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.
Try two board-style Systemic Sclerosis questions
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Question 1MusculoskeletalMedium
A 52-year-old woman reports several years of cold-induced color changes in her fingers, gradual tightening of the skin over her hands, and progressive difficulty swallowing solids and liquids. Examination shows sclerodactyly and scattered telangiectasias over the face and hands. Anti-centromere antibody is positive. Which of the following is the most likely diagnosis?
AMixed connective tissue disease
BSystemic lupus erythematosus
CDiffuse cutaneous systemic sclerosis
DLimited cutaneous systemic sclerosis
Reveal answer & full explanation
Correct answer: D — Limited cutaneous systemic sclerosis
AMixed connective tissue disease
BSystemic lupus erythematosus
CDiffuse cutaneous systemic sclerosis
DLimited cutaneous systemic sclerosis✓
Why limited cutaneous systemic sclerosis is correct
The combination of Raynaud phenomenon, sclerodactyly, telangiectasias, and esophageal dysmotility is the CREST pattern of limited cutaneous systemic sclerosis
Anti-centromere antibody is highly specific for the limited subtype and points away from diffuse disease
Skin involvement restricted to the distal extremities and face, rather than the proximal trunk, defines the 'limited' subtype
These patients warrant surveillance for pulmonary arterial hypertension, the leading cause of death in limited disease
Why the others are wrong
Mixed connective tissue disease — overlaps lupus, scleroderma, and myositis features but is defined by high-titer anti-U1 RNP, not anti-centromere (confused-with-X: wrong antibody)
Systemic lupus erythematosus — causes malar rash, serositis, and cytopenias with anti-dsDNA or anti-Smith antibodies, not sclerodactyly with anti-centromere (premature closure on the commonest connective tissue disease)
Diffuse cutaneous systemic sclerosis — produces rapid proximal and truncal skin thickening with early internal-organ disease and is associated with anti-Scl-70 (anti-topoisomerase), not anti-centromere (buzzword-matching 'scleroderma' without integrating the antibody and skin distribution)
Question 2MusculoskeletalMedium
A 44-year-old woman presents with 4 months of rapidly progressive skin thickening that began on her fingers and has spread to her forearms, upper arms, and trunk. She also reports Raynaud phenomenon, puffy hands, and new arthralgias. On exam she has diffuse skin induration proximal to the metacarpophalangeal joints and tendon friction rubs over the wrists. Blood pressure is 138/86 mm Hg and creatinine is normal. Skin biopsy confirms dermal fibrosis. Which of the following antibody findings best supports the diagnosis of diffuse cutaneous systemic sclerosis with the highest risk of scleroderma renal crisis?
ASerum anti-U1-ribonucleoprotein antibodies
BSerum anti-Jo-1 antisynthetase antibodies
CSerum anti-RNA polymerase III antibodies
DSerum anti-centromere protein antibodies
Reveal answer & full explanation
Correct answer: C — Serum anti-RNA polymerase III antibodies
ASerum anti-U1-ribonucleoprotein antibodies
BSerum anti-Jo-1 antisynthetase antibodies
CSerum anti-RNA polymerase III antibodies✓
DSerum anti-centromere protein antibodies
Why Serum anti-RNA polymerase III antibodies is correct
This patient has early diffuse cutaneous systemic sclerosis (dcSSc): rapidly progressive truncal skin thickening proximal to the MCPs, Raynaud phenomenon, puffy hands, and tendon friction rubs, all classic for the diffuse subtype.
Anti-RNA polymerase III antibody is the SSc-specific autoantibody most strongly associated with diffuse cutaneous disease and confers the highest risk of scleroderma renal crisis (malignant hypertension, microangiopathic hemolytic anemia, acute kidney injury). It also carries a concurrent malignancy association, so it best supports both the diagnosis and the prognostic concern named in the lead-in.
Why the others are wrong
Serum anti-centromere protein antibodies are the hallmark of LIMITED cutaneous SSc (CREST); they predict lower ILD risk but higher late pulmonary arterial hypertension risk, and are associated with LOW, not high, renal crisis risk.
Serum anti-U1-ribonucleoprotein antibodies define mixed connective tissue disease (overlap of SLE, scleroderma, and myositis features), not pure diffuse SSc with renal crisis risk.
Serum anti-Jo-1 antisynthetase antibodies are seen in inflammatory myopathy/antisynthetase syndrome (myositis, ILD, mechanic's hands), not a scleroderma-specific marker.
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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)
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
Limited versus diffuse cutaneous systemic sclerosis.
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
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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