Systemic Sclerosis
Summary
Systemic Sclerosis (SSc), also known as Scleroderma, is a multisystem autoimmune connective tissue disease characterised by fibrosis (hardening) of the skin and internal organs, vasculopathy (especially Raynaud's phenomenon), and immune dysregulation. It is classified into two main subtypes: Limited Cutaneous SSc (lcSSc) (formerly CREST syndrome) and Diffuse Cutaneous SSc (dcSSc). The diffuse form has more aggressive internal organ involvement and worse prognosis. Major causes of morbidity and mortality are Interstitial Lung Disease (ILD), Pulmonary Arterial Hypertension (PAH), and Scleroderma Renal Crisis (SRC). [1,2]
Clinical Pearls
Raynaud's is Universal: Virtually all SSc patients have Raynaud's phenomenon. If a patient has Raynaud's with nail fold capillary changes or specific antibodies (ACA, Scl-70), they are at high risk of developing SSc.
Steroids Cause Renal Crisis: High-dose corticosteroids (>15mg Prednisolone) are a major precipitant of Scleroderma Renal Crisis. Avoid in diffuse SSc.
ACE Inhibitors Save Lives: ACE inhibitors (e.g., Captopril) dramatically improved survival in Scleroderma Renal Crisis from less than 10% to 70%+. Do NOT withhold for rising creatinine. Dialysis is temporary; renal function often recovers.
Annual Screening: All patients need annual screening for PAH (Echocardiogram, DLCO) and ILD (HRCT, Spirometry). Early detection improves outcomes.
Demographics
- Prevalence: 50-300 per million.
- Sex: Female predominance (3-8:1).
- Age: Peak onset 30-50 years.
- Ethnicity: More common and severe in African-Americans.
Risk Factors
- Genetic: HLA associations (DRB111, DRB115).
- Environmental: Silica dust exposure, Organic solvents, possibly Cytomegalovirus.
Mechanism
- Vascular Injury: Initial endothelial damage triggers vasculopathy (Raynaud's, digital ulcers).
- Immune Activation: T-cells and B-cells are activated. Autoantibodies are produced (ACA, Scl-70, RNA Pol III).
- Fibroblast Activation: Fibroblasts are activated by TGF-beta. They deposit excessive collagen in the skin and organs.
- Fibrosis: Progressive, irreversible fibrosis replaces normal tissue in skin, lungs, heart, and GI tract.
- Vasculopathy: Small vessel obliteration leads to tissue ischaemia (digital ulcers, PAH, renal crisis).
Classification
| Feature | Limited Cutaneous (lcSSc) | Diffuse Cutaneous (dcSSc) |
|---|---|---|
| Skin Involvement | Distal to elbows/knees, Face | Proximal (Trunk, Upper Arms, Thighs) |
| Onset | Raynaud's precedes skin changes by years | Skin changes soon after Raynaud's |
| Antibody | Anti-Centromere (ACA) | Anti-Scl-70 (Topoisomerase I) or Anti-RNA Polymerase III |
| CREST Features | Prominent | Less prominent |
| Major Organ Risk | PAH (late), Mild ILD | ILD (early), Renal Crisis (esp. RNA Pol III) |
| Prognosis | Better | Worse (Early mortality from ILD/Renal) |
CREST Syndrome (Limited SSc Mnemonic)
- Calcinosis: Calcium deposits in soft tissues.
- Raynaud's Phenomenon.
- Esophageal Dysmotility.
- Sclerodactyly: Skin thickening of fingers.
- Telangiectasia.
| Condition | Key Features |
|---|---|
| Scleroedema | Associated with Diabetes (Type 2) or post-infection. Skin thickening on upper back/neck. No Raynaud's. |
| Morphoea (Localised Scleroderma) | Patches of hard skin. No internal organ involvement. No Raynaud's. |
| Eosinophilic Fasciitis | Skin thickening ("Orange peel"), Peripheral Eosinophilia. Spares fingers/face. |
| Mixed Connective Tissue Disease (MCTD) | Overlap features (SLE, SSc, Polymyositis). Anti-U1 RNP positive. |
| Nephrogenic Systemic Fibrosis | History of Gadolinium exposure in renal failure. Skin thickening on trunk/limbs. |
Cutaneous
Gastrointestinal (90% involvement)
Pulmonary
Renal
Cardiac
Serological
- ANA: Positive in >95%.
- Anti-Centromere Antibody (ACA): Associated with lcSSc and PAH.
- Anti-Scl-70 (Topoisomerase I): Associated with dcSSc and ILD.
- Anti-RNA Polymerase III: Associated with dcSSc and Scleroderma Renal Crisis.
Lung Assessment
- Pulmonary Function Tests (PFTs): Reduced FVC (Restrictive pattern in ILD), Reduced DLCO (in ILD and PAH).
- HRCT Chest: Ground-glass opacities or Fibrosis (NSIP pattern most common).
- Echocardiogram: Estimate PA systolic pressure (Screen for PAH). If RVSP >35-40 mmHg, refer for Right Heart Catheterisation.
Other
- Nail Fold Capillaroscopy: Shows dilated, distorted capillary loops. Predictive of SSc in early Raynaud's.
- Modified Rodnan Skin Score: Quantifies extent of skin thickening.
Management Algorithm
SYSTEMIC SCLEROSIS DIAGNOSED
(Clinical + Antibody + Capillaroscopy)
↓
ORGAN ASSESSMENT
(Lungs, Heart, Kidneys, GI, Skin)
↓
ANNUAL SCREENING
- PFTs / HRCT (ILD)
- Echo / DLCO (PAH)
- BP / Creatinine (Renal Crisis)
↓
TREAT ORGAN-SPECIFIC MANIFESTATIONS
1. Raynaud's Phenomenon
- Conservative: Keep warm, Smoking cessation.
- Pharmacological:
- First-line: CCB (Nifedipine, Amlodipine).
- Second-line: PDE5 Inhibitors (Sildenafil), IV Iloprost (Prostacyclin).
- Digital Ulcers: Analgesia, Wound care, Iloprost, Bosentan (Endothelin receptor antagonist) for prevention.
2. Interstitial Lung Disease (ILD)
- First-line: Mycophenolate Mofetil (MMF).
- Alternative: Cyclophosphamide (Scleroderma Lung Study I).
- Antifibrotic: Nintedanib (approved for SSc-ILD).
- Transplant: Lung transplantation if progressive.
3. Pulmonary Arterial Hypertension (PAH)
- Managed by specialist PAH centres.
- Therapies: Endothelin Receptor Antagonists (Bosentan), PDE5 Inhibitors (Sildenafil), Prostacyclins (Epoprostenol, Selexipag).
4. Scleroderma Renal Crisis (SRC)
- Medical Emergency.
- Treatment: ACE Inhibitor (e.g., Captopril). Start immediately. Continue even if creatinine rises.
- Avoid: High-dose Steroids (precipitant).
- Dialysis: May be required but renal function can recover months later.
5. Gastrointestinal
- GORD: High-dose PPI.
- Gastroparesis: Prokinetics (Metoclopramide, Domperidone).
- Small Bowel Overgrowth: Rotating Antibiotics.
6. Skin
- No proven disease-modifying therapy for skin fibrosis.
- Methotrexate: Some benefit in early diffuse disease.
- Autologous Stem Cell Transplant (ASCT): Consider in early, rapidly progressive dcSSc (ASTIS trial).
Major Organ Complications
- ILD: Leading cause of death in dcSSc.
- PAH: Leading cause of death in lcSSc.
- Scleroderma Renal Crisis: ~5-10% of dcSSc, especially with Anti-RNA Pol III.
- Cardiac Failure / Arrhythmias: Myocardial fibrosis.
- GI Bleeding: GAVE (Watermelon Stomach).
Digital Complications
- Digital Ulcers: Painful, slow to heal.
- Gangrene / Amputation: If ischaemia is severe.
- 10-Year Survival: lcSSc ~75-80%; dcSSc ~55-70%.
- Major Determinants: Extent of lung/cardiac involvement.
- Improved with: Early detection and treatment of ILD and PAH.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Systemic Sclerosis | EULAR (2017) | MMF or Cyclophosphamide for ILD. ACE-I for Renal Crisis. Annual screening. |
| PAH | ESC/ERS | Risk stratification and combination therapy. |
Landmark Evidence
1. Scleroderma Lung Study I & II (SLS I/II)
- Compared Cyclophosphamide, Mycophenolate, and Placebo for SSc-ILD.
- Result: MMF was as effective as Cyclophosphamide with better tolerability. MMF is now first-line.
2. SENSCIS Trial (NEJM 2019)
- Nintedanib vs Placebo in SSc-ILD.
- Result: Nintedanib slowed decline in FVC. Approved for SSc-ILD.
3. ASTIS Trial (JAMA 2014)
- Autologous Stem Cell Transplant vs Cyclophosphamide in severe dcSSc.
- Result: ASCT improved long-term survival but with higher early mortality.
What is Systemic Sclerosis?
It is an autoimmune condition where your body's immune system attacks its own tissues, causing scarring (fibrosis) and hardening, particularly of the skin. It can also affect internal organs like the lungs, heart, kidneys, and gut.
What causes the cold fingers (Raynaud's)?
The blood vessels in your fingers overreact to cold or stress, causing them to go white, then blue, then red. This is called Raynaud's phenomenon. We try to prevent attacks by keeping you warm and sometimes using medication to open up the blood vessels.
Is it dangerous?
It can be. The main concerns are:
- Lung scarring (ILD): Makes you breathless.
- High pressure in lung arteries (PAH): Puts strain on your heart.
- Kidney crisis: A sudden spike in blood pressure that damages your kidneys.
Can it be treated?
There is no cure, but we can manage the symptoms and protect the organs:
- Medication: Blood pressure tablets, drugs to protect the lungs.
- Monitoring: Regular scans and blood tests to catch problems early.
Primary Sources
- Kowal-Bielecka O, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017.
- Distler O, et al. Nintedanib for Systemic Sclerosis–Associated Interstitial Lung Disease (SENSCIS). N Engl J Med. 2019.
- Tashkin DP, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II). Lancet Respir Med. 2016.
Common Exam Questions
- Antibody: "Anti-Centromere positive?"
- Answer: Limited Cutaneous SSc. Associated with PAH.
- Antibody: "Anti-Scl-70 positive?"
- Answer: Diffuse Cutaneous SSc. Associated with ILD.
- Emergency: "Scleroderma Renal Crisis treatment?"
- Answer: ACE Inhibitor (e.g., Captopril). Do not stop despite rising creatinine.
- Drug: "ILD in SSc first-line?"
- Answer: Mycophenolate Mofetil.
Viva Points
- CREST: Define each component and link to lcSSc.
- Why not Steroids?: High-dose steroids precipitate Scleroderma Renal Crisis. Avoid in dcSSc.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.