Sjögren's Syndrome — Definition, Epidemiology, Pathophysiology, Presentation and Management

Sjögren's syndrome (Sjögren's disease) is a chronic systemic autoimmune exocrinopathy characterised by lymphocytic infiltration and destruction of the exocrine glands — principally the lacrimal and salivary glands — producing the sicca complex of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), together with extraglandular systemic involvement.

Primary Sjögren's occurs alone; secondary Sjögren's occurs with another connective tissue disease, most often rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis.

Prevalence is approximately 0.1–0.6%; it is one of the commonest systemic autoimmune diseases.

Female to male ratio is about 9:1, with a bimodal peak in the 20s–30s and again after the menopause, around 50–60 years, so a large proportion of patients are older adults.

Geriatric caution: sicca symptoms are extremely common in old age from age-related glandular atrophy, dehydration and anticholinergic polypharmacy — dryness in an older person is far more often drug-induced than autoimmune, and this distinction is the crux of any exam answer.

Genetic susceptibility (HLA-DR3/DQ2, HLA-DRB1*03, IRF5 and STAT4 polymorphisms) plus an environmental trigger, classically a viral infection (EBV, HCV, HTLV-1), initiates glandular epithelial activation — hence the concept of "autoimmune epithelitis".

Activated epithelial cells present autoantigens (Ro/SSA and La/SSB) and secrete chemokines that recruit CD4+ T cells and B cells, forming periductal focal lymphocytic infiltrates and, in some, ectopic germinal centres.

Type I interferon signature and BAFF (B-cell activating factor) overexpression drive B-cell survival, autoantibody production and hypergammaglobulinaemia — the rationale for anti-BAFF and B-cell directed therapy.

Glandular destruction, plus anti-muscarinic M3 receptor antibodies impairing residual secretory function, produces the sicca picture — explaining why dryness can exceed the degree of histological damage.

Persistent B-cell stimulation with germinal centre formation underlies the risk of B-cell non-Hodgkin lymphoma, typically MALT lymphoma of the parotid.

Ocular: gritty, sandy foreign-body sensation, burning, photophobia, redness, blurring, stringy discharge; complications include filamentary keratitis and corneal ulceration.

Oral: dry mouth, difficulty swallowing dry food, need to sip water while talking, altered taste, tongue fissuring and depapillation, rampant dental caries, angular cheilitis and recurrent oral candidiasis.

Salivary gland enlargement — recurrent or persistent parotid or submandibular swelling. A persistently hard, unilateral, enlarging parotid must raise suspicion of lymphoma.

Other exocrine sites: dry nose, dry cough from xerotrachea, dry skin, and vaginal dryness with dyspareunia — a common and under-asked symptom in older women. (ii) Extraglandular

Constitutional: profound fatigue (often the dominant complaint), low-grade fever, myalgia.

Musculoskeletal: non-erosive symmetrical polyarthritis and arthralgia; Raynaud's phenomenon.

Cutaneous: annular erythema and palpable purpura from hypergammaglobulinaemic or cryoglobulinaemic vasculitis.

Renal: distal (type 1) renal tubular acidosis with hypokalaemia and nephrocalcinosis; interstitial nephritis; less often glomerulonephritis with cryoglobulinaemia.

Pulmonary: interstitial lung disease (NSIP, LIP), bronchiectasis, xerotrachea.

Neurological: peripheral sensory or sensory-ataxic neuropathy, small-fibre neuropathy with burning feet, trigeminal neuropathy, mononeuritis multiplex, and rarely CNS disease.

Haematological / malignant: cytopenias, hypergammaglobulinaemia, and a 5–16 fold increased risk of non-Hodgkin lymphoma — the single most important complication. Predictors: persistent parotid enlargement, purpura, low C4, cryoglobulinaemia, lymphadenopathy, splenomegaly and a low CD4 count.

Obstetric/other: anti-Ro antibodies cause congenital heart block in offspring (not relevant in the elderly but examinable).

Autoantibodies: anti-Ro/SSA (most sensitive and part of the criteria) and anti-La/SSB; ANA positive in most; rheumatoid factor positive in about 50% even without RA.

Supporting bloods: raised ESR with normal CRP, polyclonal hypergammaglobulinaemia, anaemia, leucopenia, low C3/C4 (poor prognosis), cryoglobulins, and serum free light chains.

Ocular tests: Schirmer's test ≤5 mm in 5 minutes; ocular staining score ≥5 with lissamine green or fluorescein (or Rose Bengal ≥4 by van Bijsterveld); tear break-up time.

Oral tests: unstimulated whole salivary flow ≤0.1 mL/minute; salivary gland ultrasound showing a heterogeneous hypoechoic gland; sialography and scintigraphy are older methods.

Minor labial salivary gland biopsy — the histological gold standard; a focus score ≥1 (one focus of ≥50 lymphocytes per 4 mm²) is diagnostic.

2016 ACR/EULAR classification criteria (score ≥4): anti-Ro/SSA positive (3), focus score ≥1 (3), ocular staining score ≥5 (1), Schirmer ≤5 mm/5 min (1), unstimulated salivary flow ≤0.1 mL/min (1). Exclusions include head and neck radiotherapy, hepatitis C, HIV, sarcoidosis, amyloidosis, IgG4-related disease and graft-versus-host disease.

Disease activity tools: ESSDAI for systemic activity and ESSPRI for patient-reported dryness, pain and fatigue.

No cure exists; treatment is symptomatic for sicca and immunosuppressive for systemic disease. First, stop or substitute anticholinergic drugs — tricyclics, oxybutynin, antihistamines, antipsychotics, diuretics — which is frequently the highest-yield intervention in an older patient.

Dry eyes: preservative-free artificial tears and gels, ocular lubricant ointment at night, humidification, avoidance of fans and air conditioning; topical ciclosporin 0.05% or short-course topical steroid for inflammatory dryness; punctal plugs or cautery for refractory cases; treat coexisting blepharitis.

Dry mouth: frequent sips of water, sugar-free gum and lozenges, saliva substitutes, meticulous oral hygiene with high-fluoride toothpaste and 3-monthly dental review, and prompt treatment of candidiasis with nystatin or fluconazole (avoid sugar-containing preparations).

Muscarinic agonists: pilocarpine 5 mg four times daily or cevimeline 30 mg three times daily stimulate residual secretion. Cautions in older adults: sweating, flushing, nausea, urinary frequency, bradycardia; avoid in uncontrolled asthma, narrow-angle glaucoma and significant cardiac disease.

Musculoskeletal disease: hydroxychloroquine for arthralgia, fatigue and cutaneous disease (though RCT evidence for fatigue is weak); short courses of NSAIDs with caution; low-dose prednisolone for flares.

Severe systemic disease (vasculitis, interstitial lung disease, glomerulonephritis, severe neuropathy, cytopenias): glucocorticoids with methotrexate, azathioprine, mycophenolate or cyclophosphamide; rituximab for cryoglobulinaemic vasculitis, severe parotid swelling and lymphoma-associated disease, although the large TEARS and TRACTISS trials failed to show benefit for dryness itself.

Vaginal dryness: non-hormonal lubricants and, where appropriate, topical vaginal oestrogen — frequently overlooked in older women.

Lymphoma surveillance: examine glands and lymph nodes at each visit; investigate any persistent hard parotid swelling, new lymphadenopathy, falling C4, monoclonal band or cryoglobulins with imaging and biopsy.

Prognosis: life expectancy is near-normal in uncomplicated disease; excess mortality is driven by lymphoma, vasculitis and interstitial lung disease. Fatigue and dryness dominate quality of life.