Systemic Sclerosis

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Systemic Sclerosis

• Morning Report
• Leslie P. Scheunemann
• December 3, 2007

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Overview

• Basics
• Epidemiology
• Pathogenesis
• Pathology
• Clinical features
• Laboratory evaluation
• Treatment

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Basics

• Definition A systemic disorder characterized by
  accumulation of connective tissue in the skin and
  visceral organs, causing structural and
  functional abnormalities
• Etiology Unknown
• Clinical characteristics
• vascular damage
• immune activation
• excessive synthesis and deposition of
  extracellular matrix

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Epidemiology

• Peak incidence in patients aged 35-65 years
  (MKSAP says 30-50)
• Female predominance most pronounced during mid-
  and late-childbearing years, peaking at 7-121
  (MKSAP says 31)
• Incidence 19/million, prevalence 19-75/100,000
• Some increased incidence with family history of
  autoimmune disorders
• Occurs at a younger age and has a worse prognosis
  in African American women

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More epi

• Genetic associations are poorly defined and
  correlate better with specific autoantibodies
  than with disease susceptibility
• Chocktaw Native Americans have the highest
  incidence of disease
• Incidence also increased in coal and gold miners
  polyvinyl chloride, epoxy resins, and aromatic
  hypdrocarbons (benzine, toluene,
  trichloroethylene), rapeseed oil, pentazocine,
  bleomycin, and possibly silicone breast implants
  are associated with development of some features
  of SSc

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Pathogenesis

• Autoantibody production
• Chromosomal abnormalities
• Endothelial cell dysfunction
• Fibroblast activation, most notably in the skin
  but also in other organs
• Role for infectious agents has been proposed
• Latent CMV infection implicated in SSc vascular
  injury
• Parvovirus B19 was isolated from the bone marrow
  of gt50 of SSc patients in one study (none in
  controls)

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More pathogenesis

• Extracellular matrix proteins that are
  overproduced include fibronectin, tenascin,
  fibrillin-1, and glycosaminoglycans

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Endothelial damage

• Elevated levels of factor VIII/vWF occur in
  response to endothelial damage
• Type IV collagenase (also granzyme I)
• secreted by activated T cells
• cytotoxic to endothelial cells
• degrades the basal lamina
• Type IV collagen and laminin fragments are
  released and may stimulate an immune response to
  the basal lamina
• Possible impairment in NO synthesis, increased
  alpha-2 adrenergic vasoconstriction, and
  increased endothelin-1
• Antiendothelial cell antibodies
• implicated in apoptosis and antibody-mediated
  cytotoxicity against endothelial cells
• Induce expression of VCAM-1, ICAM-1, E-selectin,
  P-selectin
• Stimulate IL-1, IL-8,MCP production

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More endothelial talk
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Role of cell-mediated immunity

• Initially, activated TH2 cells surround small
  vessels and dermis, then invade normal skin
• CD4CD8 rises, IL-2 and IL-2 receptors are
  increased
• IL-4 stimulates fibroblast chemotaxis and
  collagen synthesis
• Occasionally, decreased interferon-gamma, which
  inhibits collagen synthesis, occurs
• Activated macrophages also produce cytokines,
  including IL-6 which may stimulate tissue
  inhibitor metalloproteinase and limit the
  breakdown of collagen, and fibronectin
• Similar to GVHD
• Mast cell activation

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Pathology

• Skinthin epidermis with compact bundles of
  collagen parallel to the epidermis, dermal
  appendages atrophy, rete pegs lost. T cell,
  monocyte, plasma cell, mast cell infiltrate
• GIatrophy of the muscularis predominates over
  fibrosis Barretts, as well as atrophy of the
  muscularis of the 2nd and 3rd portions of the
  duodenum, jejunum, and large intestine, with
  development of large-mouth diverticulae can occur
• Pulmonarydiffuse interstitial fibrosis,
  thickening of the alveolar membrane, and
  peribronchial and pleural fibrosis cysts and
  bullous emphysema PH
• MSK
• Cardiacirregular fibrosis most prominent around
  blood vessels, leading to contraction band
  necrosis AV conduction defects and arrhythmias
  pericardial disease
• Renalintimal phyerplasia of the interlobular
  arteris, fibrinoid necrosis of the afferent
  arterioles, and thickening of the GBM. IgM,
  complement, and fibrinogen are demonstrated in
  the walls of affected vessels

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Diagnostic criteria

• Sclerodactyly proximal to the MCPs
• 2 of the following
• Sclerodactyly
• Digital pitting or tissue loss on the volar pads
  of the fingertips
• Basilar fibrosis on CXR

• Sensitivity of these criteria is 97, with 98
  specificity but are not
• applicable to clinical practice b/c some pts with
  limited SSc do not meet them

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Subsets of systemic sclerosis
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C is for calcinosis
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R is for Raynauds
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E is for esophageal dysmotility

• actually, you have to imagine this one
• and S is for sclerodactyly, seen earlier in this
  presentation

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T is for telangiectasia
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GI features

• Most patients of both subsets have some GI
  involvement
• Called SSc sine scleroderma if little other organ
  involvement
• Symptoms
• Epigastric fullness
• Burning pain in the epigastric of retrosternal
  regions
• Dysphagia and rgurgitation of gastric contents
• Strictures
• Barretts
• Delayed gastric empyting
• GI outlet obstruction
• Bloating
• Malabsorption due to bacterial overgrowth or
  obliteration of lymphatics
• Pneumatosis intestinalis (cystic small intestinal
  lesions)
• Chronic constipation
• Intussusception
• Incontinence or anal prolapse
• GI bleeding
• Watermelon stomach

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Pulmonary features

• Occurs in 2/3 of patients
• Leading cause of death
• Signs and Symptoms
• Exertional dyspnea
• Dry cough
• PFTs decreased VC, compliance, DLCO, and hypoxia
• Alveolitis
• Right heart failure
• Aspiration pneumonia

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Other features

• Cardiac and renal mostly already covered
• Microangiopathic hemolytic anemia and large
  pericardial effusions may herald hypertensive
  crisis
• Corticosteroid therapy is a risk factor for
  normotensive renal crisis
• Treat with ACE-I
• Sicca syndrome occurs (with antiSSA and antiSSB
  antibodies)
• Hypothyroidism (with antithyroid antibodies)
• Trigeminal neuralgia
• Male impotence

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Laboratory evaluation

• Elevated
• ESR
• RF (25)
• Polyclonal IgG
• Cryos
• ANA (antitopoisomerase 1 (Scl-70), antinucleolar,
  and anticentromere)
• Decreased
• Hgb (CKD or GI bleed)
• B12 or folate (bacterial overgrowth)

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Treatment

• Monitoring
• Inconclusive results with D-penicillamine,
  colchicine, IFN-g, IFN-a, recombinant human
  relaxin, MTX, azathioprine, chlorambucil,
  cyclosporine, 5-FU
• Cyclophosphamide may help pulmonary function
• Autologous stem cell transplantation is under
  investigation
• ASA and dipyridamole have not been shown to help
• Glucocorticoids have limited uses
• Iloprost, losartan, fluoxetine, sildenafil,
  nitropaste, CCBs, bosentan, warfarin
• Sympathectomy
• Skin care
• PPI, metoclopramide, H2 blockers, CCBs, abx,
  octreotide, stool softeners

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Other (minor) forms
Morphea
Eosinophilic fasciitis
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Bibliography

• Harrisons online
• Primer on the Rheumatic Diseases, 12th edition
• MKSAP