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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

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Co-morbidity and skin disease: The psoriasis model

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    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

    2. 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? Fitzpatrick’s Dermatology in General Medicine

    3. Historical Overview of Psoriasis

    4. 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 Extensive psoriasis is characterized by an estimated 20 billion T cells infiltrating the skin Krueger JG, Bowcock, A. Ann Rheum Dis 2005;64:30-36.

    5. 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 Nijsten, T et al, Clinical severity of psoriasis in last 20 years of PUVA study. Arch Dermatol, 2007;143:1113-21. Gelfand, J.M., Long-term treatment for severe psoriasis: we're halfway there, with a long way to go. Arch Dermatol, 2007;143:1191-3. Horn, E.J., et al., Are patients with psoriasis undertreated? Results of National Psoriasis Foundation survey. J Am Acad Dermatol, 2007; 57:957-62. Azfar, R.S. and J.M. Gelfand, Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol, 2008.20:416-22.

    6. Paradigm of the Natural History of Psoriasis and Co-morbidities Outcomes • Cancer • Cardiovascular disease • Metabolic disease • Arthritis • Mortality Risk factors Genes Environment Mediating Factors • Pathophysiology (inflammation,hyper-proliferation, angiogenesis) • Treatment • Psychosocial impact

    7. Why is this important? Severe psoriasis • 50% increased risk of mortality • 3-5 years of life lost • Excess mortality not explained by predictors routinely measured in medical care

    8. 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 JAAD 2008;58:1031-42

    9. 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 Hansson GK NEJM 2005;352:1685-1695

    10. Psoriasis is Associated with Cardiovascular risk factors • Smoking • Obesity • Dyslipidemia • Hypertension • Diabetes Neiman AN, Porter S, and Gelfand JM. Expert Review of Derm. 2006;1:63-75

    11. Prevalence of cardiovascular risk factors Neimann et al. JAAD 2006;55:829-835

    12. Diabetes is independently associated with psoriasis Incident diabetes in severe psoriasis*: adjusted OR 2.6 (95% CI 1.1-5.9) *Defined as: >2 years duration and > 2 oral psoriasis Rx’s per year Neimann et al. JAAD 2006;55:829-835 Brauchli, YB. BJD 2008; In press

    13. Psoriasis: a risk factor for CAD and MI? Psoriasis CAD MI Smoking HTN DM Obesity Lipids

    14. 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

    15. JAMA. 2006 Oct 11;296(14):1735-41

    16. 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)

    17. 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) Neimann A et al. JAAD 2006;55:829-835 Meir CR et al. Lancet 1998;351:1467-71

    18. 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

    19. Conceptual Underpinning of Case-control, Cohort, and Clinical Trials o o o o o o o o o o o o o o o o Exposed o o allocation process o o o End of observation period o o o o o Unexposed o o o o o o o o o o o o o o Study population study time ♦ = Study outcome

    20. Characteristics of Study Population

    21. Systemic therapies received by patients with severe psoriasis Note: Percentages do not add to 100 because patients could have received more then one systemic therapy.

    22. Risk of MI in psoriasis

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

    24. Excess risk of MI due to psoriasis

    25. Stroke risk in psoriasis patients Gelfand JM et al. J Investigative Dermatol. 2008;128:S81

    26. 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

    27. 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

    28. Psoriasis: An Independent Risk Factor for Atherosclerosis Ludwig RJ Br J Dermatol 2007;156:271-6

    29. 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

    30. 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)

    31. 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

    32. 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

    33. 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

    34. 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

    35. 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

    36. 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?

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