Systemic Sclerosis (Scleroderma)

• Chronic disease characterised by abnormal accumulation of fibrous tissue in the skin and multiple organs
• Skin is most commonly affected but GIT, kidneys, heart, muscle and lungs are also frequently involved
• Death generally results from renal failure, cardiac failure, pulmonary insufficiency or intestinal malabsorption
• M:F ratio 1:3
• Peak incidence in 50-60 age group
• Systemic sclerosis can be divided into two categories;
• Diffuse scleroderma – characterised by widespread skin involvement at onset, rapid progression and early visceral involvement
• Limited scleroderma – whereby skin involvement in confined to fingers, forearm and face. Clinical course is relatively benign as visceral involvement occurs late. Some patients with limited scleroderma develop CREST syndrome

 

Aetiology/Pathogenesis

 

• Cause is unknown
• Likely trigger for excessive fibrosis is a combination of abnormal immune responses and vascular damage, resulting in local accumulation of growth factors that act on fibroblasts to stimulate collagen production
• Believed to be CD4+ T cell mediated
• TGF-b, IL-13 and PDGF stimulate collagen production
• Fibroblasts from patients may be hyper-responsive to TGF-b
• Microvascular disease predominates and intimal proliferation of digital arteries are found in patients with systemic sclerosis
• Capillary dilation and leakage is common
• Nailfold capillary loops are distorted
• Widespread narrowing of the microvasculature leads to ischaemic injury and scarring
• Some genetic component involved – HLA Class II alleles have been implicated as well as genes which encode or regulate production of ECM proteins e.g. fibrillin-1
• There is also evidence for inappropriate humeral immunity – virtually all patients are ANA positive
• Antibodies which recognised DNA topoisomerase I (anti-scl70) is highly specific
• Patients specific for this antibody are more likely to have pulmonary fibrosis and peripheral vascular disease
• Anti-centromere antibody is found in 20-30% of patients with Systemic sclerosis but is also seen in patients with primary biliary cirrhosis.
• Anti-centromere antibody is particularly associated with CREST syndrome

 

 

Morphology

 

• Skin
  • Majority of patients have diffuse sclerotic atrophy of the skin which begins in the fingers and extends proximally to involve the upper arms, shoulders, neck and face
  • In the early stages skin is oedematous and ‘doughy’
  • As it progresses the dermis becomes more fibrotic and bound the subcutaneous structures
  • There is a marked increase in collagen in the dermis, thinning of the epidermis, loss of rete pegs and hyaline thickening of the walls of arteriole and capillaries
  • In advanced stages, fingers look like claws with limited movement and the face becomes a drawn mask
  • Loss of blood supply may lead to ulceration of the terminal phalanges and the tips of the fingers may undergo autoamputation
• Alimentary tracts
  • Particulary affects the lower 2/3 of the oesophagus – leading to reflux and its complications such as Barrett metaplasia and strictures
  • Loss of villi in the small bowel is the basis for malabsorption
• Musculoskeletal system
  • Inflammation of the synovium is common and this may develop into fibrosis
  • Can look similar to RA but there is little joint destruction
  • Inflammatory myositis may develop
• Kidneys
  • Intimal thickening of the interlobular arteries – changes resemble malignant hypertension
  • Hypertension occurs in 30% of patients
  • No specific glomerular changes
• Lungs
  • Involvement manifests as pulmonary hypertension and interstitial fibrosis
• Heart
  • Pericarditis with effusion and myocardial fibrosis along with thickening of the myocardial arteries occurs in 1/3 of patients

 

Clinical Course

 

• Raynauds is seen in virtually all patients
• Mild proteinuria occurs in most patients but rarely progresses to nephrotic syndrome
• Most serious manifestation is malignant hypertension with the subsequent development of renal failure
• Disease tends to be more severe in black people
• As treatment of renal failure has improved, pulmonary disease has become the most common cause of death in systemic sclerosis