1. 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

2. 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

3. 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

4. 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

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

6. 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 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 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

7. 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

8. 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

9. 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

10. SSc
Data from the Pittsburgh Scleroderma Database (July 1980-July 1995)
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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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):
Steen V: Epidemiology of Systemic Sclerosis. Rheumatology. London, Elsevier Limited, 2005;
Systemic Sclerosis, 2006