Sjögren syndrome

Sjögren syndrome (SjS) is a chronic systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands — primarily salivary and lacrimal glands — causing the hallmark features of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). It may occur as primary Sjögren syndrome (pSjS) or secondary to another connective tissue disease (most commonly rheumatoid arthritis, SLE, or systemic sclerosis). SjS predominantly affects women in the fourth to fifth decade (female:male ~9:1) and has an estimated prevalence of 0.5–1% in the general population. Beyond sicca features, SjS can cause significant extraglandular manifestations including fatigue, arthralgia, peripheral neuropathy, interstitial lung disease, and renal tubular acidosis. Patients with pSjS have a markedly elevated risk of non-Hodgkin B-cell lymphoma (predominantly MALT lymphoma).

Classification requires score ≥4 in a patient with ocular or oral dryness symptoms (or positive ESSDAI extraglandular disease) after exclusion of conditions that mimic SjS (head/neck radiation, hepatitis C, HIV, active sarcoidosis, pre-existing lymphoma, graft-versus-host disease, IgG4-related disease, cholinergic drugs).

SjS results from loss of tolerance to self-antigens expressed in ductal epithelial cells. Genetic susceptibility, environmental triggers (particularly viral), and dysregulation of both innate and adaptive immunity combine to produce glandular and extraglandular inflammation.

Key Pathogenic Mechanisms

• Type I interferon pathway — the interferon signature is present in ~75% of pSjS; plasmacytoid dendritic cells and salivary gland epithelial cells produce IFN-α/β in response to viral triggers (particularly EBV and CMV)
• B cell hyperactivation — polyclonal B cell activation produces anti-Ro/SSA, anti-La/SSB, rheumatoid factor, and ANA; germinal centre formation in glands drives lymphoma risk
• Anti-Ro/SSA and anti-La/SSB antibodies — pathogenic; anti-Ro52/TRIM21 and anti-Ro60; anti-La/SSB associated with secondary Sjögren features; transplacental passage causes neonatal lupus
• T cell infiltration — CD4+ T cells (predominantly Th1 and Th17) infiltrate salivary and lacrimal glands; pro-inflammatory cytokines (IL-6, IL-17, TNF-α, BLyS/BAFF) drive glandular dysfunction
• Glandular dysfunction — not solely due to destruction; anti-muscarinic antibodies (anti-M3R) impair neurotransmitter-mediated secretion; neurogenic dysfunction contributes
• Lymphomagenesis — persistent germinal centre activity in minor salivary glands → MALT lymphoma risk; risk factors include parotid swelling, palpable purpura, low C4, cryoglobulinaemia, lymphopenia

Genetic and Environmental Factors

• HLA associations — HLA-DQ2 and HLA-DRw52 associated with anti-Ro/SSA positivity; HLA-DR3 with pSjS
• Non-HLA genes — IRF5, STAT4, BLK, TNFSF13B (BAFF gene); shared with SLE
• Viral triggers — EBV, CMV, HTLV-1, coxsackievirus implicated; molecular mimicry between viral antigens and Ro/La antigens

SjS presents with sicca symptoms in most patients, but extraglandular manifestations are common and can dominate the clinical picture. The diagnosis is frequently delayed due to the insidious onset of dry eye and dry mouth, which are often attributed to ageing or medication.

Glandular Manifestations

Extraglandular Manifestations

Diagnosis requires clinical assessment, serological testing, and objective assessment of glandular dysfunction. Lip biopsy is the gold standard histological test. Ophthalmological and salivary function tests provide objective sicca quantification.

• Essential
  ANA + anti-Ro/SSA and anti-La/SSB

  Anti-Ro/SSA positive in ~70–80% pSjS (highest specificity when anti-Ro60 positive). Anti-La/SSB positive in ~40–50%. ANA homogeneous or speckled pattern. Negative serology does not exclude SjS — seronegative SjS exists.
• Essential
  Rheumatoid factor (RF) and immunoglobulins

  RF positive in ~60–70% pSjS. Hypergammaglobulinaemia common. IgG4 level to exclude IgG4-RD. Monoclonal band on SPEP/UPEP raises lymphoma concern.
• Essential
  FBC, UEC, LFTs, ESR, CRP

  Lymphopenia and leucopenia; renal function (RTA screening); hepatic involvement; ESR elevated; CRP typically normal unless vasculitis present.
• Essential
  Complement C3, C4

  Low C4 is a lymphoma risk factor in SjS. Low C3/C4 with cryoglobulinaemia indicates vasculitis. Check at baseline and when lymphoma concern arises.
• Essential
  Urinalysis and blood gas (renal tubular acidosis screen)

  Urine pH — inability to acidify urine below pH 5.5 despite systemic acidosis = distal RTA. Serum bicarbonate, potassium, and urine anion gap if RTA suspected.
• Recommended
  Minor salivary gland (lip) biopsy

  Gold standard for diagnosis. Focal lymphocytic sialadenitis with focus score ≥1/4 mm² is highly specific. Indicated when serology is negative but clinical suspicion high, or to confirm diagnosis before treating extraglandular disease.
• Recommended
  Ophthalmological assessment — Schirmer's test + Rose Bengal/lissamine green staining

  Schirmer's test ≤5 mm/5 min = reduced lacrimal production. Ocular staining score ≥5 = keratoconjunctivitis sicca. Mandatory for all patients with sicca symptoms.
• Recommended
  Unstimulated salivary flow rate

  ≤0.1 mL/min = significant salivary hypofunction. Quantifies glandular dysfunction. Collected over 15 minutes. Scintigraphy (salivary gland scan) is an alternative if available.
• Recommended
  Cryoglobulins

  Sample must be collected warm and transported immediately. Cryoglobulinaemia is a lymphoma risk factor and indicates vasculitis. Check annually in high-risk patients.
• Recommended
  HRCT chest

  Indicated if respiratory symptoms, desaturation, or ILD suspected. NSIP and LIP patterns most common in SjS. Pulmonology co-management if ILD present.

Disease activity in SjS is assessed using the EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) for extraglandular manifestations, and patient-reported symptoms using the EULAR Sjögren Syndrome Patient Reported Index (ESSPRI). Risk stratification guides treatment intensity and lymphoma surveillance frequency.

There is no disease-modifying therapy proven to alter the natural history of primary SjS in the way that immunosuppression does in SLE or RA. Management is therefore stratified: symptomatic management for sicca features, and immunosuppression for significant extraglandular disease. Hydroxychloroquine is the anchor drug for most patients.

Directed therapy addresses specific organ manifestations of SjS that require targeted management.

Sicca Management

• Dry eyes — preservative-free artificial tears (hourly if needed); lubricating eye ointment at night; punctal plugs for refractory dry eye; ciclosporin 0.1% eye drops (Restasis®) for moderate-severe keratoconjunctivitis sicca; humidifier in bedroom
• Dry mouth — frequent sips of water; sugar-free gum and lozenges (stimulate salivary flow); saliva substitutes (Biotène®, Oral Balance®); pilocarpine 5 mg TID–QID; avoid anticholinergic medications
• Dental care — fluoride toothpaste daily; chlorhexidine rinses; 3–6 monthly dental review; remineralisation agents; immediate dental attention for caries — dry mouth causes rampant decay

Interstitial Lung Disease

• HRCT characterisation — NSIP pattern most common; LIP (lymphoid interstitial pneumonia) also seen
• Progressive ILD — prednisolone + azathioprine or MMF; consider rituximab for refractory cases
• Pulmonology co-management; 6-monthly PFTs and HRCT; monitor for progression; low threshold for nintedanib in progressive fibrosing ILD

Renal Tubular Acidosis

• Distal RTA — potassium citrate or sodium bicarbonate supplementation; correct hypokalaemia (risk of paralysis)
• Nephrocalcinosis and nephrolithiasis — hydration, citrate supplementation, nephrology input
• Interstitial nephritis — prednisolone ± azathioprine if progressive; renal biopsy to guide therapy

Peripheral Neuropathy

• Small fibre neuropathy — predominantly sensory; pregabalin, duloxetine, or amitriptyline for neuropathic pain; IVIg in severe cases
• Sensorimotor or mononeuritis multiplex — immunosuppression escalation; neurology referral; EMG/nerve conduction studies
• Trigeminal neuropathy — common in SjS; carbamazepine or oxcarbazepine for pain; ophthalmology for corneal sensation

Cryoglobulinaemic Vasculitis

• Palpable purpura + low C4 + positive cryoglobulins + hepatitis C exclusion
• Rituximab is first-line for cryoglobulinaemic vasculitis in SjS; prednisolone for severe disease
• Lymphoma exclusion mandatory before rituximab — exclude MALT and DLBCL

Non-pharmacological measures are fundamental to SjS management — particularly for sicca symptoms, oral health, and fatigue.

Oral Health

• Daily fluoride toothpaste + after-brush fluoride gel — essential to prevent rampant dental caries
• Avoid sugary beverages and foods that promote caries in the context of reduced salivary buffering capacity
• Dental review every 3–6 months — SjS patients develop caries and periodontal disease rapidly
• Oral candidiasis — common; treat with nystatin troches or fluconazole; denture hygiene important

Eye Care

• Preservative-free artificial tears — key word is preservative-free; preserved tears worsen ocular surface disease with frequent use
• Humidifiers at night and protective eyewear (moisture chamber spectacles) for severe dry eye
• Avoid air conditioning, fans, and windy environments — exacerbate tear evaporation
• Screen time breaks — 20-20-20 rule (every 20 minutes, look 20 feet away for 20 seconds)

Fatigue Management

• Fatigue affects >70% of SjS patients and is the most common symptom — often poorly correlated with ESSDAI
• Regular graded aerobic exercise — improves fatigue and quality of life; physiotherapy-supervised programme
• Sleep hygiene and cognitive behavioural therapy — anxiety, depression, and poor sleep amplify fatigue
• Psychology referral — chronic sicca symptoms and fatigue have significant psychological burden

Patient Education

• Avoid anticholinergic medications (antihistamines, tricyclics, bladder anticholinergics) — worsen sicca symptoms
• Avoid diuretics and dehydrating medications when possible
• Sjögren's Australia and Arthritis Australia — patient resources, peer support

SjS requires regular monitoring for disease activity, extraglandular complications, medication toxicity, and lymphoma surveillance. Monitoring frequency depends on disease activity and treatment.

When to Refer Urgently

• Haematology: Suspected lymphoma — persistent asymmetric parotid swelling, lymphadenopathy, monoclonal band, rapidly falling complement, B symptoms (fever, night sweats, weight loss)
• Nephrology: Interstitial nephritis, RTA with nephrocalcinosis, rising creatinine
• Neurology: Mononeuritis multiplex, CNS involvement, progressive neuropathy
• Pulmonology: ILD with progression, oxygen desaturation, new respiratory symptoms

Specific patient groups with SjS require additional consideration.

SjS in Pregnancy

• Anti-Ro/SSA positive mothers — neonatal lupus risk; fetal echocardiography weekly from 16–26 weeks for congenital heart block (CHB); CHB risk ~2% per pregnancy (higher if prior CHB infant)
• Hydroxychloroquine — continue throughout pregnancy; reduces CHB recurrence risk; safe in breastfeeding
• Pilocarpine — limited safety data in pregnancy; avoid unless benefit clearly outweighs risk
• SjS does not typically flare in pregnancy; however, monitor closely for sicca worsening and new extraglandular features

Secondary Sjögren Syndrome

• Sjögren features occur in 10–20% of RA patients, 30% of SLE patients, and 50–80% of systemic sclerosis patients
• Manage sicca features as for primary SjS; systemic immunosuppression directed at the primary CTD
• Lymphoma risk in secondary SjS is lower than in primary SjS

Elderly Patients

• Sicca symptoms from ageing, medications (anticholinergics, diuretics), and diabetes are common — carefully exclude before diagnosing SjS
• HCQ dose reduction — lower ideal body weight and reduced eGFR increase HCQ toxicity risk; dose accordingly
• Oral health particularly important in elderly — dental caries causes tooth loss and nutritional compromise

Male Patients

• SjS in men is often more severe with higher rates of extraglandular manifestations, neuropathy, and lymphoma
• Diagnosis frequently delayed — low clinical suspicion in males; include SjS in differential for dry eye/dry mouth in males

Stewardship in SjS focuses on appropriate use of hydroxychloroquine, avoidance of medications that worsen sicca, and vigilant lymphoma surveillance without over-investigation.

GP Role in SjS Management

• Medication review — remove or replace anticholinergic medications wherever possible
• Dental referral — 3–6 monthly dental review; prescribe fluoride gel and recommend sugar-free oral hygiene
• Ophthalmology referral — annual review; urgent referral if eye pain, photophobia, or reduced vision
• Monitor urinalysis for RTA (urine pH, creatinine) and FBC for lymphopenia 6-monthly
• Lymphoma vigilance — refer to haematology promptly if new parotid swelling, B symptoms, or falling complement

SjS requires long-term rheumatologist-led follow-up with multidisciplinary co-management (ophthalmology, dentistry, neurology, pulmonology as indicated). Lymphoma surveillance and sicca management are the two primary ongoing responsibilities.

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