What can systemic sclerosis be categorised into?
Limited cutaneous systemic sclerosis (more common, 55%)
- characterized by distal (face, neck, and hands), but not proximal, skin thickening; it is usually unaccompanied by internal organ fibrosis
- CREST syndrome: calcinosis, raynauds, esophageal dysmotility, sclerodactyly (skin tightening), telangiectasia
- Raynauds take years to occur
- Gradual onset skin changes limited to upper limbs, face
- Clinically significant ILD less frequent (<20%), cardiac and renal disease rare
- Anti-centromere ab; CREST
Diffuse cutaneous systemic sclerosis (less common 35%)
- characterized by extensive distal and proximal skin thickening (chest, abdomen, and arms proximal to wrists) and is commonly accompanied by internal organ fibrosis + ILD
- Raynauds - short history
- Rapid onset skin changes causing contractures
- Skin of trunk and proximal limbs
- Tendon friction rubs
Constitutional symptoms
- Early onset internal organ involvement: ILD 40%, renal crisis 10%
- Anti-Scl-70 ab: ILD
- Anti RNA polymerase I, III antibodies: scleroderma renal crisis
- ANA with nucleolar pattern
Pulmonary artery hypertension ~10% in both subtypes.
Autoantibodies in scleroderma
- Anti-centromere: limited SSc, Pulmonary HTN
- Topoisomerase I = SCL70 = ILD
- RNA polymerase III = severe renal and skin
- anti Scl 70: speckled ANA, diffuseSc, ILD
- RNA polymease III: fine speckled nucleolar, diffuse Sc, associated with renal crisis, skin involvement and malignancy within 2-5 years of diagnosis
- anti-centromere: centromere pattern, limited SC, protection from ILD/renal disease, causes more PAH and oesophageal disease
U1-RNP: Limited + diffuse, overlap features
PM-SCL, limited + diffuse, myositis overlaps
Th/T0: limited + diffuse, associated with PAH and worse prognosis
What is the leading cause of death in scleroderma?
Cardiopulmonary manifestations - pulmonary fibrosis and pulmonary arterial hypertension (PAH has worst prognosis)
Previously would be scleroderma renal crisis but due to ACEi this has now improved survival
The most common cause of death in systemic sclerosis is respiratory involvement: interstitial lung disease and pulmonary arterial hypertension
What is the most common ILD in scleroderma?
Non specific interstitial pneumonitis > usual interstitial pneumonitis
Usual Interstitial Pneumonia (UIP): subpleural reticulation, apical-basal gradient, traction bronchiectasis, honeycombing
Non specific interstitial pneumonia: ground glass change, apical basal gradient, subpleural sparing, traction bronchectaisis
What is the follow-up for early ILD?
Patients with early diffuse SSc with ILD should be monitored with spirometry and DLCO every 3-4 months for 3-5 years after disease onset then yearly.
No advantage in serial HRCT if PFTs are stable.
What are the high risk phenotype for ILD?
- Early diffuse + anti-SCL70
- Early diffuse + elevated CRP
Treatment for scleroderma ILD
- 1st line: mycophenolate (purine synthesis inhibitors)
- Severe or progressive disease unresponsive to mycophenolate: cyclophosphamide for 6-12 months followed by mycophenolate OR azathioprine
Other:
- Nintedanib: tyrosine kinase inhibitor with antifibriotic and anti-inflammatory effects
- Pirfenidone
- Rituximab
- Tocilizumab: IL6
- Lung transplant
- Autologous stem cell transplant
Cutaneous findings of scleroderma
- Thickening and hardening of the skin
- Sclerodactyly
- Painful ischaemic digital ulcers with atrophy and necrotic spots
- Microstoma - small sized mouth
Muscle involvement in scleroderma.
- Arthralgia, myalgia, fatigue
- Later in disease, fibrosis of the periarticular structures lead to joint pain, immobility and contractures especially in fingers and extremities
- Fibrosis of tendons associated with palpable and/or audible deep tendon friction rubs, occur more commonly in diffuse and may indicate internal organ invovement.
Raynaud phenomenon
Raynaud phenomenon (sequential white, blue, and red color changes in the digits precipitated by cold or stress) occurs in almost all patients with SSc. Raynaud phenomenon is initially transient and reversible; later, structural changes develop within small blood vessels, resulting in permanently impaired flow that produces acrocyanosis, digital pitting, and/or ulcerations.
> 50% have a digital ulcer at some point
Treatment for raynaud’s phenomenon
Non pharmacological
- Keep warm
- Avoid triggers, eg: caffeine
- Smoking cessation
- Selective sympathectomy
- Botox injections
Pharmacological - 1st line: dihydropyridine CCB (nifedipine) - 2nd line: Angiotensin II receptor antagonist Phosphdiesterase-5 inhibitors: sildenafil Topical or systemic nitrates Alpha blockers SSRI Antiplatelet/statin therapy - If severe IV prostacyclin: iloprost
Treatment for digital ulcers
- IV iloprost
- Phosphdiesterase-5 inhibitors: sildenafil
- Endothelin 1 blocker: bonsentan
Gastrointestinal symptoms
- More than 70% of patients with SSc have clinical gastrointestinal involvement. Upper involvement is common, with fibrosis causing pharyngeal dysfunction, esophageal hypomotility, and lower esophageal sphincter incompetence.
- Consequences include dysphagia, chronic gastroesophageal reflux (90%), esophagitis, stricture, Barrett esophagus, and pulmonary microaspiration.
Tx: antireflux with PPI or H2 blocker
Characteristics of scleroderma renal crisis
- Life-threatening rapidly progressive renal impairment usually occurring within 5 years of disease onset
Characterised by
- abrupt onset of moderate to severe HTN
- Normal urine sediment or only mild proteinuria with few cells or casts
- The most important warning sign is a sudden rise in blood pressure. Other symptoms are headache, visual disturbances, shortness of breath, chest pain or discomfort, or mental confusion.
Occurs in patients with diffuse Sc
RF: RNA polymerase III, tendon friction rubs
Triggers include corticosteroids, to reduce scleroderma renal crisis, it is recommended to use <15mg steroids especially for diffuse scleroderma
Signs of severe scleroderma renal crisis
Reflects the underlying vasculopathy and marked HTN
- Microangiopathic haemolytic anaemia and thrombocytopenia
- HF and flash APO
- Blurred vision due to retinopathy
- Headache/fever/malaise
- Encephalopathy - complicated by generalised seizures
- Pericardial effusion
Management of scleroderma renal crisis
ACEI - most experience with captopril (rapid onset, short duration of action)
The mechanism of action of ACE inhibitors is believed to be mitigation of the effect of interstitial fibrosis and vascular dysfunction in the glomerular arterial bed.
Evidence of CNS involvement: captopril and IV nitroprusside
Treatment for pulmonary arterial hypertension
- All patients with PAH should be considered for oxygen supplementation.
- Vasodilating agents, including phosphodiesterase-5 inhibitors (sildenafil or vardenafil) and prostacyclin analogues (iloprost, epoprostenol, or treprostinil), have demonstrated efficacy in relieving symptoms of PAH associated with SSc.
- Endothelin receptor antagonists (bosentan and ambrisentan) have also shown efficacy in improving symptoms and delaying progression of PAH in SSc.
- Select patients may benefit from a vasodilator in combination with an endothelin receptor antagonist. Patients with PAH must be closely monitored using 6-minute walk tests and serial RHC studies
Characteristics of mixed connective tissue disease
Overlap syndrome of SLE, scleroderma and/or polymoyositis with anti-RNP ab.
ANA very high titre in speckled pattern
Mortality increased due to pulmonary arterial hypertension
Antibody associated with limited SsC and complication
Anti centromere
Pulmonary HTN
Antibody and complications associated with diffuse SSc
Bad disease
Potentially extensive cutaneous, MSK and internal organ complications
- SCL70/topoisomerase I: ILD
- RNA polymerase I/III: severe renal and skin
Pulmonary manifestations of SSc
> 20% extent a useful marker for progression
ILD: normally NSIP (most common)
Cardiac manifestations of scleroderma
- Arrhythmias/conduction defects: ventricular Ectopics –> VT (increased in late limited SSc)
- Myocarditis (often with skeletal muscle disease
- Cardiac fibrosis
- Valvular heart disease
MSK effects of systemic sclerosis
- Arthritis is not common but associated with CCP/RF and mostly reflects an overlap disease
- TENDON involvement especially common in diffuse Ssc with RNA polymerase III - friction rubs!
- Contractures
- Calcinosis
Gastroinestinal manifestations
- Most frequent internal organ manifestation
- Dental disease
- Oesophageal involvement - universal
- Delayed gastric emptying
- GAVE ( Gastric antral vascular ectasia )
- Small bowel overgrowth (increased folate)
- Diverticular disease
