Co-morbidity and skin disease: The psoriasis model

1. Co-morbidity and skin disease: The psoriasis model Joel M. Gelfand, MD, MSCE Medical Director, Clinical Studies Unit Assistant Professor of Dermatology Associate Scholar, Center for Clinical Epidemiology and Biostatistics University of Pennsylvania Joel.Gelfand@uphs.upenn.edu

3. Fitzpatrick�s Dermatology in General Medicine Fitz wanted to show the dermatology was relevant to medical practice Key aspect of this was internal diseases which presented in the skin Can skin diseases present internally?

6. Historical Overview of Psoriasis

7. Why might psoriasis be a systemic inflammatory disease? Immune abnormalities are profound Psoriasis severity is associated with greater levels of systemic inflammation (e.g. CRP, Th-1 cytokines) Inflammation may be a common pathway to a variety of diseases including atherosclerosis, obesity, and insulin resistance

8. Natural history of psoriasis Disease severity 85% Mild, 10% Moderate, 5% severe Control of severe disease 50% of patients intensively treated continue to have very active disease (PUVA cohort) 75% of patients with severe disease are not receiving appropriate therapies (NPF survey) Pathways affected and possible outcomes Inflammatory atherosclerosis, thrombosis Angiogenesis EPC & endothelial dysfunction Metabolic oxidative stress

9. Paradigm of the Natural History of Psoriasis and Co-morbidities

11. New Standard of Care �At the very least, dermatologists, who may be the only health care provider for psoriasis patients, must alert these patients to the potentially negative effects of their disease as it relates to other aspects of their health.� National Psoriasis Foundation clinical consensus on psoriasis co-morbidities and recommendations for screening

12. Cardiovascular Disease and Psoriasis Psoriasis associated with excess risk of CVD since 1960�s Th-1 inflammation is central to pathogenesis of atherosclerosis and MI

13. Psoriasis is Associated with Cardiovascular risk factors

14. Prevalence of cardiovascular risk factors

15. Diabetes is independently associated with psoriasis

16. Psoriasis: a risk factor for CAD and MI?

17. Key Question Is the association between psoriasis and MI Indirect (confounding) Bias (study design) Direct If the association is not explained by confounding or bias then psoriasis is a RISK FACTOR for MI Risk factors may be in the causal pathway of an association

19. Study Design � data source General practice research database (GPRD) is a medical records database established in UK in 1987 Data is recorded by GP on diagnoses and medications Diagnoses and treatments by specialists well captured Over 9 million patients and > 40 million person years of follow-up data from 1987-2002 Use of GPRD has been validated for numerous medical conditions (psoriasis, MI, smoking, and other co-variables)

20. Validation of Exposure/Outcome Psoriasis Epidemiology and treatment patterns very similar to UK estimates 90% of patients with a psoriasis code were confirmed to have psoriasis 3-4 years later based on questionnaire sent to GP (N=100) MI 90% of patients with a code for MI were confirmed to have MI based on having 2 of the following criteria: characteristic chest pain, characteristic changes in the electrocardiogram, characteristic serial rises in the concentrations of cardiac enzymes, an arteriogram documenting a recent coronary occlusion, or fibrinolytic therapy (N=400)

21. Study design Study Design: Cohort study Age 20-90 Exposure Psoriasis Mild Severe psoriasis (received systemic therapy) Control � no history of psoriasis code matched from same practice and start date Start date: max psoriasis, registration End Date: min endpoint, death, transfer

22. Conceptual Underpinning of Case-control, Cohort, and Clinical Trials

23. Characteristics of Study Population

24. Systemic therapies received by patients with severe psoriasis

25. Risk of MI in psoriasis

26. Adjusted relative risk of MI in psoriasis patients based on patient age

27. Excess risk of MI due to psoriasis

28. Stroke risk in psoriasis patients Our primary analysis for risk of stroke in patients with psoriasis showed a modest increased risk for stroke in our mild psoriasis patients with a HR of 1.07. However, our severe psoriasis pts had a more clinically significant increased risk of stroke with a HR of 1.44. When adjusted for the known stroke and cardiovascular risk factors, these risks did not change significantly.Our primary analysis for risk of stroke in patients with psoriasis showed a modest increased risk for stroke in our mild psoriasis patients with a HR of 1.07. However, our severe psoriasis pts had a more clinically significant increased risk of stroke with a HR of 1.44. When adjusted for the known stroke and cardiovascular risk factors, these risks did not change significantly.

29. Sensitivity Analyses Information bias Patients seen at least once per year End of observation was last visit to GP Directionality of association Excluded patients with h/o MI or stroke Excluded events occurring within the first 6 months Disease/Treatment effects Exclusion of methotrexate treated patients Exclusion of cyclosporine and retinoid treated patients Exclusion of PsA

30. Limitations Unknown or unmeasured confounding variables Mild group is heterogeneous Skin severity not measured directly Use of methotrexate in severe group may underestimate the relative risk of MI Mechanism not investigated

31. Psoriasis: An Independent Risk Factor for Atherosclerosis

32. Psoriasis and Atherosclerosis: Study Design & Methods Design � Cross-sectional study 32 psoriasis patients treated in an inpatient setting & 32 matched controls Prior history of CVD was exclusionary Non contrast-enhanced 16-row spiral CT performed and Agatston score was calculated

33. Prevalence and Severity of CAD in Psoriasis Prevalence of CAD greater in psoriasis patients 59% vs. 28%, P=0.02 Severity of CAD associated with psoriasis Mean CAC 78 in psoriasis vs. 22 in controls, (P=0.02) Severity of psoriasis (based on # of treatments/yr) correlated with CAC score (r=0.29)

34. Psoriasis: An Independent Risk Factor for Atherosclerosis Psoriasis independently predicts atherosclerosis Controlled for age, sex, hypertension, lipids, FH of cardiovascular disease, diabetes, smoking, BMI, and CRP Psoriasis explained an estimated 8% of the variance

35. Limitations Small study in highly selected psoriasis inpatients vs. controls who were outpatients Could not determine impact of disease vs. impact of therapy Mechanism not investigated

36. Late Breaking News Psoriasis is independently associated with carotid atherosclerotic disease and impaired endothelial function Balci DD et al, Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis JEADV ISSN 1468-3083 In patients with PsA, psoriasis severity is an independent predictor of cardiovascular disease Gladman, DD et al. Cardiovascular morbidity in psoriatic arthritis. Ann Rheum Dis 2008.094839

37. Conclusion Evolving literature identifying: Burden of cardiovascular risk in patients with psoriasis Independent effect of psoriasis on DM and CV risk More research needed to determine how psoriasis severity and activity and psoriasis treatment alters the risk of cardiovascular events Important implications for the management of patients with psoriasis

38. New Questions and Directions Which other skin diseases confer excess CV risk? What additional approaches can be used to confirm existing data? What is the role of "unconventional" CV risk factors in explaining the risk of CV disease in patients with psoriasis such as depression, stress, physical inactivity, etc What is the magnitude of CV risk in order to inform treatment decisions such as ATPIII What is the risk of CVD in patients with severe disease who are not being treated

39. New Questions and Directions Can the risk of CVD attributable to psoriasis be modified with treatment - observational vs. experimental approaches What CV pathways are affected by psoriasis activity - endothelial dysfunction? endothelial precursor cells? cardiac load? metabolic demand and oxidative stress, etc What surrogates of cv risk would be most useful to study? What existing US data sources could be used to investigate these associations - who could fund these studies? How can existing post marketing studies be combined to address these questions?

40. Acknowledgements Funding through NIH/NIAMS K23 Career development support from Dermatology Foundation, the Herzog Foundation and the American Skin Association