Systemic Sclerosis (Scleroderma)

By Isra

Definition

• Systemic sclerosis is a chronic autoimmune connective tissue disease characterized by:
  • Fibrosis of skin and internal organs.
  • Vasculopathy (obliterative small-vessel disease).
  • Immune dysregulation with autoantibody production.

Note: ‘Sclero’ = hard, ‘derma’ = skin, but disease is systemic, not only cutaneous.

Epidemiology

• Prevalence: 50–300 per million (rare disease).
• Gender: Female : Male $\approx$ 4–6 : 1.
• Age: Onset typically 30–50 years.
• Ethnic variation: African ancestry $\to$ more severe, diffuse disease, worse outcomes. Caucasians $\to$ more limited disease.
• Genetics: HLA associations (e.g. DRB11104, DQA10501).

Pathophysiology (Stepwise)

• Trigger + Genetic susceptibility → environmental exposures (silica, solvents) in a predisposed person.
• Vascular injury → endothelial apoptosis, intimal proliferation, narrowing/obliteration → Raynaud’s, digital ulcers.
• Immune activation → T cells, B cells, cytokines (IL-4, IL-6, TGF- $\beta$ ), autoantibodies (anti-centromere, anti-Scl-70, anti-RNA pol III).
• Fibroblast activation → overproduction of collagen.
• End-organ fibrosis → skin thickening, lung fibrosis, renal crisis, cardiac fibrosis, GI dysmotility.

Classification (EULAR/ACR 2013)

A. Localized forms (not systemic):

• Morphea: patchy areas of skin thickening, only skin/subcutaneous tissue.
• Linear scleroderma: streak of thickened skin, may involve muscle/bone.

These forms do NOT involve internal organs.

B. Systemic sclerosis (two major subsets):

• Limited cutaneous systemic sclerosis (lcSSc / CREST)
• Diffuse cutaneous systemic sclerosis (dcSSc)

Limited cutaneous systemic sclerosis (lcSSc / CREST)

• Skin thickening limited to face, hands, distal forearms/legs.
• CREST: Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia.
• Organ features: Pulmonary arterial hypertension (PAH), GI reflux, dysmotility.
• Antibody: Anti-centromere.
• Course: Slow, indolent.

The limited symptoms of scleroderma are referred to as CREST

Calcinosis - Calcium deposits in the skin.

Raynaud’s phenomenon - spasms of blood vessels in response to cold or stress.

Esophageal dysfunction - acid reflux and decrease in motility of esophagus.

Sclerodactyly - thickening and tightening of the skin on the fingers and hands.

Telangiectasias - dilation of capillaries causing red marks on surface of the skin.

Diffuse cutaneous systemic sclerosis (dcSSc)

• Skin thickening extends proximally (upper arms, thighs, trunk).
• Rapid progression.
• Organ features: Interstitial lung disease (fibrosis), Renal crisis (malignant HTN, AKI, MAHA), Cardiac involvement.
• Antibodies: Anti-Scl-70 (topoisomerase I), Anti-RNA polymerase III.
• Course: Aggressive, early visceral disease.

Clinical Manifestations (by system)

• Skin: Tight shiny skin, sclerodactyly, digital ulcers, calcinosis.
• Vascular: Raynaud’s phenomenon, telangiectasia, PAH.
• GI tract: Reflux, dysphagia, small bowel dysmotility, malabsorption.
• Lungs: Interstitial lung disease (diffuse), Pulmonary hypertension (limited).
• Renal: Scleroderma renal crisis, MAHA (diffuse).
• Cardiac: Restrictive cardiomyopathy, arrhythmias, pericardial effusion.

R 6

Investigations

• Autoantibodies: ANA (>90%), Anti-centromere (limited), Anti-Scl-70 (diffuse, ILD), Anti-RNA polymerase III (renal crisis).
• Nailfold capillaroscopy: capillary dropout, dilatation.
• HRCT chest: interstitial lung disease.
• Echocardiography / RHC: pulmonary hypertension.
• Renal function and BP monitoring.

Management

• General: Avoid cold, stop smoking, vaccinate (influenza, pneumococcus).
• Vascular / Raynaud’s: Calcium channel blockers, PDE-5 inhibitors, prostacyclin analogs, bosentan.
• Fibrosis / Skin: Methotrexate, mycophenolate, cyclophosphamide; stem cell transplant in severe diffuse cases.
• Lungs: ILD → mycophenolate, cyclophosphamide, nintedanib; PAH → sildenafil, bosentan, epoprostenol.
• Renal crisis: ACE inhibitors (captopril), avoid high-dose steroids.
• GI: PPIs for reflux, prokinetics, antibiotics for bacterial overgrowth.

Cancers Associated with Systemic Sclerosis

• Lung Cancer: Most strongly associated. Risk highest in patients with interstitial lung disease (ILD) and long-standing pulmonary fibrosis. Smoking further increases risk.
• Breast Cancer: Increased incidence, especially in women with diffuse cutaneous SSc. Sometimes appears within a few years of onset.
• Esophageal Carcinoma: Due to long-standing esophageal dysmotility and reflux (GERD).
• Hematological Malignancies: Non-Hodgkin lymphoma.
• Other Solid Tumors (less frequent): Liver cancer, Bladder cancer.

Antibody Associations & Cancer Risk

• Anti-RNA polymerase III antibodies → strongest link with cancer (breast, lung). Often cancers diagnosed within 2–3 years of SSc onset.
• Anti-Scl-70 (topoisomerase I) → linked with ILD, hence indirect lung cancer risk.
• Anti-centromere antibodies → lower cancer association.

Notes

• Scleroderma = vascular disease + immune dysregulation + fibrosis.
• Limited (CREST): slow, distal, pulmonary hypertension.
• Diffuse: rapid, proximal, ILD + renal crisis.
• Localized (morphea/linear): skin only.
• Prognosis depends on lungs, kidneys, heart involvement.
• There is no consistent disease-specific antibody for localized forms.
• Always consider associated malignancies screening.

GOOD LUCK