Systemic Sclerosis

Morning Report Leslie P. Scheunemann December 3, 2007

Overview

Basics Epidemiology Pathogenesis Pathology Clinical features Laboratory evaluation Treatment

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

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

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

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 >50% of SSc patients in one study (none in controls)

More pathogenesis

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

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

More endothelial talk

Endothelial damage Vasoconstriction Tissue ischemia Decreased production of prostacyclin Platelet aggregation More vasoconstriction

TXA

PDGF

TGF-beta

chemotaxis

Stimulates collagen synethsis

Mitogenesis

CTGF

Role of cell-mediated immunity

Initially, activated TH2 cells surround small vessels and dermis, 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 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

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

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

Subsets of systemic sclerosis

Diffuse cutaneous sclerosis Course
Rapidly progressive Within 1 year of onset of disease or at onset ofskin changes Dilated loops with dropout Symmetric Proximal and distal Extremities, face, and trunk

Limited cutaneous sclerosis (CREST)

Raynaud's Capillary nail beds Skin involvement

Can develop years prior to disease Dilated loops without dropout Symmetric Distal to elbows and knees Extremities and face Gastrointestinal PAH (after 10-15 years in <10% of patients) Biliary cirrhosis

Organ involvement

Pulmonary (fibrosis)

Renal (renovascular hypertensive crisis)

Gastrointestinal Cardiac

Antibodies

Anti-topoisomerase

Anti-centromere

C is for calcinosis

R is for Raynauds

E is for esophageal dysmotility

actually, you have to imagine this one

and S is for sclerodactyly, seen earlier in this presentation

T is for telangiectasia

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

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

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

Laboratory evaluation

Elevated:

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

Decreased:

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

Other (minor) forms

Eosinophilic fasciitis

Morphea

Bibliography

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