12.3.07 Scleroderma Scheunemann

7/31/2019 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

12.3.07 Scleroderma Scheunemann

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