Scleroderma, limited and diffuse
Description
- Multisystem autoimmune disease: vasculopathy + autoimmunity + fibrosis of skin and internal organs
- The only rheumatic disease in which fibrosis, not inflammation, is the dominant end-organ process
Subtypes - defined by the EXTENT of skin involvement
| Limited cutaneous (lcSSc / CREST) | Diffuse cutaneous (dcSSc) | |
|---|---|---|
| Proportion | ~55% | ~35% |
| Skin | Distal to elbows and knees + face; gradual onset | Proximal to elbows/knees, trunk; rapid onset |
| Raynaud | Precedes skin change by years | Onset within ~1 year of skin change |
| Antibody | Anti-centromere | Anti-Scl-70 (topoisomerase I); nucleolar ANA pattern |
| ILD | <20%, later onset | ~40%, early and can be severe (~15%) |
| Renal crisis | Rare | ~10% |
| PAH | More common - the late killer of limited disease | Less common |
- CREST: Calcinosis, Raynaud, o(E)sophageal dysmotility, Sclerodactyly, Telangiectasia
- *Sclerodactyly above the elbows or across the chest = diffuse. That single examination finding assigns the subtype, the antibody, and the prognosis*
- "Scleroderma sine scleroderma" - visceral disease (pulmonary fibrosis, renal crisis, cardiac failure, GI pseudo-obstruction) without skin thickening; the diagnosis rests on autoantibodies (ANA, anti-centromere, anti-Scl-70)
Cutaneous features
- Raynaud phenomenon (>95%), telangiectasia including on the lips, subcutaneous calcinosis with fingertip ulceration, skin tightening (sclerodactyly)
- General inspection: smooth, shiny, tight facial skin; facial telangiectasia with hyper- or hypo-pigmentation ("salt and pepper"); pinched beaked nose; microstomia with radial perioral furrowing
- Skin evolves through oedematous -> indurative -> atrophic phases
Epidemiology
- Prevalence ~20-25 per 100,000; incidence ~1-2 per 100,000/yr
- F>M ~4:1 (up to 8:1 in the childbearing years)
- Peak onset 30-50 yrs
- Male sex predicts worse outcome at every stage
- Higher prevalence and earlier, more severe disease in Aboriginal and Torres Strait Islander Australians and in African-American populations
Aetiopathogenesis
The three-hit model
1. Vasculopathy - endothelial injury -> intimal proliferation, loss of capillaries, absent angiogenesis -> obliterative, non-inflammatory vasculopathy
- This underlies Raynaud, digital ulcers, PAH and renal crisis alike
2. Autoimmunity - T cell and B cell activation, specific autoantibodies that are mutually exclusive and phenotype-defining
3. Fibrosis - TGF-beta, CTGF, IL-6, PDGF -> fibroblast activation -> excess collagen I and III deposition, refractory to normal feedback
Environmental triggers
- Silica dust (mining, stonemasonry - engineered stone benchtops are a current Australian occupational issue)
- Organic solvents, vinyl chloride, epoxy resins
- Bleomycin, taxanes, pentazocine, cocaine
- Genetic: HLA-DRB1, STAT4, IRF5 - modest effect
Differential of diffusely thickened skin
- Scleroderma (limited or diffuse)
- Mixed connective tissue disease
- Chemical exposure (e.g. bleomycin), vinyl chloride, toxic oil
- Scleroedema (e.g. associated with diabetes)
- Also: nephrogenic systemic fibrosis (gadolinium in renal failure), eosinophilic fasciitis ("groove sign", spares fingers, no Raynaud), scleromyxoedema, graft-versus-host disease, morphoea (localised, no Raynaud, no nailfold change)
Diagnosis
- ACR/EULAR 2013 classification criteria - score >=9 classifies as systemic sclerosis
| Item | Score |
|---|---|
| Skin thickening of the fingers extending proximal to the MCP joints | 9 (sufficient alone) |
| Puffy fingers (2) / sclerodactyly distal to MCP (4) | 2-4 |
| Fingertip lesions: digital tip ulcers (2) / pitting scars (3) | 2-3 |
| Telangiectasia | 2 |
| Abnormal nailfold capillaries | 2 |
| PAH and/or ILD | 2 |
| Raynaud phenomenon | 3 |
| SSc-related antibody: anti-centromere, anti-Scl-70, anti-RNA polymerase III | 3 |
Examination - what to look for and why
- Hands: loss of normal transverse digital skin creases, sparse hair, skin thickening and sclerodactyly, finger-pulp atrophy and ulceration, phalangeal resorption (acro-osteolysis), atrophic or beaked nails, telangiectasia, nailfold capillary dropout with dilated loops, Raynaud, calcinosis
- Extent of sclerodactyly - above the elbows? across the chest? -> subtype
- Face: loss of wrinkles, reduced oral aperture, microstomia, beaked nose, telangiectasia
- Trunk: skin tightening; bibasal fine inspiratory crackles (ILD)
- Cardiovascular: loud or palpable P2, right ventricular heave, raised JVP (PAH); BLOOD PRESSURE - the renal crisis screen
- Water swallow for oesophageal dysmotility
- Urinalysis at every visit
Antibodies - they define phenotype and prognosis
| Antibody | Association |
|---|---|
| Anti-centromere | Limited (CREST); PAH; better skin outcome, longer survival |
| Anti-Scl-70 (topoisomerase I) | Diffuse; ILD; digital ulceration |
| Anti-RNA polymerase III | Scleroderma renal crisis; rapidly progressive skin; occult malignancy - screen |
| Anti-U1-RNP | Overlap/MCTD |
| Anti-Th/To, anti-U3-RNP (fibrillarin) | PAH, worse prognosis |
- ANA positive in >90%; a nucleolar pattern is characteristic of diffuse disease
Baseline and surveillance work-up
- Renal function and urinalysis; FBE; blood pressure at every visit
- HRCT chest if ILD suspected; PFTs with DLCO
- Echocardiography +/- right heart catheterisation for pulmonary hypertension
- Nailfold capillaroscopy - dropout, giant loops, haemorrhage; distinguishes secondary from primary Raynaud years before other features
- Barium swallow or manometry; ECG; NT-proBNP; CK
ILD - the detail that is examined
- NSIP (ground-glass with fine fibrosis) is the COMMONER pattern; UIP (peripheral reticulonodular change, honeycombing, traction bronchiectasis) is less common
- Predictors of clinically significant or progressive ILD
- Baseline FVC <70%
- Baseline DLCO <55%
- HRCT fibrosis extent >20-25%, or total lung involvement >20%
Working up worsening breathlessness
- Assess for pulmonary hypertension - DETECT algorithm, echocardiography
- *An FVC/DLCO ratio >1.6 with NT-proBNP more than twice the upper limit of normal warrants referral to a pulmonary hypertension clinic*
- Echocardiography for PH screening: sensitivity ~88%, specificity ~83%, but systolic PAP cannot be estimated in up to 39% because there is no tricuspid regurgitant jet - so a "non-diagnostic" echo does not exclude PAH
- Repeat HRCT for ILD progression
- Also consider: neuromuscular dysfunction, thoracic restriction from chest wall skin, aspiration, deconditioning, anaemia, cardiac disease
Management
Organised by organ, because there is no single disease-modifying therapy. EULAR 2023 introduced "therapeutic continuums" - several equivalent options per domain rather than a strict ladder.
A. Raynaud phenomenon and digital ulcers
- Non-pharmacological first: keep the whole body warm, gloves, hand warmers, stop smoking, avoid beta blockers, ergotamine, sympathomimetics and cold exposure
- Dihydropyridine calcium channel blocker (nifedipine, amlodipine) - first-line
- Add or substitute: PDE5 inhibitor (sildenafil, tadalafil), topical GTN, ARB, SSRI
- Severe or ulcerating disease: IV iloprost (prostacyclin analogue) - used to heal digital ulcers
- Bosentan reduces the number of NEW digital ulcers - it does not heal existing ones
- Digital sympathectomy, botulinum toxin injection in refractory cases
- Treat infected ulcers and osteomyelitis promptly; analgesia is often inadequate
B. Skin fibrosis (progressive diffuse disease)
- Mycophenolate, methotrexate, or rituximab - the recommended options
- Tocilizumab - lower level of evidence and weaker recommendation, but effective in early inflammatory skin/lung disease
- *D-penicillamine is NO LONGER recommended* - randomised evidence showed no benefit over low-dose therapy
- *Corticosteroids have a very limited role - doses above ~15 mg/day of prednisolone precipitate scleroderma renal crisis*
C. Interstitial lung disease
- Rituximab, mycophenolate, cyclophosphamide and nintedanib all carry the strongest recommendation
- Mycophenolate - the usual first choice (better tolerated than cyclophosphamide with equal efficacy, SLS-II)
- Nintedanib (antifibrotic) slows FVC decline (SENSCIS) - can be added to mycophenolate
- Tocilizumab preserves FVC in early inflammatory disease with raised CRP
- Surveillance: spirometry and DLCO every 3-4 months for the first 3-5 years (when FVC decline is most likely), then annually
- Oxygen, pulmonary rehabilitation, vaccination; lung transplantation referral for progressive disease
D. Pulmonary arterial hypertension
- Annual screening in every patient - echocardiography, PFTs with DLCO, NT-proBNP (DETECT algorithm)
- Confirm with right heart catheterisation before treating - do not start PAH therapy on an echo alone
- Early combination therapy: endothelin receptor antagonist (ambrisentan, bosentan, macitentan) + PDE5 inhibitor (sildenafil, tadalafil); add a prostacyclin pathway agent (selexipag, epoprostenol) for high-risk disease
- Refer to a specialist PH centre
E. Scleroderma renal crisis - the emergency
- Abrupt severe hypertension + acute kidney injury + a relatively BLAND urinary sediment with only mild proteinuria
- Immediate ACE inhibition - captopril preferred (short-acting, titratable)
- Aim for a reduction of about 10% in blood pressure per day - too rapid a fall worsens renal ischaemia
- *Continue the ACE inhibitor even as creatinine rises and even if dialysis is required - it is the treatment, not the cause*
- *Avoid beta blockers* - they worsen the vasospasm
- Add plasma exchange if there is microangiopathic haemolysis
- Add IV nitroprusside to captopril if there is CNS involvement
- Dialysis in ~50%; up to half of those recover enough renal function to come off dialysis, sometimes after 12-24 months - do not list for transplant early
- *Prevention: avoid corticosteroid doses >15 mg/day in early diffuse disease, and teach at-risk patients home BP monitoring*
F. Gastrointestinal
- Reflux: PPI, often double dose, lifestyle measures, small frequent meals, elevate the head of the bed
- Dysmotility: prokinetics (metoclopramide, domperidone, erythromycin)
- Small intestinal bacterial overgrowth: rotating antibiotics (rifaximin, amoxicillin-clavulanate, metronidazole); check B12, folate, fat-soluble vitamins
- Pseudo-obstruction: conservative management, decompression, octreotide; avoid surgery
- Faecal incontinence from anorectal involvement - ask, because patients do not raise it
- Nutrition: dietitian; enteral or parenteral feeding in severe malabsorption
- Gastric antral vascular ectasia ("watermelon stomach") - argon plasma coagulation
G. Musculoskeletal and calcinosis
- Arthritis: methotrexate, hydroxychloroquine, low-dose prednisolone (with renal crisis caution); rituximab or tocilizumab for refractory disease
- Myositis: immunosuppression; check CK and cardiac involvement
- Calcinosis: no reliably effective therapy; minocycline, diltiazem, sodium thiosulfate, surgical excision for disabling lesions
- Hand physiotherapy and stretching from diagnosis - contractures are preventable, not treatable
H. Autologous haematopoietic stem cell transplant
- Considered in NON-SMOKERS who fail standard therapy
- Diffuse cutaneous disease within the first 4-5 years with mild-to-moderate organ involvement, OR
- Limited cutaneous disease with progressive visceral involvement
- Improves event-free and overall survival (ASTIS, SCOT) at the cost of significant treatment-related mortality - specialist centres only
I. General
- Education and psychosocial support - body image, sexual function, disability, employment
- Smoking cessation is non-negotiable (vasculopathy)
- Screen for depression; peer support (Scleroderma Australia)
- Vaccination, bone health, cardiovascular risk
- Anti-RNA polymerase III positive: age-appropriate malignancy screening - the disease may be paraneoplastic
Associations
- Overlap syndromes - MCTD, myositis, Sjogren syndrome, SLE, rheumatoid arthritis
- Autoimmune thyroid disease, primary biliary cholangitis (classically with limited disease and anti-centromere antibodies)
- Malignancy - especially with anti-RNA polymerase III (breast, lung), and lung cancer in ILD
- Occupational silica exposure (engineered stone), organic solvents, vinyl chloride; bleomycin
- Anaemia in scleroderma - identify the mechanism
- Iron deficiency from chronic oesophagitis-related blood loss or gastric antral vascular ectasia
- Folate or B12 deficiency from small-bowel bacterial overgrowth
- Anaemia of chronic disease
- Microangiopathic haemolytic anaemia (renal crisis)
- Erectile dysfunction - common, early, vascular; often the first vascular manifestation in men
- Osteoporosis, sarcopenia and malnutrition
- Depression and body image disturbance
Natural history & complications
- Skin thickening in diffuse disease peaks at 1-3 years then often softens spontaneously - do not attribute late softening to the drug
- Limited disease generally carries a better systemic prognosis than diffuse disease
- Good when involvement is confined to skin and gut; worse with renal disease and in MALE patients
- Overall 10-year survival ~65-75%; diffuse disease with early organ involvement is substantially worse
- *The most common organ complication is severe oesophageal dysfunction; but PULMONARY involvement (ILD and PAH) is the leading cause of death; and renal crisis with malignant hypertension carries the poorest prognosis*
Organ involvement
- Lung
- ILD is a leading cause of morbidity and mortality - early and can be severe (~15%) in diffuse disease, later in limited disease; usually NSIP; more prevalent with anti-Scl-70
- PAH - the characteristic late complication of limited disease
- Kidney - scleroderma renal crisis
- Highest risk: diffuse cutaneous disease, early disease (<4 years from onset), corticosteroid use, anti-RNA polymerase III antibodies
- Presents with abrupt severe hypertension, bland sediment with mild proteinuria, progressive renal failure
- Severe cases add microangiopathic haemolytic anaemia and thrombocytopenia, heart failure with flash pulmonary oedema, hypertensive retinopathy with blurred vision, headache, malaise, fever, encephalopathy with or without seizures, and pericardial effusion
- ~10% are normotensive renal crises - usually steroid-associated and with a worse prognosis
- Gastrointestinal - dysphagia and reflux oesophagitis from oesophageal dysmotility; large- or small-bowel dysmotility leading to pseudo-obstruction; malabsorption, GAVE, anorectal dysfunction
- Cardiac - myocardial fibrosis leading to heart failure; arrhythmia and conduction disease, pericardial effusion; often clinically silent until advanced
- Musculoskeletal - inflammatory arthritis, myositis or myopathy, acro-osteolysis (resorption of the distal phalanges) from bone ischaemia, tendon friction rubs (a marker of rapidly progressive diffuse disease), contractures
Monitor - the annual minimum
- Blood pressure and urinalysis at every visit (renal crisis)
- PFTs with DLCO 3-4 monthly for 3-5 years, then annually; HRCT if declining
- Annual echocardiography and NT-proBNP for PAH
- Modified Rodnan skin score; digital ulcer count; weight and nutrition
- FBE (anaemia and its mechanism), renal function, B12/folate/iron
- Malignancy screening in anti-RNA polymerase III positive disease
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