Systemic Sclerosis

1. Systemic Sclerosis Morning Report Leslie P. Scheunemann December 3, 2007

2. Overview Basics Epidemiology Pathogenesis Pathology Clinical features Laboratory evaluation Treatment

3. 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

4. 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

5. 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

6. 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)

7. More pathogenesis Extracellular matrix proteins that are overproduced include fibronectin, tenascin, fibrillin-1, and glycosaminoglycans

8. 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

9. More endothelial talk

10. 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

11. Pathology Skin�thin epidermis with compact bundles of collagen parallel to the epidermis, dermal appendages atrophy, rete pegs lost. T cell, monocyte, plasma cell, mast cell infiltrate GI�atrophy of the muscularis predominates over fibrosis; Barrett�s, 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 Pulmonary�diffuse interstitial fibrosis, thickening of the alveolar membrane, and peribronchial and pleural fibrosis; cysts and bullous emphysema; PH MSK Cardiac�irregular fibrosis most prominent around blood vessels, leading to contraction band necrosis; AV conduction defects and arrhythmias; pericardial disease Renal�intimal 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

12. 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

13. Subsets of systemic sclerosis

14. C is for calcinosis

15. R is for Raynaud�s

16. E is for esophageal dysmotility �actually, you have to imagine this one �and S is for sclerodactyly, seen earlier in this presentation

17. T is for telangiectasia

18. 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 Barrett�s 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

19. 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

20. 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

21. 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)

22. 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

23. Other (minor) forms

24. Bibliography Harrison�s online Primer on the Rheumatic Diseases, 12th edition MKSAP