Silica-Associated Autoimmune Disease

Silica associated autoimmune disease is autoimmune disease occurring more frequently in people with silica exposure. It includes rheumatoid arthritis (with Caplan syndrome), systemic sclerosis (Erasmus syndrome), systemic lupus erythematosus, ANCA-associated vasculitis and silica associated renal disease.

Epidemiology. Silica exposure raises risk of rheumatoid arthritis and lupus about 2 to 3 fold, with a larger rise for systemic sclerosis; vasculitis risk also increases. Smoking compounds risk for anti-citrullinated protein antibody positive rheumatoid arthritis.

Exposure. Mining, quarrying, sandblasting, stone and artificial stone work, foundry and ceramics.

Timing. Disease may arise with or without silicosis and can appear after exposure has ceased.

Pathophysiology.

Silica particles activate macrophages and the NLRP3 inflammasome, driving cell death, release of autoantigens and pro inflammatory cytokines. Adjuvant effects on innate and adaptive immunity promote loss of tolerance.

Citrullination in the airways of smokers and silica exposed individuals can generate neoantigens relevant to rheumatoid arthritis.

• Rheumatoid arthritis: symmetric small joint synovitis, morning stiffness; Caplan nodules as multiple peripheral lung nodules of 0.5 to 5 cm.
• Systemic sclerosis: Raynaud phenomenon, skin thickening, digital ulcers, reflux and interstitial lung disease.
• Lupus: rash, arthritis, cytopenias, serositis, nephritis.
• Vasculitis: sinus disease, haemoptysis, haematuria, neuropathy.
• Silica nephropathy: asymptomatic proteinuria or declining eGFR.

Red flags.

• Pulmonary haemorrhage or rapidly progressive glomerulonephritis.
• Sudden severe hypertension with renal decline in systemic sclerosis.
• Digital ischaemia or rapidly progressive dyspnoea.

• Exposure history and cumulative dose.
• Serology: rheumatoid factor, anti-CCP, ANA, extractable nuclear antigens, anti-Scl-70, anti-centromere, anti-dsDNA, ANCA, complement.
• Inflammatory markers, FBC, creatinine, urinalysis with protein quantification.
• HRCT, spirometry and gas transfer.
• Interferon gamma release assay and tuberculosis assessment before immunosuppression.
• Biopsy (renal, skin or lung) when diagnosis is uncertain.

Differential diagnosis. Silicosis alone, drug induced lupus, mixed connective tissue disease, sarcoidosis, hypersensitivity pneumonitis, tuberculosis, lung cancer.

• Stop exposure and smoking.
• Screen for and treat latent tuberculosis before or alongside immunosuppression; remain alert to reactivation.
• Methotrexate orally, 7.5 to 15 mg once weekly, increased by 2.5 to 5 mg every 2 to 4 weeks to 20 to 25 mg weekly (maximum 25 mg weekly), long term, with folic acid 5 mg once weekly on a different day. Monitor FBC, liver enzymes and creatinine every 2 weeks until stable, then monthly for 3 months, then every 3 months. Avoid if eGFR is under 30; reduce dose when eGFR is 30 to 59. Contraindicated in pregnancy (stop at least 3 months before conception). Use with caution in pre-existing lung disease, with baseline radiograph and gas transfer.
• Hydroxychloroquine orally, 200 to 400 mg daily (maximum 5 mg/kg of actual body weight daily), long term. Monitor with retinal screening at baseline and yearly after 5 years (earlier with renal impairment or tamoxifen). Reduce dose when eGFR is under 30.
• Systemic sclerosis, vasculitis and lupus with organ involvement need specialist immunosuppression and organ specific care.
• Vaccinate before immunosuppression; avoid live vaccines during it.

Monitoring. Disease activity, organ function and drug toxicity at intervals set by the regimen; annual spirometry and gas transfer.

Referral and escalation. Rheumatology and respiratory physicians; nephrology for renal involvement; urgent admission for pulmonary haemorrhage, rapidly progressive glomerulonephritis or scleroderma renal crisis; occupational notification and compensation where required.

Special groups. Pregnancy needs preconception review and drug changes; breastfeeding and renal or hepatic impairment need drug specific adjustments.