Research Project: The outcome of African American patients with scleroderma in relationship to autoantibody, genetics and socioeconomic status Donna Swistowski, MD Department of Medicine Research Presentation 12/15/06

Systemic Sclerosis (scleroderma) Systemic sclerosis is a chronic multisystem disorder of unknown etiology characterized by the overproduction and accumulation of collagen with thickening of the skin and by structural and functional abnormalities of visceral organs, including the GI tract, lung, heart and kidneys Classification of Systemic Sclerosis Limited Cutaneous Disease (CREST) Diffuse Cutaneous Disease Sine Scleroderma (visceral involvement without skin involvement) Undifferentiated Connective Tissue Disease Overlap Syndromes

Systemic Sclerosis Diffuse Limited Skin Involvement Distal and proximal extremities, face, trunk Distal to elbows, face Raynaud’s Phenomenon Onset within one year or at time of skin changes May precede skin disease by years Organ Involvement Pulmonary (interstitial fibrosis); renal (renal crisis); gastrointestinal; cardiac GI, pulmonary hypertension Nail Fold Capillaries Dilation and dropout Dilation without significant dropout Antinuclear Antibodies Anti-topoisomerase Anti-centromere

Clinical Features of Systemic Sclerosis (% Patients during course of disease) Limited Diffuse Raynaud’s 95-100 90-95 Skin thickening 98 100 Subcutaneous calcinosis 50 10 Telangiectasia 85 40 Arthralgias/arthritis 70 Myopathy 5 Esophageal dysmotility 80 Pulmonary fibrosis 35 Pulmonary HTN 1 CHF 30 Renal crisis 15

Clinical Features (courtesy of Dermnet.com) Calcinosis Vitiligo Sclerodactyly Digital Ulceration

Systemic sclerosis incidence and prevalence Systemic sclerosis has a worldwide distribution and affects all races Annual incidence of 1-2 individuals per every 100,000 in the US Prevalence between 19-75 per every 100,000 individuals Highest prevalence in the Choctaw Native Americans in Oklahoma – prevalence of 469 people per every 100,000 Women affected 3 times as often as men Peak onset at 30-50 years of age Genetic factors influence susceptibility and expression of SSc SSc in a first degree relative is a very strong relative risk factor for SSc Increased risk of other autoimmune conditions in family members of SSc patients including SLE, RA, and positive ANA ANA antibodies are even found in the spouses of patients with SSc suggesting a possible environmental role

Multifactorial Pathogenesis of SSc Host Genetic susceptibility Infection Environmental factors Microchimerism Vascular Endothelial cell injury Vasoconstriction Vascular occlusion Tissue hypoxia Immune T cell activation Macrophage activation Autoantibodies Cytokines Genetics – HLA haplotypes ex-Chocktaws have haplotype DQ7 and DR2 Infection – CMV(latent) or B19 (B19 detected in BM of 50% of SSc patient v’s none in normal controls) Environmental – more common in coal and gold miners, workers exposed to polyvinylchloride can develop symptoms similar to SSc, bleomycin, also aromatic hydrocarbons and epoxy resins Fibroblast activation and growth Fibrosis

Scleroderma in African Americans Younger age of onset Affected twice as frequently as Caucasians More likely to have diffuse cutaneous scleroderma More likely to have pulmonary involvement Decreased survival in African American patients In North American African Americans antibodies to U3-RNP are associated with a severe form of diffuse SSC and an increased risk of pulmonary HTN

Scleroderma Autoantibodies There are 7 known scleroderma specific autoantibodies Anticentromere Antibodies (ACA) Anti-Scl-70 or anti-topoisomerase (TOPO) Anti-U1-RNP (U1-RNP) or (antifibrillarin) Anti-RNA Polymerase III (Pol 3) Anti-U3-RNP (U3-RNP) Anti-Th/To (Th/To) Anti-Pm/Scl (Pm/Scl) “Antibodies in scleroderma are not known to have any role in the pathogenesis of the disease but rather appear to be markers of clinical, genetic, and possible etiologic patient subsets….” Virginia Steen, MD

SSc Data from the Pittsburgh Scleroderma Database (July 1980-July 1995) - 1432 patients had autoantibody analysis performed Antibody ACA Th/To PmScl U1RNP U3RNP TOPO Pol3 Number of patients 291 72 36 71 55 318 120 Male (%) 8 19 21 29 27 African American 3 4 13 17 Age of Onset 42 40 38 33 35 43 44 Diffuse SSc (%) 5 7 22 20 64 85 Disease Duration   *at diagnosis 8.7 7.9 3.2 2.9 2.2 1.5 *at last visit 16.3 14.3 16.5 12 11.3

SSc – Organ Involvement in Patients with Scleroderma-Specific Antibodies Antibody ACA Th/To PmScl U1RNP U3RNP TOPO Pol 3 Number of patients 291 72 36 71 55 318 120 Any GI (%) 57 33 39 59 56 37 Severe GI (%) 8 13 14 25 5 Number with PFTs 184 49 22 40 235 74 Any Lung (%) 45 62 58 53 67 73 Severe Fibrosis (%) 6 16 27 24 23 7 Lowest FVC (Predicted) 87 70 75 68 81 Isolated PHT 19 32 3 2 Severe Heart Disease(%) 4 11 18 Renal Crisis (%) 1 10 28

U3-RNP and Anti-TOPO antibodies Patients with the nucleolar antibody, U3-RNP, present with classic diffuse scleroderma and severe multi-organ involvement including pulmonary HTN and GI involvement Over 50% of the patients with this autoantibody pattern are African American This is true at Georgetown were over 50% of the African American patients have U3-RNP along with severe manifestations including pulmonary HTN, pulmonary fibrosis as well as severe small bowel involvement and peripheral neuropathy African Americans also have anti-TOPO antibodies in a higher proportion of individuals, and this finding puts them at increased risk for interstitial fibrosis and Pulmonary HTN

Project selection “…the relationship between ethnicity, socioeconomic status, psychological, genetic and biologic factors in systemic sclerosis are complex…” “With the goal and recognition that the health of the nation depends on the health of its communities along with a plan to deal with disparities” Our project aims to determine a predominant factor which best predicts outcome in African American patients with scleroderma This study seeks to the sort out the interplay of the many factors contributing to the outcome in systemic sclerosis Determinants of outcome include demographics, organ system damage, auto-antibody status, disability, socioeconomic features and survival

Study Design Prospective study of the outcome and risk factors for severe disease in African American patients with scleroderma at Georgetown and Johns Hopkins Scleroderma Centers Study open to African Americans patients with clinically diagnosed systemic sclerosis 5 year study

Studies at Baseline and yearly follow-up Demographic Questionnaire Age, race, sex Socioeconomic Factors Marital Status, children, employment history Alcohol, smoking history, pregnancy history Health insurance Education level Standard Medical Care Complete Medical History Scleroderma Specific History – symptoms at diagnosis, time of diagnosis, time to see rheumatologist Medication history Complete scleroderma examination including a skin evaluation as measured by Rodnan Skin Score

Studies at Baseline and yearly follow-up Baseline and Follow-up Studies CBC, Chem 10, ESR, CPK Chest X-ray, EKG PFT including DLCO Exercise Echo with evaluation of pulmonary arterial pressure High Resolution CT Serum for autoantibody analysis – Studies performed under the direction of Dr. Antony Rosen at Johns Hopkins Additional Instruments Health Assessment Questionnaire SF-36 – questionnaire for psychosocial issues Body image dissatisfaction

Studies at Baseline and yearly follow-up Evidence of Severe Organ Involvement Skin score greater than 40 Gastrointestinal – malabsorption requiring TPN or long term antibiotics, pseudo-obstruction, watermelon stomach Lung – FVC < 55% of predicted or pulmonary HTN with PAP > 40 Heart – pericarditis requiring treatment, CHF, arrhythmias Kidney – renal crisis, ESRD Neuropathic symptoms

Study Follow-up Patients will be seen every 6 months for the first 2 years of the study and then yearly Follow-up visits will include reviewing and updating the baseline studies Death – dates, primary and secondary causes of death and there relation to scleroderma will be determined

Study Analysis Each of the following determinants of outcome will be correlated with different autoantibodies seen in African-American patients Demographics Clinical – subset (diffuse, limited), organ system involvement Genetics – HLA genotypes associated with different auto-antibodies Socioeconomic status Psychosocial status These factors are likely to play a rule in the outcome of patients with scleroderma-our research aims to reach a better understanding of these factors and how they affect African American scleroderma patients in particular

References Kasper et al: Harrison’s Principles of Internal Medicine, 16th edition. New York, McGraw-Hill, 2005. Steen, V. Autoantibodies in Systemic Sclerosis. Seminars in Arthritis and Rheumatism, 2005: 35:35-42. Steen, VD, Powell DL, Medsger Jr TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheumatology 2000;43(11): 2437-44 Steen V: Epidemiology of Systemic Sclerosis. Rheumatology. London, Elsevier Limited, 2005; 1455-1462 www.uptodate.com Systemic Sclerosis, 2006