Key Facts

SSc is a devastating multisystem disease with the highest mortality of any autoimmune rheumatic disease. Early detection of organ involvement and targeted treatment are essential.

Epidemiology

• UK prevalence: ~20 per 100,000
• F:M 4:1; peak onset 30-50 years
• lcSSc more common than dcSSc (3:1)
• Higher prevalence in Afro-Caribbean populations (more severe)

Aetiology

• Genetic: HLA-DRB1, IRF5, STAT4
• Environmental: silica, vinyl chloride, organic solvents
• Triggers: possibly viral (CMV, parvovirus B19)

Pathophysiology

• Three key processes: vasculopathy (endothelial damage → Raynaud, PAH), immune activation (T cells, B cells, autoantibodies), fibrosis (TGF-β, PDGF-driven collagen deposition)
• Early endothelial injury → intimal proliferation → obliterative vasculopathy
• Activated fibroblasts → excessive collagen deposition in skin and organs
• Raynaud phenomenon is often the earliest manifestation (precedes other features by years)

Raynaud Phenomenon (>95%)

• Triphasic colour change: white (vasospasm) → blue (cyanosis) → red (reperfusion)
• Often first manifestation, may precede other features by years
• Digital ulcers, pitting scars, gangrene in severe cases

Limited Cutaneous SSc (lcSSc/CREST)

• Skin thickening distal to elbows/knees + face
• Calcinosis cutis: subcutaneous calcium deposits
• Raynaud phenomenon
• Esophageal dysmotility: dysphagia, GORD
• Sclerodactyly: tight, shiny skin on fingers
• Telangiectasia: face, hands
• PAH: major late complication (10-15%)

Diffuse Cutaneous SSc (dcSSc)

• Skin thickening proximal to elbows/knees + trunk
• Rapid progression of skin involvement in first 3-5 years
• ILD: most common cause of death (~40%)
• Scleroderma renal crisis: 10-15%; acute hypertensive emergency
• Cardiac: myocardial fibrosis, arrhythmias, pericarditis
• GI: oesophageal dysmotility, small bowel dysmotility (pseudo-obstruction), malabsorption

Red Flags

• Scleroderma renal crisis: new severe hypertension + rising creatinine + MAHA → ACE inhibitor URGENTLY
• Breathlessness: investigate for ILD and PAH
• Digital gangrene: IV iloprost, surgical debridement

Bloods

• ANA: positive in >90%
• Anti-centromere: lcSSc (50-70%); associated with PAH
• Anti-Scl-70 (topoisomerase I): dcSSc (30-40%); associated with ILD
• Anti-RNA polymerase III: dcSSc; associated with scleroderma renal crisis and malignancy
• FBC: MAHA in renal crisis
• U&Es: renal function
• ESR/CRP: may be modestly elevated

Organ Screening

• PFTs (FVC, DLCO): annual; FVC decline indicates ILD progression; isolated DLCO decline suggests PAH
• HRCT chest: ILD assessment (NSIP most common pattern, UIP less common)
• Echocardiogram: annual; estimate PA pressure (PAH screening)
• Right heart catheterisation: if echocardiogram suggests PAH (mPAP ≥20mmHg)
• Nailfold capillaroscopy: enlarged/dropout capillaries (distinguishes SSc-related Raynaud from primary Raynaud)
• Barium swallow/manometry: oesophageal dysmotility

Special Tests

• Modified Rodnan skin score: quantify skin thickening (0-3 at 17 sites; max 51)
• 6-minute walk test: PAH and ILD functional assessment
• NT-proBNP: screening for PAH/cardiac involvement

Raynaud and Digital Ulcers

• Nifedipine 10-20mg TDS (or amlodipine): first-line vasodilator
• IV iloprost (prostacyclin analogue): for severe Raynaud, digital ulcers
• Bosentan (endothelin receptor antagonist): prevents new digital ulcers (RAPIDS-2 trial)
• Sildenafil 25-50mg TDS: PDE5 inhibitor; alternative
• Lifestyle: keep warm, avoid smoking, avoid beta-blockers

ILD

• Mycophenolate mofetil 2-3g/day: first-line (Scleroderma Lung Study II – non-inferior to CYC with fewer side effects)
• Nintedanib 150mg BD: antifibrotic; slows FVC decline (SENSCIS trial); NICE TA691
• Cyclophosphamide: alternative induction (Scleroderma Lung Study I)
• Rituximab: emerging evidence
• Autologous stem cell transplant: severe, progressive dcSSc (ASTIS, SCOT trials)

PAH

• Ambrisentan (ERA) + tadalafil (PDE5i): first-line combination (AMBITION trial)
• IV epoprostenol: for severe/refractory PAH
• Riociguat: sGC stimulator
• Managed by specialist PAH centres

Scleroderma Renal Crisis

• ACE inhibitor (captopril): IMMEDIATELY; titrate aggressively to control BP
• DO NOT use ARBs (inferior outcomes)
• Dialysis: if severe AKI; 50% may recover enough to stop dialysis within 2 years
• Avoid high-dose corticosteroids (>15mg prednisolone may precipitate renal crisis)

GI

• PPI (omeprazole 20-40mg): for GORD
• Prokinetics (domperidone, erythromycin): for gastroparesis
• Rotating antibiotics: for small bowel bacterial overgrowth (SIBO)

Referral Criteria

• All suspected SSc → rheumatology
• ILD → respiratory medicine
• PAH → specialist PAH centre
• Scleroderma renal crisis → nephrology + rheumatology
• Raynaud with nailfold changes or ANA positive → rheumatology

• lcSSc: 10-year survival ~80%; PAH is the major cause of death
• dcSSc: 10-year survival ~65%; ILD and cardiac disease are leading causes of death
• Scleroderma renal crisis: mortality 20-30%; ~50% recover renal function with ACE inhibitors
• PAH: median survival without treatment ~3 years; improved with modern therapy
• Skin disease in dcSSc may plateau and improve after 3-5 years
• Anti-RNA polymerase III: associated with concurrent malignancy screening recommended

SSc Antibody Associations

lcSSc vs dcSSc