Systemic Sclerosis (Scleroderma)
Autoimmune connective tissue disease with vasculopathy and fibrosis of skin and internal organs.
Also known as: scleroderma, systemic sclerosis, SSc, limited cutaneous SSc, CREST, diffuse cutaneous SSc
Overview
A heterogeneous autoimmune connective tissue disease characterized by small-vessel vasculopathy, autoantibody production, and progressive fibrosis of the skin and internal organs. Two principal subtypes: limited cutaneous systemic sclerosis (lcSSc, including CREST — calcinosis, Raynaud, esophageal dysmotility, sclerodactyly, telangiectasias) and diffuse cutaneous systemic sclerosis (dcSSc).
Epidemiology
Prevalence 50-300 per million. Female-to-male ratio 3-7:1. Peak onset 30-50 years. African American patients have earlier onset, more severe disease, and worse survival than White patients.
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Risk factors
- Female sex and ages 30-50
- African American ancestry (more severe disease)
- Environmental exposures: silica dust, organic solvents, vinyl chloride, epoxy resins (Erasmus syndrome and similar)
- Genetic predisposition (HLA-DRB1, BANK1, IRF5, STAT4)
- Family history of autoimmune disease
Pathophysiology
Three interrelated processes: small-vessel vasculopathy with endothelial injury and proliferative intimal disease, immune dysregulation with autoantibody production (anti-centromere, anti-Scl-70/topoisomerase, anti-RNA polymerase III), and progressive fibrosis of skin and organs driven by myofibroblast accumulation and TGF-beta signaling.
Clinical presentation
Symptoms
- Raynaud phenomenon — often the earliest manifestation, may predate other findings by years
- Puffy hands progressing to skin tightening
- Skin tightening that begins distally (fingers, face) and progresses proximally in dcSSc
- Dysphagia and reflux from esophageal dysmotility
- Dyspnea from interstitial lung disease or pulmonary hypertension
- Arthralgias, myalgias, fatigue
Signs / physical exam
- Sclerodactyly with loss of fingertip pulp and digital pits or ulcers
- Telangiectasias on the face, palms, mucous membranes
- Calcinosis cutis
- Mat-like telangiectasias and abnormal nailfold capillaries (dilated loops and dropout)
- Facial findings: mask-like facies, pursed lips with radial furrowing, decreased oral aperture
- Tendon friction rubs (dcSSc)
- Hypertension and rising creatinine in scleroderma renal crisis
Classic findings
Middle-aged woman with longstanding Raynaud phenomenon, sclerodactyly, telangiectasias, and esophageal reflux — the limited cutaneous (CREST) phenotype.
Differential diagnosis
- Localized scleroderma (morphea) — Skin involvement only, no Raynaud, no systemic features, no antibodies; typically self-limited
- Eosinophilic fasciitis — Peau d'orange induration of forearms and legs sparing fingers, eosinophilia, no Raynaud, no nailfold changes
- Mixed connective tissue disease — Anti-U1-RNP antibody; overlap features of SLE, scleroderma, polymyositis
- Nephrogenic systemic fibrosis — Gadolinium exposure in patients with advanced renal disease; symmetric induration of extremities and trunk
- Scleromyxedema — Lichenoid papules and skin thickening with monoclonal gammopathy
- Primary Raynaud phenomenon — Onset in adolescence, female, negative ANA, normal nailfold capillaries, no systemic features
Diagnostic workup
Diagnostic criteria
ACR/EULAR 2013 classification criteria — a score ≥9 confirms SSc. Skin thickening of the fingers extending proximal to MCPs is sufficient. Other weighted items include sclerodactyly, fingertip lesions, telangiectasias, abnormal nailfold capillaries, pulmonary involvement, Raynaud phenomenon, and SSc-related autoantibodies.
Labs
- ANA — positive in >95 percent
- Anti-centromere (limited cutaneous SSc), anti-Scl-70/topoisomerase I (diffuse cutaneous SSc, ILD), anti-RNA polymerase III (diffuse, renal crisis, malignancy association)
- CBC, CMP, urinalysis with creatinine to monitor for renal crisis
- BNP and inflammatory markers to track cardiopulmonary disease
Imaging
- High-resolution chest CT for interstitial lung disease (NSIP pattern more common than UIP)
- Pulmonary function testing with DLCO at baseline and serially — declining DLCO is an early marker of ILD or pulmonary hypertension
- Echocardiogram annually to screen for pulmonary hypertension (right heart catheterization to confirm if estimated PASP elevated)
- Barium swallow or manometry for esophageal symptoms
- Nailfold capillaroscopy for early diagnosis and to distinguish primary from secondary Raynaud
Diagnostic algorithm
| Feature | Limited cutaneous SSc | Diffuse cutaneous SSc |
|---|---|---|
| Skin involvement | Distal to elbows and knees + face | Proximal to elbows and knees, trunk |
| Course | Insidious; Raynaud may predate by years | Rapid skin progression |
| Antibody | Anti-centromere | Anti-Scl-70, anti-RNA pol III |
| Renal crisis | Rare | More common (early disease) |
| ILD | Less common | More common and severe |
| PAH | Late, isolated | Often with ILD |
Treatment
First-line
- Organ-based therapy is the cornerstone — no single agent treats all manifestations
- Raynaud phenomenon: dihydropyridine calcium channel blockers (amlodipine, nifedipine ER), topical nitrates, PDE5 inhibitors (sildenafil) for severe or ulceration-prone disease
- GERD and esophageal dysmotility: PPI (omeprazole, pantoprazole), prokinetics for delayed gastric emptying
- Skin disease: mycophenolate mofetil or methotrexate for early diffuse disease
- Interstitial lung disease: mycophenolate mofetil (Scleroderma Lung Study II) or nintedanib (SENSCIS trial); cyclophosphamide for severe progressive disease
- Pulmonary arterial hypertension: endothelin receptor antagonists (bosentan, macitentan, ambrisentan), PDE5 inhibitors (sildenafil, tadalafil), prostacyclins (epoprostenol, treprostinil), riociguat
Second-line / adjunct
- Scleroderma renal crisis: ACE inhibitor (captopril preferred; titrate aggressively) — avoid in stable disease, but cornerstone of treatment in crisis
- Tocilizumab (focuSSced trial) for early skin and lung disease
- Autologous hematopoietic stem cell transplantation for selected patients with rapidly progressive dcSSc
- Iloprost or bosentan to reduce digital ulcers in severe Raynaud
- Surgical sympathectomy for refractory digital ischemia
Complications
- Scleroderma renal crisis (most common in early diffuse disease with anti-RNA pol III; presents with malignant hypertension, MAHA, acute kidney injury)
- Interstitial lung disease (most common cause of disease-related death)
- Pulmonary arterial hypertension
- Cardiac fibrosis with arrhythmia, conduction disease, and heart failure
- Severe digital ischemia with ulceration and amputation
- Gastric antral vascular ectasia (watermelon stomach)
- Esophageal dysmotility, aspiration pneumonia, Barrett esophagus
PANCE pearls
- High-dose glucocorticoids (>15-20 mg/day prednisone) precipitate scleroderma renal crisis — use the lowest effective dose, particularly in early diffuse disease.
- Anti-RNA polymerase III antibody confers the highest risk of renal crisis and is also associated with concurrent malignancy.
- Anti-centromere is associated with limited cutaneous disease and lower risk of ILD but a higher risk of late pulmonary arterial hypertension.
- Routine annual screening for pulmonary hypertension with echocardiogram and PFTs (DLCO) is essential for early detection.
References
- ACR/EULAR 2013 — van den Hoogen F et al., 2013 classification criteria for systemic sclerosis (Arthritis Rheum 2013)
- SENSCIS — Distler O et al., Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease (NEJM 2019)
- Scleroderma Lung Study II — Tashkin DP et al., Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (Lancet Respir Med 2016)
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