12.3.07 scleroderma scheunemann
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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 characterizedby accumulation of connective tissue in theskin and visceral organs, causing structuraland functional abnormalities
Etiology: Unknown
Clinical characteristics:
vascular damage immune activation
excessive synthesis and deposition ofextracellular 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 7-12:1(MKSAP says 3:1)
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 andcorrelate better with specific autoantibodies thanwith disease susceptibility
Chocktaw Native Americans have the highestincidence of disease
Incidence also increased in coal and gold miners;polyvinyl chloride, epoxy resins, and aromatichypdrocarbons (benzine, toluene,trichloroethylene), rapeseed oil, pentazocine,bleomycin, and possibly silicone breast implants areassociated with development of some features ofSSc
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Pathogenesis
Autoantibody production
Chromosomal abnormalities
Endothelial cell dysfunction
Fibroblast activation, most notably in theskin but also in other organs
Role for infectious agents has beenproposed Latent CMV infection implicated in SSc vascular
injury
Parvovirus B19 was isolated from the bonemarrow of >50% 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 toendothelial 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 maystimulate an immune response to the basal lamina
Possible impairment in NO synthesis, increased alpha-2adrenergic 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
Endothelial damage
Vasoconstriction Tissue ischemia Decreased production of prostacyclin
More vasoconstrictionPlatelet aggregation
TXA PDGF TGF-beta
chemotaxis
Mitogenesis
Stimulates collagen synethsis
CTGF
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Role of cell-mediated immunity
Initially, activated TH2 cells surround small vessels anddermis, then invade normal skin
CD4:CD8 rises, IL-2 and IL-2 receptors are increased
IL-4 stimulates fibroblast chemotaxis and collagen synthesis
Occasionally, decreased interferon-gamma, which inhibitscollagen synthesis, occurs
Activated macrophages also produce cytokines, including IL-6which may stimulate tissue inhibitor metalloproteinase andlimit 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, retepegs 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 and3rd 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 bloodvessels, leading to contraction band necrosis; AV conductiondefects and arrhythmias; pericardial disease
Renalintimal phyerplasia of the interlobular arteris, fibrinoidnecrosis of the afferent arterioles, and thickening of the GBM.IgM, complement, and fibrinogen are demonstrated in thewalls 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
CXRSensitivity 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
Diffuse cutaneous sclerosisLimited cutaneous sclerosis
(CREST)
Course Rapidly progressive
Raynaud'sWithin 1 year of onset of disease
or at onset ofskin changes Can develop years prior to disease
Capillary nail beds Dilated loops with dropout Dilated loops without dropout
Skin involvement Symmetric Symmetric
Proximal and distal Distal to elbows and knees
Extremities, face, and trunk Extremities and face
Organ involvement Pulmonary (fibrosis) GastrointestinalRenal (renovascular hypertensive
crisis) PAH (after 10-15 years in
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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 forsclerodactyly,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 ofpatients
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 normotensiverenal crisis
Treat with ACE-I
Sicca syndrome occurs (with antiSSA and antiSSBantibodies)
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 humanrelaxin, MTX, azathioprine, chlorambucil,cyclosporine, 5-FU
Cyclophosphamide may help pulmonary
function Autologous stem cell transplantation is under
investigation
ASA and dipyridamole have not been shownto 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
Eosinophilic fasciitis Morphea
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Bibliography
Harrisons online
Primer on the Rheumatic Diseases,
12th edition
MKSAP
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