not predict systemic disease
In children
- Recurrent parotitis is the commonest presentation, then sicca (dry mouth, halitosis, painful oral mucosa)
Epidemiology
- Prevalence ~0.1-0.6%; one of the commonest autoimmune diseases
- F:M ~9:1
- Peak diagnosis 40-60 yr
- Long diagnostic delay - sicca is attributed to age or drugs
Aetiopathogenesis
- Epithelial cell activation ("autoimmune epithelitis") -> type I interferon signature
- Lymphocytic infiltration: CD4 T cells + B cells -> ectopic germinal centres in the gland
- BAFF overexpression -> B-cell survival and clonal expansion
- -> the direct link to MALT lymphoma
- Autoantibodies to Ro (SSA) and La (SSB) ribonucleoproteins
- Glandular destruction + anti-M3 muscarinic receptor antibodies -> secretory failure disproportionate to the tissue loss
- Genetic: HLA-DR3/DQ2, IRF5, STAT4, TNFAIP3 (germline mutation -> lymphoma risk)
- Triggers: EBV, other viruses
Diagnosis
2016 ACR/EULAR classification criteria - score >=4 classifies
Entry: sicca symptoms, or suspicion from the ESSDAI
| Item | Points |
|---|---|
| Labial salivary gland focal lymphocytic sialadenitis, focus score >=1 (>=1 focus of >=50 lymphocytes per 4 mm2) | 3 |
| Anti-SSA/Ro60 positive | 3 |
| Ocular staining score >=5 (or van Bijsterveld >=4) in at least one eye | 1 |
| Schirmer test <=5 mm/5 min in at least one eye | 1 |
| Unstimulated whole salivary flow <=0.1 mL/min | 1 |
- *Isolated anti-Ro52 does not count - only Ro60 is specific*
- *Anti-La/SSB alone does not count in the 2016 criteria* (a change from earlier systems)
- Exclusions (mimics that must be ruled out first): head/neck radiotherapy, active HCV, HIV, sarcoidosis, amyloidosis, IgG4-related disease, GVHD
Serology
| Frequency | Note | |
|---|---|---|
| Anti-Ro/SSA | ~60-70% | Also SLE, SCLE, neonatal lupus, congenital heart block |
| Anti-La/SSB | ~40% | Rarely alone |
| ANA | ~85% | Speckled |
| Rheumatoid factor | ~50% | A positive RF in a sicca patient does not mean RA |
| Anti-dsDNA | Typically ABSENT | Presence suggests SLE |
| inc ESR | 80-90% | CRP typically normal |
| Polyclonal hypergammaglobulinaemia | ~30% | Loss of the polyclonal band + a new monoclonal band = think lymphoma |
| Cryoglobulins | ~15% | Lymphoma and vasculitis risk marker |
| Low C4 | Lymphoma and mortality risk marker | |
| Cytopenias | ~20% each | Anaemia, leucopenia, thrombocytopenia |
Objective tests
- Schirmer - <=5 mm wetting in 5 min
- Ocular staining (lissamine green/fluorescein) by ophthalmology; tear break-up time
- Unstimulated whole salivary flow <=0.1 mL/min
- Labial minor salivary gland biopsy - focal lymphocytic sialadenitis, focus score >=1
- Reserve for seronegative patients where the diagnosis would change management
- Salivary gland ultrasound - heterogeneous hypoechoic areas; increasingly used, not yet in the criteria
Parotid mass - the differential to run
- Infection: mumps, EBV, HCV, HIV (diffuse infiltrative lymphocytosis syndrome), bacterial parotitis, TB
- Autoimmune: Sjogren, GPA
- Inflammatory: IgG4-related disease, allergic parotitis, Kimura disease
- Metabolic: diabetes, bulimia, alcoholism, hyperlipoproteinaemia
- Neoplastic: lymphoma, leukaemia, Warthin tumour, pleomorphic adenoma
- Granulomatous: sarcoidosis
- *Persistent, unilateral or hard parotid enlargement in known Sjogren = lymphoma until proven otherwise*
Systemic activity
- ESSDAI - 12 domains; >=5 = moderate activity and a lymphoma risk marker
- ESSPRI - patient-reported dryness, fatigue, pain
Management
Axis: by presenting problem. Sicca, fatigue and pain are managed separately from systemic disease, and systemic therapy does NOT improve sicca.
A. Sicca - dry eyes
- Review and stop drying drugs first: anticholinergics, tricyclics, antihistamines, diuretics, opioids
- Preservative-free artificial tears and ocular gels/ointments at night
- Topical ciclosporin 0.05% or lifitegrast for inflammatory dry eye
- Punctal plugs or punctal occlusion if refractory
- Short courses of topical corticosteroid under ophthalmology supervision
- Autologous serum eye drops for severe keratoconjunctivitis sicca
- Environmental: humidifier, avoid air-conditioning and wind, moisture-chamber glasses
- *Annual ophthalmology review - corneal ulceration and perforation are the sight-threatening risks*
B. Sicca - dry mouth
- Meticulous dental care - 6-monthly dentist, high-fluoride toothpaste, sugar-free gum, avoid sugary drinks
- Rampant cervical and root caries is the commonest serious glandular complication
- Frequent water sips, saliva substitutes
- Muscarinic agonists (secretagogues) if residual gland function
- Pilocarpine 5 mg 3-4x daily, or cevimeline
- Side effects: sweating, flushing, nausea, urinary frequency. Contraindicated in uncontrolled asthma, narrow-angle glaucoma, significant bradycardia**
- Treat oral candidiasis (often angular cheilitis/denture stomatitis) - topical antifungal; look under dentures
- Sialendoscopy for obstructive symptoms
C. Fatigue and pain
- Structured aerobic exercise - the only intervention with consistent evidence for fatigue
- Sleep assessment, mood assessment
- Arthralgia/arthritis: NSAIDs and hydroxychloroquine
- Neuropathic pain: gabapentin, pregabalin or duloxetine
- Immunosuppression does not treat fatigue - resist escalating for it
D. Systemic / extra-glandular disease
Treat according to organ and severity, guided by ESSDAI.
- Mild: hydroxychloroquine +/- low-dose prednisolone
- Moderate: prednisolone + a steroid-sparing agent - methotrexate, azathioprine, mycophenolate, leflunomide, ciclosporin
- Severe/organ-threatening (vasculitis, severe ILD, glomerulonephritis, transverse myelitis, mononeuritis multiplex):
- Pulse methylprednisolone, then cyclophosphamide or rituximab
- Rituximab is the agent of choice where cryoglobulinaemic vasculitis is present
- Plasma exchange for severe cryoglobulinaemic or hyperviscosity disease
- Interstitial lung disease: mycophenolate or rituximab; antifibrotic if progressive fibrosing phenotype
- Distal (type 1) RTA: potassium and bicarbonate replacement, treat hypokalaemia (may present as paralysis or nephrocalcinosis)
- *TNF inhibitors (infliximab, etanercept) are ineffective in Sjogren* - negative trials
- B-cell targeted therapy is where the field is: rituximab (mixed trial results but used in practice), ianalumab (anti-BAFF-R) and other agents in trials
E. Lymphoma surveillance - the reason to keep reviewing
- Examine parotids, spleen and nodes at every visit
- Monitor: RF, C4, cryoglobulins, immunoglobulins, protein electrophoresis, FBE
- Investigate: persistent/unilateral parotid swelling, new lymphadenopathy or splenomegaly, new monoclonal band, falling immunoglobulins with prior hypergammaglobulinaemia, new or falling C4, B symptoms
F. Pregnancy
- Anti-Ro/La -> risk of neonatal lupus and congenital complete heart block (~2%, up to ~20% if a previously affected child)
- Continue hydroxychloroquine - reduces the risk of heart block
- Fetal echocardiographic surveillance weekly from 16-28 weeks
Associations
Renal
- Tubulointerstitial nephritis -> distal (type 1) RTA - hypokalaemia, nephrocalcinosis, renal stones, may present as hypokalaemic paralysis
- Cryoglobulinaemic membranoproliferative glomerulonephritis
- Nephrogenic diabetes insipidus
Neurological
- Peripheral neuropathy - sensory axonal, small-fibre, or pure sensory ganglionopathy with pseudoathetosis and sensory ataxia (the characteristic Sjogren neuropathy)
- Mononeuritis multiplex (vasculitic)
- Trigeminal neuropathy
- CNS: transverse myelitis, optic neuritis, cerebral vasculitis, MS-like demyelinating lesions
- Overlap with NMOSD (anti-AQP4)
Pulmonary
- ILD - NSIP most common, also LIP, UIP, organising pneumonia
- Lymphocytic interstitial pneumonia with thin-walled cysts on HRCT - near-pathognomonic in the right context
- Follicular bronchiolitis, bronchiectasis, xerotrachea
Cutaneous
- Palpable purpura (hypergammaglobulinaemic or cryoglobulinaemic vasculitis)
- Annular erythema, subacute cutaneous lupus, Raynaud phenomenon (~30%)
Other
- Primary biliary cholangitis, autoimmune hepatitis
- Autoimmune thyroid disease
- Coeliac disease
- Vaginal dryness, dyspareunia
- Lymphoma - see natural history
Natural history & complications
- Glandular disease is slowly progressive and irreversible
- Most patients have a normal life expectancy; mortality excess is confined to those with systemic disease, cryoglobulinaemia, low C4, or lymphoma
Lymphoma - the defining complication
- ~15-20x increased risk of B-cell non-Hodgkin lymphoma (5-9x for lymphoma overall)
- MALT lymphoma of the parotid is the commonest subtype; also DLBCL
- Median onset ~7 years after diagnosis; lifetime risk ~5%
- Predictors of lymphoma
- Recurrent or persistent parotid swelling - the strongest clinical predictor
- Splenomegaly and/or lymphadenopathy
- Palpable purpura
- Cryoglobulinaemia
- Low C4 (and low C3)
- Rheumatoid factor positivity
- ESSDAI >5
- High focus score with ectopic germinal centres on salivary gland biopsy
- CD4 T-cell lymphopenia; monoclonal gammopathy
- Germline TNFAIP3 mutation
Two mechanisms of systemic complication
- Lymphocytic organ infiltration -> interstitial nephritis, primary biliary cholangitis, obstructive bronchiolitis, ILD
- Chronic B-cell activation + immune complex deposition -> palpable purpura, cryoglobulinaemic glomerulonephritis, interstitial pneumonitis, peripheral neuropathy
Complications
- Dental caries and tooth loss, oral candidiasis
- Corneal ulceration and perforation
- Renal tubular acidosis and hypokalaemia; nephrocalcinosis
- Progressive ILD
- Disabling fatigue and chronic pain
- Lymphoma
- Neonatal lupus and congenital heart block in offspring
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