Systemic sclerosis

Systemic sclerosis (SSc), also known as scleroderma, is a complex multisystem autoimmune disease characterised by three hallmark processes: vasculopathy (Raynaud phenomenon and ischaemia), immune dysregulation (autoantibodies and inflammation), and progressive tissue fibrosis affecting the skin and internal organs. SSc is the most severe connective tissue disease in terms of disease-related mortality. It predominantly affects women (female:male ~4–6:1), typically presenting between ages 30–50. The two main subtypes — limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) — differ in the extent of skin involvement and pattern of organ disease. Early recognition and targeted organ-based management are essential to reduce mortality from pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and scleroderma renal crisis.

The 2013 ACR/EULAR classification criteria require a total score ≥9 for classification. Skin thickening of the fingers extending proximal to the metacarpophalangeal joints (score 9) is sufficient alone.

SSc pathogenesis involves three interconnected processes: vasculopathy (endothelial injury and microvascular obliteration), immune activation (T and B cell dysregulation, autoantibody production), and fibroblast activation leading to progressive collagen deposition.

Key Pathogenic Mechanisms

• Vasculopathy — endothelial injury is the earliest event; Raynaud phenomenon reflects vasospasm; intimal proliferation and luminal obliteration cause ischaemia, digital ulcers, and PAH
• Immune activation — T cell (predominantly Th2 and Th17) and B cell infiltration in early skin disease; cytokines (TGF-β, IL-4, IL-6, IL-13) drive fibroblast activation; autoantibodies are biomarkers rather than direct pathogenic agents
• Fibroblast activation — TGF-β is the master fibrogenic cytokine; myofibroblast differentiation leads to irreversible collagen deposition in skin, lungs, heart, and gastrointestinal tract
• Autoantibodies — anti-Scl-70 (anti-topoisomerase I): associated with dcSSc and ILD; anti-centromere (ACA): associated with lcSSc and PAH; anti-RNA polymerase III: associated with dcSSc, rapid skin progression, and scleroderma renal crisis; anti-U1 RNP: overlap syndromes

Genetic and Environmental Factors

• HLA associations — HLA-DQ7, DRB1*11:04 with anti-Scl-70; HLA-DQ2 with ACA
• Occupational exposures — silica (strongest), organic solvents, vinyl chloride; risk factor for dcSSc
• Microchimerism — fetal cells persisting in maternal circulation may contribute to SSc pathogenesis

SSc presents with diverse organ manifestations. Raynaud phenomenon is usually the first symptom and may precede other features by years. Clinical assessment should systematically evaluate all organ systems.

SSc requires comprehensive baseline assessment across all organ systems, with structured annual screening for PAH and ILD. Autoantibody profile is essential for risk stratification and predicts specific organ complications.

• Essential
  ANA + SSc autoantibody panel (anti-Scl-70, anti-centromere, anti-RNA pol III)

  ANA positive in >95% SSc. Anti-Scl-70 (anti-topoisomerase I): dcSSc, ILD, worse prognosis. Anti-centromere (ACA): lcSSc, PAH, calcinosis. Anti-RNA pol III: dcSSc, rapid skin thickening, scleroderma renal crisis. These antibodies are almost mutually exclusive — only one major antibody typically present.
• Essential
  Nailfold capillaroscopy

  SSc pattern: dilated/giant loops, avascular areas, haemorrhages. Abnormal capillaroscopy in context of Raynaud phenomenon is highly predictive of SSc — present in early/undifferentiated SSc before other features develop. Essential for early diagnosis.
• Essential
  PFTs (spirometry + DLCO) — baseline and annual

  Forced vital capacity (FVC) — ILD marker; declining FVC >10% in 12 months = significant progression. DLCO — reduced in ILD and PAH; DLCO <70% = PAH risk; DLCO/VA ratio separates ILD (both reduced) from PAH (DLCO reduced, DLCO/VA preserved).
• Essential
  Echocardiogram — baseline and annual PAH screening

  Estimated RVSP >40 mmHg = further PAH evaluation. Australian guidelines (DETECT algorithm for lcSSc, ASIG algorithm for dcSSc) recommend annual screening in all SSc patients with specific cutoffs. Formal right heart catheterisation (RHC) required to confirm PAH diagnosis.
• Essential
  HRCT chest — baseline; repeat based on risk

  NSIP pattern most common (anti-Scl-70); UIP also seen. Extent of fibrosis on HRCT is the most reliable ILD prognostic marker. Repeat at 12 months if ILD present; baseline HRCT in all anti-Scl-70 patients.
• Essential
  FBC, UEC, LFTs, ESR, CRP

  Baseline and 3–6 monthly; renal function for SRC surveillance; LFTs for hepatic involvement (PBC overlap); haematological parameters.
• Recommended
  ECG and Holter monitor

  Arrhythmias and conduction abnormalities in cardiac SSc; 24-hour Holter if palpitations or syncope.
• Recommended
  NT-proBNP

  Elevated NT-proBNP with dyspnoea = PAH or cardiac SSc investigation required. Useful for PAH screening algorithm.
• Recommended
  Modified Rodnan Skin Score (mRSS)

  Quantifies skin involvement — 17 areas scored 0–3 (total 0–51). Useful for monitoring skin progression in dcSSc. Declining mRSS in first 3–5 years may indicate transition to atrophic phase or treatment response.
• Recommended
  Upper GI endoscopy / oesophageal manometry

  Indicated if significant GERD, dysphagia, or Barrett oesophagus surveillance required. Manometry for oesophageal dysmotility assessment.

Risk stratification in SSc is based on disease subtype, autoantibody profile, organ involvement, and rate of progression. The two most feared outcomes are PAH and scleroderma renal crisis.

SSc management is organ-based — there is no global disease-modifying therapy that reverses fibrosis. Management targets specific complications: immunosuppression for ILD, vasodilators and endothelin antagonists for PAH, ACE inhibitors for renal crisis, and proton pump inhibitors and prokinetics for GI disease.

Directed therapy in SSc addresses specific organ manifestations requiring targeted treatment.

Raynaud Phenomenon and Digital Ulcers

• Lifestyle — warming gloves, heated gloves, hand warmers; avoid cold exposure and smoking (vasoconstrictive); avoid beta-blockers if possible
• Nifedipine modified release — first-line pharmacological Raynaud treatment (PBS-listed for Raynaud in SSc); 20–40 mg twice daily
• Sildenafil or other PDE-5 inhibitors — for refractory Raynaud or digital ulcers not responding to calcium channel blockers
• Iloprost IV infusion — for severe digital ischaemia or impending gangrene; admitted inpatient; 0.5–2 ng/kg/min over 6 hours for 5 consecutive days; PBS-listed for critical digital ischaemia
• Bosentan — PBS-listed for prevention of new digital ulcers in SSc with recurrent digital ulcers
• Digital sympathectomy — surgical last resort for critical digital ischaemia; vascular surgery referral

Gastrointestinal Disease

• GERD — high-dose PPI (omeprazole 40 mg twice daily or pantoprazole 40 mg twice daily); avoid lying flat after meals; head of bed elevation; small frequent meals
• Gastroparesis — prokinetics (metoclopramide or domperidone 10 mg TID before meals); small frequent meals; liquid feeds if severe
• SIBO — rotating antibiotics (metronidazole, doxycycline, rifaximin); nutritional support (dietitian); malabsorption monitoring
• Consti6 months, HRCT annually
• Progressive ILD (FVC decline ≥5–10% over 12 months) — nintedanib (PBS) ± MMF; or cyclophosphamide IV × 6 followed by MMF
• Pulmonology co-management; lung transplant evaluation for end-stage ILD (FVC <50%)
• Avoid corticosteroids >15 mg/day (risk of triggering scleroderma renal crisis)

Pulmonary Arterial Hypertension

• Confirm with RHC — do not treat based on echo alone
• WHO class II: ERA monotherapy (bosentan or macitentan) or PDE5 inhibitor monotherapy
• WHO class III–IV: combination therapy (ERA + PDE5 inhibitor); consider riociguat (soluble guanylate cyclase stimulator; NOT with PDE5 inhibitor); prostanoid (iloprost or epoprostenol IV) for severe or refractory PAH
• All PAH patients referred to specialist PAH centre; consider transplant evaluation for WHO class IV or refractory disease

Gastrointestinal Manifestations

• GERD — high-dose PPI (omeprazole 40 mg twice daily or equivalent); elevate head of bed; avoid large meals and meals within 3 hours of lying down
• Dysphagia — soft diet; prokinetics (metoclopramide, domperidone); endoscopy to assess strictures and Barrett oesophagus
• SIBO — rotating antibiotics (rifaximin, metronidazole, ciprofloxacin); gastroenterology referral
• Gastroparesis — prokinetics; small frequent meals; jejunal feeds if severe

Skin Fibrosis

• Immunosuppression for active inflammatory skin disease — MMF, methotrexate, or rituximab may slow skin progression in early dcSSc
• Skin care — intensive moisturisation; avoid extreme temperatures; physiotherapy for contractures
• Calcinosis — no effective medical treatment; pain management; surgical excision for large/infected deposits

Non-pharmacological management is central to SSc care — particularly for Raynaud phenomenon, skin care, contracture prevention, and nutritional support.

Raynaud and Vascular Protection

• Temperature protection — heated gloves, hand warmers, layered clothing; battery-heated garments for severe cases
• Smoking cessation — non-negotiable; tobacco dramatically worsens vasospasm and digital ischaemia
• Avoid vasoconstrictors — beta-blockers, sympathomimetics, ergotamines, cocaine; decongestants
• Digital ulcer wound care — non-adherent dressings; avoid pressure; vascular nursing input

Skin Care and Physiotherapy

• Intensive skin moisturisation — multiple times daily; urea-based or lanolin creams; prevent dryness and cracking
• Physiotherapy — range-of-motion exercises for hands, face, and trunk; facial stretching for microstomia; splinting for contractures
• Occupational therapy — adaptive devices for hand weakness; splints; functional assessment
• Speech pathology referral — if dysphagia significant; swallowing assessment

Nutrition and GI Support

• Dietary assessment — malnutrition is common due to dysphagia, GERD, and GI dysmotility; dietitian referral
• Dental care — microstomia impairs oral hygiene; frequent dental review; custom dental appliances
• Nutritional supplementation — enteral feeding (jejunal if gastroparesis) for patients who cannot maintain oral nutrition

Psychological Support

• SSc has significant psychological burden — disfigurement (skin changes, telangiectasias), disability, sexual dysfunction, pain
• Psychology referral for depression, anxiety, body image concerns, and adjustment difficulties
• Scleroderma Australia patient support resources; Arthritis Australia

SSc requires structured, intensive organ monitoring. The goal is early detection of ILD progression, PAH, and scleroderma renal crisis before irreversible damage occurs. Monitoring is lifelong and should be coordinated by a rheumatologist.

When to Refer Urgently

• Emergency: Suspected scleroderma renal crisis (acute hypertension + AKI) — ACE inhibitor immediately; admit for monitoring and dose titration
• Respiratory: New dyspnoea, worsening PFTs, elevated echo RVSP — urgent right heart catheterisation for PAH confirmation
• Vascular: Digital gangrene, non-healing digital ulcers — vascular surgery ± iloprost IV
• Cardiac: New pericardial effusion, cardiac failure — cardiology; tamponade if large effusion

Specific groups within the SSc population require modified management.

SSc in Pregnancy

• Pregnancy in SSc is high-risk — scleroderma renal crisis risk (especially early dcSSc), pre-eclampsia, preterm birth, and fetal growth restriction
• Pre-conception counselling — disease should be stable for ≥12 months; avoid pregnancy in early dcSSc or active ILD/PAH
• PAH is a contraindication to pregnancy — maternal mortality risk >25%
• Continue low-dose aspirin for renal crisis prevention in high-risk patients; avoid high-dose steroids
• Teratogenic drugs — MMF, bosentan, nintedanib must be stopped ≥3 months before conception; methotrexate ≥3 months

Undifferentiated CTD / Early SSc

• Raynaud phenomenon + positive ANA + abnormal nailfold capillaroscopy = high risk of evolution to SSc — monitor closely
• SSc-specific autoantibody (anti-Scl-70, ACA, or anti-RNA pol III) without skin thickening = "pre-SSc" — rheumatology follow-up and organ screening

Male SSc

• Male SSc is often more severe — higher rates of ILD, PAH, and cardiac involvement; worse prognosis than females
• Erectile dysfunction common — caused by vasculopathy; sildenafil is both vasodilatory (Raynaud) and erectile dysfunction treatment

Overlap Syndromes

• SSc-myositis overlap (scleromyositis) — anti-PM-Scl antibody; treat myositis with steroids + immunosuppression; monitor cardiac and ILD
• MCTD (anti-U1 RNP) — features of SSc, SLE, and myositis; generally better prognosis than pure SSc

Stewardship in SSc focuses on preventing the most dangerous iatrogenic complication (scleroderma renal crisis triggered by corticosteroids), avoiding drug interactions with bosentan and sildenafil, and ensuring teratogenic drugs are managed with mandatory contraception.

GP Role in SSc Management

• Avoid prescribing high-dose steroids (≥15 mg/day) — use lowest effective dose; warn patients to seek urgent review if BP rises
• Home blood pressure monitoring — provide patients with early dcSSc / anti-RNA pol III positive with BP machine; educate on SRC warning signs
• Medication review — avoid vasoconstrictors (beta-blockers, nasal decongestants); check for nitrate co-prescription with PDE5 inhibitors
• Monitor immunosuppression — FBC and LFTs 3-monthly for patients on MMF or azathioprine
• Bosentan LFT monitoring — monthly LFTs mandatory; withhold if transaminases >3× ULN

SSc requires lifelong multidisciplinary follow-up. The two most important goals are preventing scleroderma renal crisis and detecting PAH/ILD progression before irreversible end-organ damage occurs.

• 01
  Kowal-Bielecka O, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–1339.
• 02
  Distler O, et al. Nintedanib for Systemic Sclerosis–Associated Interstitial Lung Disease (SENSCIS). N Engl J Med. 2019;380(26):2518–2528.
• 03
  Tashkin DP, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II). Lancet Respir Med. 2016;4(9):708–719.
• 04
  van den Hoogen F, et al. 2013 Classification Criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737–2747.
• 05
  Pharmaceutical Benefits Scheme (PBS). Schedule of Pharmaceutical Benefits. Canberra: Department of Health; 2025.
• 06
  Therapeutic Guidelines. Rheumatology. Melbourne: Therapeutic Guidelines Ltd; 2024.