Definition and epidemiology
Scleroderma (systemic sclerosis, SSc) is a chronic autoimmune disorder characterized by excessive extracellular matrix deposition in the skin and internal organs, driven by vascular injury, immune activation, and fibroblast dysfunction. It is distinguished from localized scleroderma (morphea, linear scleroderma), which affects skin and underlying tissue without systemic organ involvement.
- Peak incidence: women aged 30-50 years (female-to-male ratio approximately 4:1 to 8:1)
- Relatively rare, with prevalence estimated at roughly 1 in 10,000 in most populations, higher in some registries
- Two major systemic subtypes:
- Limited cutaneous SSc (lcSSc) — skin involvement distal to elbows/knees, often with CREST features
- Diffuse cutaneous SSc (dcSSc) — skin involvement proximal to elbows/knees and trunk, more rapid progression, higher risk of early internal organ involvement
- Localized scleroderma (morphea, linear) is more common in children and does not progress to systemic disease
- Anti-centromere antibody = limited cutaneous SSc (CREST); anti-Scl-70 = diffuse cutaneous SSc with ILD risk
- Anti-RNA polymerase III antibody predicts scleroderma renal crisis risk
- Raynaud phenomenon is often the earliest manifestation, preceding skin changes by years
- Avoid high-dose corticosteroids in SSc — they can trigger scleroderma renal crisis
- ACE inhibitors are first-line and life-saving in scleroderma renal crisis
- Reduced DLCO on PFTs is an early marker of pulmonary vascular or interstitial disease
- Nailfold capillaroscopy shows capillary dropout, useful for early diagnosis
- CREST = Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia
Etiology and risk factors
The exact cause is unknown, but it is considered multifactorial, involving genetic susceptibility and environmental triggers that lead to autoimmunity, vascular damage, and fibrosis.
- Genetic predisposition: certain HLA alleles increase risk; family history of autoimmune disease
- Environmental exposures: silica dust, organic solvents, vinyl chloride (occupational associations)
- Female sex and reproductive-age hormonal factors
- Possible role of microchimerism (fetal cells in maternal circulation) as a triggering mechanism
- Not infectious and not contagious
- Localized scleroderma (morphea) has no established systemic risk factor overlap with SSc
Pathophysiology
Three interrelated processes drive disease: vascular injury, immune dysregulation, and fibrosis.
- Vascular injury: endothelial damage leads to intimal proliferation, vessel narrowing, and chronic tissue ischemia — the basis of Raynaud phenomenon, digital ulcers, and pulmonary arterial hypertension
- Immune activation: autoantibody production (anti-centromere, anti-Scl-70, anti-RNA polymerase III) and T-cell/B-cell activation release profibrotic cytokines, notably TGF-beta and PDGF
- Fibrosis: activated fibroblasts (myofibroblasts) overproduce collagen and extracellular matrix, replacing normal tissue architecture in skin, lungs, GI tract, heart, and kidneys
- The result is progressive thickening and hardening of skin (sclerosis) and fibrotic remodeling of internal organs, which determines morbidity and mortality more than the skin findings themselves
Clinical features
Limited cutaneous SSc (CREST syndrome)
- Calcinosis cutis — subcutaneous calcium deposits
- Raynaud phenomenon — often the earliest symptom, years before other findings
- Esophageal dysmotility — reflux, dysphagia
- Sclerodactyly — thickened, tight skin of fingers
- Telangiectasias — dilated capillaries, especially face and hands
Diffuse cutaneous SSc
- Rapid, widespread skin thickening (trunk, proximal limbs, face)
- Earlier and more severe internal organ involvement: interstitial lung disease, scleroderma renal crisis, myocardial fibrosis
- "Salt and pepper" skin pigmentation changes
- Tendon friction rubs on exam
Shared features
- Puffy/edematous fingers progressing to tight, shiny skin
- Microstomia (small mouth opening), beaked nose
- Digital pitting scars or ulcers from chronic ischemia
- Dyspnea from interstitial lung disease or pulmonary hypertension
- Hypertensive crisis with acute kidney injury (scleroderma renal crisis), more common in diffuse disease, often precipitated by high-dose corticosteroids
Diagnosis
Diagnosis is clinical, supported by autoantibody testing and organ-specific evaluation.
- Antinuclear antibody (ANA): positive in the large majority of patients, used as a screening test
- Anti-centromere antibody: associated with limited cutaneous disease (CREST) and pulmonary arterial hypertension risk
- Anti-Scl-70 (anti-topoisomerase I): associated with diffuse cutaneous disease and interstitial lung disease risk
- Anti-RNA polymerase III: associated with diffuse disease and scleroderma renal crisis risk
- Nailfold capillaroscopy: shows capillary dropout and dilated loops, useful early in disease
- High-resolution CT chest: screens for interstitial lung disease
- Pulmonary function tests: reduced DLCO is an early sign of lung or vascular involvement
- Echocardiography: screens for pulmonary hypertension
- Skin biopsy is rarely needed but shows dermal fibrosis with loss of adnexal structures
Classification (ACR/EULAR criteria) combines skin thickening proximal to the MCP joints (sufficient alone) with weighted criteria including sclerodactyly, digital ulcers/pitting scars, telangiectasia, interstitial lung disease, Raynaud phenomenon, and specific autoantibodies.
Differential diagnosis
| Condition | Distinguishing feature |
|---|---|
| Mixed connective tissue disease | Overlap features, anti-U1-RNP antibody |
| Eosinophilic fasciitis | Skin sparing of hands/face, peripheral eosinophilia, no Raynaud |
| Scleromyxedema | Associated with monoclonal gammopathy, papular skin lesions |
| Nephrogenic systemic fibrosis | History of gadolinium exposure, renal failure, no Raynaud or ANA positivity |
| Diabetic cheiroarthropathy | Long-standing diabetes, no Raynaud, no autoantibodies |
| Graft-versus-host disease | History of hematopoietic stem cell transplant |
| Morphea/localized scleroderma | No internal organ involvement, no Raynaud, usually negative or low-titer antibodies |
Management
There is no cure and no single disease-modifying drug approved for all manifestations; management is organ-based and supportive, following consensus from ACR/EULAR and national rheumatology societies.
Vascular (Raynaud, digital ulcers)
- Calcium channel blockers (e.g., nifedipine) as first-line
- Phosphodiesterase-5 inhibitors or endothelin receptor antagonists for refractory cases or digital ulcers
- Avoid cold exposure and smoking
Skin and immunosuppression
- Methotrexate may be used for progressive skin disease in diffuse SSc
- Mycophenolate mofetil for skin and interstitial lung disease
- Cyclophosphamide historically used for severe ILD, largely replaced by mycophenolate due to similar efficacy and better tolerability
- Nintedanib (antifibrotic) approved for SSc-associated interstitial lung disease
GI involvement
- Proton pump inhibitors for reflux/esophagitis
- Prokinetics for dysmotility
- Antibiotics for small intestinal bacterial overgrowth
Pulmonary hypertension
- Endothelin receptor antagonists, PDE-5 inhibitors, or prostacyclin analogues depending on severity
Scleroderma renal crisis
- ACE inhibitors are first-line and should be started promptly; high-dose corticosteroids are avoided as they can precipitate this complication
General
- Regular screening (annual echocardiography, PFTs, HRCT as indicated) for early organ complication detection
- Physical therapy to maintain joint mobility and hand function
- Hematopoietic stem cell transplantation is considered in select severe, rapidly progressive diffuse cases at specialized centers
Complications and prognosis
- Interstitial lung disease and pulmonary arterial hypertension are the leading causes of death
- Scleroderma renal crisis is a medical emergency; early ACE inhibitor use has markedly improved outcomes
- Cardiac involvement (myocardial fibrosis, arrhythmias, pericarditis) carries poor prognosis
- GI dysmotility can lead to malnutrition, bacterial overgrowth, and malabsorption
- Digital ulcers can progress to critical ischemia and gangrene, occasionally requiring amputation
- Diffuse cutaneous disease generally has a worse prognosis than limited disease, though limited disease carries significant pulmonary hypertension risk
- Overall survival has improved over recent decades with better organ-specific screening and treatment, but mortality remains elevated compared with the general population
CREST = Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia
Practice questions
1. A 42-year-old woman presents with a 2-year history of episodic blue-white discoloration of her fingers in cold weather, followed by puffy swelling of the fingers and now tight, shiny skin extending to her upper arms. Laboratory testing reveals a positive ANA and anti-topoisomerase I antibody. Which of the following is the most likely associated complication she is at risk for?
2. A 55-year-old woman with known diffuse cutaneous systemic sclerosis is started on high-dose corticosteroids for worsening skin induration. One week later she develops severe hypertension, headache, and rising creatinine. Which of the following is the most appropriate immediate treatment?
3. A 38-year-old woman has limited cutaneous systemic sclerosis with calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias. Which autoantibody is most specifically associated with her clinical subtype?
Frequently asked questions
What causes scleroderma?
The exact cause is unknown, but it results from a combination of genetic susceptibility and environmental triggers (such as silica dust exposure) that lead to autoimmune activation, vascular injury, and excessive collagen production. It is not contagious or caused by a single identifiable agent. Family history and certain HLA genes modestly increase risk.
What are the first symptoms of scleroderma?
Raynaud phenomenon, episodic color changes in the fingers triggered by cold or stress, is typically the earliest symptom and can precede other features by years. This is often followed by puffy, swollen fingers that gradually progress to tight, thickened skin. Joint stiffness and fatigue are also common early complaints.
How is scleroderma diagnosed?
Diagnosis combines clinical findings (skin thickening, Raynaud phenomenon, sclerodactyly) with blood tests for antinuclear antibodies and specific markers like anti-centromere or anti-Scl-70 antibodies. Nailfold capillaroscopy and imaging such as high-resolution CT of the chest help assess organ involvement. Formal classification uses ACR/EULAR criteria combining these features.
Is scleroderma curable?
No, scleroderma currently has no cure. Treatment focuses on controlling symptoms, slowing fibrosis progression, and preventing or managing organ complications such as lung and kidney disease. With modern organ-specific monitoring and therapy, many patients live for decades with manageable disease, though severe diffuse cases carry higher risk.
Scleroderma vs lupus — what is the difference?
Scleroderma primarily causes skin and organ fibrosis (hardening) due to excess collagen, while systemic lupus erythematosus causes inflammation across multiple organs without the characteristic skin thickening. Both are autoimmune and can share features like Raynaud phenomenon, but lupus more commonly causes malar rash, nephritis, and hematologic abnormalities, while scleroderma is defined by sclerodactyly and specific antibodies like anti-Scl-70 or anti-centromere.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: M34
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.