Scleroderma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Overview[edit | edit source]

Scleroderma is an autoimmune connective tissue disease. The hallmark of the underlying pathophysiology is production of autoantibodies against various cellular antigens, small vessel vasculopathy, fibrosis of skin and internal organs, and excess collagen deposition in the skin and internal organs. Circulating autoantibodies found in patients with scleroderma are anti-topoisomerase I (Scl-70) antibody, anti-centromere antibody, anti-RNA polymerase III antibody, anti-nucleolar antibody. Growth factors and cytokines play an important role in the underlying pathogenesis of scleroderma. Increased fibroblast activity leads to the excessive collagen deposition in scleroderma. Although the hallmark of this disease is skin fibrosis, internal organ involvement is a fatal complication and includes, esophageal dysmotility, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, myocardial fibrosis, pericardial fibrosis and pericardial effusion. Although scleroderma occurs in a sporadic pattern in the general population, variations in the human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma. On gross pathology, sclerodactyly, skin fibrosis, edema and calcinosis are characteristic findings of scleroderma. On microscopic histopathological analysis, characteristic findings of scleroderma include microvascular damage, perivascular infiltrates of immune cells, loss of microvasculature, perivascular edema, fibrosis, densely packed collagen in the lower dermis and upper subcutaneous layer, atrophy, and loss of cells in the later stages of the disease.

Pathophysiology[edit | edit source]

Pathogenesis[edit | edit source]

• Scleroderma, also known as systemic sclerosis (SSc) is an autoimmune connective tissue disease.^[1][2]
• Important features of scleroderma include:^[3]
  • Production of autoantibodies against various cellular antigens
  • Small vessel vasculopathy
  • Fibrosis of the skin and internal organs
  • Excess of collagen deposition in the skin and internal organs
• Other features of Scleroderma include:
  • Sclerodactyly (thickened skin of the fingers) is common
  • Extensive skin fibrosis may be present
  • Raynaud phenomenon
  • Esophageal dysmotility
  • Pulmonary arterial hypertension
  • Cardiac involvement
  • Interstitial lung disease
  • Inflamatory arthritis
  • Digital ulcers
• There is an association between scleroderma and malignancy:^[4]
  • Patients with RNA polymerase III autoantibodies are at high risk for scleroderma associated malignancy
  • Patients with an older age of onset of scleroderma are at higher risk for cancer
  • Screening for malignancy is recommended in these patients at risk
• An increase in alpha2-adrenergic activity in vascular smooth muscle is responsible for vasospasm in scleroderma.^[5]
• Circulating autoantibodies found in patients with scleroderma include:
  • Anti-topoisomerase I (Scl-70) antibody^[6][7][8]
    • Associated with higher risk of interstitial lung disease
    • Increased disease activity
  • Anti-centromere antibody
    • Present in limited cutaneous scleroderma (CREST syndrome)
  • Anti-RNA polymerase III antibody^[9]
    • Associated with higher prevalence of malignancy in scleroderma patients
  • Anti-nuclear antibody (ANA)
• Growth factors and cytokines play a role in the underlying mechanism of disease:^[1]
  • Transforming growth factor-beta (TGF-beta)^[10]
  • Platelet-derived growth factor^[11]
  • Interleukins^[12]
    • IL-1, IL-6, IL-8, IL-17
  • Basic fibroblast growth factor (bFGF)^[13]
  • Interferon-gamma
  • Tumor necrosis factor (TNF) alpha
• Increased fibroblast activity leads to excess collagen deposition^[14]
  • The mechanism responsible is thought to be increased transcription of collagen specific mRNA^[15]
  • The transformation of fibroblasts to myofibroblasts leads to the over expression of cytokines and growth factors^[16][10]
  • Reactive oxygen species also play a role in the differentiation of fibroblasts^[17]
• Internal organ involvement:
  • Gastrointestinal system^[18][19][20]
    • Esophageal dysmotility
    • Lower esophageal sphincter incompetence
  • Pulmonary system
    • Interstitial lung disease (pulmonary fibrosis)^[21]
    • Pulmonary arterial hypertension
  • Renal system
    • Scleroderma renal crisis^[22][23]
      • Microalbuminuria
      • Elevated plasma creatinine
      • Hypertension
  • Cardiovascular system^[24]
    • Pericarditis^[25]
    • Pericardial effusion
    • Myocardial fibrosis^[26]
    • Myocardial ischemia leading to myocardial infarction^[27][28]
    • Arrhythmia
      • Ventricular arrhythmias
      • Due to fibrosis of the myocardium and conduction system

Genetics[edit | edit source]

Genetics associated with the development of scleroderma include:^[29]

• Scleroderma occurs in a sporadic pattern in the general population.
• Variations in human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma.
• Other genes that increase the risk of developing scleroderma include:
  • IRF5
  • STAT4
• Genetic variation in the IRF5 gene predisposes an individual to developing diffuse cutaneous systemic scleroderma.
• Genetic variation in the STAT4 gene predisposes an individual to developing limited cutaneous systemic scleroderma.

Associated Conditions[edit | edit source]

Conditions that are associated with scleroderma include:^[2]

• Nephrogenic sclerosing fibrosis
• Scleroderma diabeticorum
• Scleromyxedema
• Erythromyalgia
• Porphyria
• Lichen sclerosis
• Diabetic cheiroarthropathy
• Primary biliary cirrhosis^[30]

• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis
• Polymyositis
• Sjögren's syndrome
• Graft-versus-host disease^[31]
• Mixed connective tissue disease
• Malignancy^[32][4]

Gross Pathology[edit | edit source]

• On gross pathology, sclerodactyly, skin fibrosis, edema and calcinosis are characteristic findings of scleroderma.^[33][34][2]

Microscopic Pathology[edit | edit source]

• On microscopic histopathological analysis characteristic findings of scleroderma include:
  • Microvascular damage^[35]
    • Arterioles are primarily affected
    • Perivascular edema
    • Large gaps between endothelial cells
    • Loss of integrity of the endothelial lining
    • Platelet aggregation in the vessels
    • Vacuolization of the cytoplasm of endothelial cells
    • Perivascular infiltrates of mononuclear immune cells in the walls of arterioles^[36]
    • Obliterative microvascular lesions
    • Rarefaction of capillaries
    • Small vessel effacement^[37]
  • Fibrosis^[38]
    • Densely packed collagen in the lower dermis
    • Upper subcutaneous layer also affected
    • Loss of reticular structure
    • Accumulation of proteoglycans, fibrillar and elastic fibers^[39]
    • Accumulation of type I collagen^[40]
  • Atrophy and loss of cells in later stages

References[edit | edit source]

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