http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/09546634.2014.952609
ORIGINAL ARTICLE
Risk of myocardial infarction in psoriasis patients: a retrospective cohort study Jashin J. Wu1 Young M. Choi2, and Judith D. Bebchuk3 Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and 3Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
1
Abstract
Keywords
Background: Psoriasis may or may not be associated with a higher risk for myocardial infarction (MI). We sought to assess differences in MI incidence between control, mild psoriasis and severe psoriasis patients. Methods: We performed a retrospective cohort study of Kaiser Permanente Southern California members with psoriasis between 1 January 2004 and 30 June 2012, assessing the risk and incidence rates of MI. Results: There were 50 865 control patients matched to 10 173 patients with mild psoriasis and 19 205 control patients matched to 3841 patients with severe psoriasis. The MI incidence per 1000 person-years for mild psoriasis controls, mild psoriasis, severe psoriasis controls and severe psoriasis were 4.9, 6.7, 3.7 and 5.1, respectively. Upon multivariable analysis, mild psoriasis patients had a significantly higher risk of MI compared to matched control patients {hazard ratio (HR) ¼ 1.31 [95% confidence interval (CI): 1.14, 1.51]} and severe psoriasis patients had a significantly higher risk of MI compared to matched control patients [HR ¼ 1.28 (95% CI: 1.02, 1.60)]. Conclusion: Patients with psoriasis are at higher risk for MI compared to control patients.
Biologics, cardiovascular, inflammation History Received 14 May 2014 Accepted 2 August 2014 Published online 26 August 2014
Introduction
Study population and data source
Psoriasis is a chronic skin condition affecting 2–3% of the population (1), which is 125 million of the world population and 7.5 million of the US population. Many recent studies have suggested that psoriasis is associated with a higher prevalence of myocardial infarction (MI) when compared to the general population (2–5), and that those with more severe psoriasis are at higher risk compared to those with mild psoriasis (5). However, other studies have not found psoriasis patients to have a higher incidence or risk of MI compared to the general population (6–9). The primary objective of this study was to assess differences in MI incidence between control, mild psoriasis and severe psoriasis.
KPSC is a large integrated health maintenance organization that has served 3.6 million members as of 31 December 2012. KPSC comprises 15% of the region’s population. The membership in KPSC spans the geographic area from Bakersfield in the lower California Central Valley to San Diego on the Mexican border. Attrition averages 10% per year. Membership demographics, socioeconomic status and ethnicity composition are representative of California. Health plan members receive the majority of their health care at KPSC-owned facilities, including medical centers and offices. However, the health plan is also financially responsible for KPSC members’ emergency medical care received at non-plan facilities. More than 92% of members have prescription drug benefits and obtain their prescription medication from a KPSC pharmacy. All patients have blood chemistry and other laboratory test benefits. All the data were extracted from HealthConnect, the electronic databases of KPSC clinic and hospital systems. The local Institutional Review Board at KPSC approved the study protocol.
Methods Design overview This retrospective cohort study was conducted within the Kaiser Permanente Southern California (KPSC) Health Plan. The study period was from 1 January 2004 to 30 June 2012. We evaluated the MI incidence rates in those with no psoriasis (control), mild psoriasis (those with no systemic therapy or phototherapy) and severe psoriasis (those with any use of systemic therapy or phototherapy).
Correspondence: Dr Jashin J Wu, MD, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Avenue, 5th Floor, Los Angeles, CA 90027, USA. Tel: +1(323)783-4171. Fax: +1(323)783-1629. E-mail: [email protected]
Inclusion/exclusion criteria Inclusion criteria: (i) all patients had been continuously enrolled (30-day gaps allowed) for at least 1 year before and 1 year after the index date (third psoriasis diagnosis date); (ii) patients had a medical encounter at least every 2 years between index date and 30 June 2012. Patients who had a prior MI (ICD9 410 or 412) anytime before the index date or were 518 years old at the index date were excluded from the study.
2
J. J. Wu et al.
J Dermatolog Treat, Early Online: 1–5
To form the psoriasis cohorts, we included KPSC members with at least three recorded diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification) of psoriasis (696.1) on three different dates between 1 January 2004 and 30 June 2012. A physician in a hospital or clinic setting performed all the coding. Patients with psoriasis who received one of the following therapies during the study period were considered to have severe psoriasis: UVB phototherapy, PUVA, methotrexate, acitretin, cyclosporine, etanercept, adalimumab, infliximab, ustekinumab, efalizumab or alefacept. Patients with psoriasis who did not receive one of the above therapies during the study period were considered to have mild psoriasis. Controls were excluded if they ever had psoriasis or psoriatic arthritis (696.0) diagnosis. Two separate control groups were matched by age and gender to patients with mild psoriasis or with severe psoriasis.
variables and t-test for continuous variables. All statistical tests were two tailed. The rates of MI in the mild and severe psoriasis groups were compared with the rate of MI in the control group using an unadjusted Cox proportional hazards model. The rates were then adjusted for age, sex, diabetes, dyslipidemia, hypertension, diabetes therapy, statin therapy, hypertension therapy and betablocker therapy. Body mass index and smoking were not included in the model as they were only recorded for 73 and 70% of the patients respectively. Each dichotomous variable in the model was checked for proportionality while adjusting for the other covariates in the model by examining diagnostic log–log survival plots. All statistical analyses were performed using SAS Enterprise Guide version 4.3 (SAS Institute Inc., Cary, NC). All p values are two-sided and p50.05 was considered statistically significant.
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
Results Outcomes and follow-up The primary outcome was acute MI as defined as any ICD9 code for 410.xx after diagnosis of psoriasis. Follow-up ended (censored) with the first occurrence of any of the following: (i) MI, (ii) death during the study period, (iii) disenrollment from KPSC or (iv) end of study on 30 June 2012. For patients who did not experience any of these events, the last visit before the end of the study period was used as that patient’s end date to minimize information bias. Potential confounding variables We evaluated the potential confounding effects of patient level demographics, comorbidities and concomitant medications. Potential confounding variables were collected within 12 months prior to the index date. We evaluated the following demographics and comorbidities: age, gender, diabetes, hypertension and dyslipidemia. We also evaluated the potential confounding effects of the following medications during the baseline exposure window: anti-diabetic drugs, cholesterol lowering drugs, antihypertensive medications, and statins and beta-blockers in particular due to their known function to lower MI risk. Statistical analysis Categorical variables were summarized as counts and percentages and continuous variables were summarized as mean and standard deviation. Associations between the presence of psoriasis and various covariates were tested using v2 test for categorical
There were 50 865 control patients matched to 10 173 patients with mild psoriasis and 19 205 control patients matched to 3841 patients with severe psoriasis (Table 1). Diabetes was present in 9000 (17.7%) control matched to mild psoriasis, 2102 (20.7%) with mild psoriasis, 2760 (14.4%) controls matched to severe psoriasis and 697 (18.1%) with severe psoriasis. Dyslipidemia was present in 24 820 (48.8%) controls matched to mild psoriasis, 5326 (52.4%) with mild psoriasis, 7268 (37.8%) controls matched to severe psoriasis and 1514 (39.4%) with severe psoriasis. Hypertension was present in 25 233 (49.6%) controls matched to mild psoriasis, 5439 (53.5%) with mild psoriasis, 7686 (40%) controls matched to severe psoriasis and 1862 (48.5%) with severe psoriasis. When compared with their respective controls, those with mild psoriasis were more likely to be younger, to have diabetes, dyslipidemia, hypertension and to be on therapy for diabetes, dyslipidemia, hypertension and on a beta-blocker or statin. When compared with their respective controls, those with severe psoriasis were more likely to be younger, to have diabetes, hypertension and to be on therapy for diabetes, dyslipidemia and on a beta-blocker or statin. For those with severe psoriasis, UVB phototherapy was most commonly prescribed for 1569 (24.3%) patients (Table 2). Methotrexate was the most commonly prescribed systemic therapy for 1509 (23.4%) patients. Etanercept was the most commonly prescribed biological therapy for 1241 (19.2%) patients. The MI incidence per 1000 person-years for controls matched to mild psoriasis, mild psoriasis, control matched to severe
Table 1. Cohort characteristics. Study group Mild Characteristics Age at diagnosis, mean (SD) Male, n (%)* Non-Hispanic White, n (%) Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Lipid medication, n (%) Hypertension medication, n (%) Statin, n (%) Beta blocker, n (%) Diabetic medication, n (%)
Controls (N ¼ 50865) 57.7 23 965 23 685 25 233 24 820 9000 19 636 27 871 19 592 14 973 7682
(14.87) (47.1) (48.4) (49.6) (48.8) (17.7) (38.6) (54.8) (38.5) (29.4) (15.1)
p value Severe
Psoriasis (N ¼ 10173)
Controls (N ¼ 19205)
57.2 4793 5869 5439 5326 2102 4209 5942 4203 3322 1824
52.9 9660 8647 7686 7268 2760 5579 8763 5572 4436 2404
(14.87) (47.1) (59.8) (53.5) (52.4) (20.7) (41.4) (58.4) (41.3) (32.7) (17.9)
(13.70) (50.3) (46.9) (40) (37.8) (14.4) (29) (45.6) (29) (23.1) (12.5)
Psoriasis (N ¼ 3841) 52.4 1932 2041 1862 1514 697 1223 2031 1217 1086 640
(13.69) (50.3) (55) (48.5) (39.4) (18.1) (31.8) (52.9) (31.7) (28.3) (16.7)
*The study groups were matched on gender so it is not appropriate to calculate a p value for the comparison.
Mild psoriasis versus control
Severe psoriasis versus control
0.003
0.042
50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001
50.001 50.001 0.067 50.001 50.001 50.001 50.001 50.001 50.001
Myocardial infarction in psoriasis
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
DOI: 10.3109/09546634.2014.952609
psoriasis and severe psoriasis was 4.9, 6.7, 3.7 and 5.1, respectively (Table 3). The population attributable risk (PAR) indicates the number of MI that would not occur if the psoriasis were not present. In mild psoriasis, for those in the 45–54 years, 55–64 years and 65 years age groups, the PAR (%) is 13.2 [95% confidence interval (CI): 4.5, 18.3], 6.8 (95% CI: 0.0, 11.1) and 2.9 (95% CI: 0.3, 5.2), respectively. In severe psoriasis, for those in the 45–54 years, 55–64 years and 65 years age groups, the PAR (%) is 11.8 (7.2, 19.2), 8.0 (2.2, 13.1) and 1.2 (8.2, 5.8), respectively. Since BMI and smoking status was missing for 20 and 25% of the cohort, respectively, these variables were not included in the multivariable analysis (Table 4). After adjusting for other comorbidities, patients with mild psoriasis were significantly more likely to develop an MI compared to their respective controls [hazard ratio (HR) ¼ 1.31 (95% CI: 1.14, 1.51)]. After adjusting for other co-morbidities, patients with severe psoriasis were significantly more likely to develop an MI compared to their respective controls [HR ¼ 1.28 (95% CI: 1.02, 1.60)]. The traditional MI comorbidities were associated with an increased MI risk: older age [65 + versus 545 years: HR ¼ 6.27 (95% CI: 4.66, 8.42)], male versus female [HR ¼ 2.02 (95% CI: 1.82, 2.25)], dyslipidemia [yes versus no: HR ¼ 1.27 (95% CI: 1.10, 1.46)] and hypertension [yes versus no: HR ¼ 1.25 (95% CI: 1.06, 1.48)]. Diabetes was not significantly associated with MI risk [yes versus no: HR ¼ 1.19 (95% CI: 0.98, 1.43)]. The cumulative incidence of MI by age of the four groups is illustrated in Figure 1.
Table 2. Prescribed therapies for severe psoriasis. No. of patients (%) with severe psoriasis (N ¼ 3841)
Treatment UVB phototherapy Methotrexate Etanercept Acitretin Adalimumab Cyclosporine Infliximab Ustekinumab Methoxsalen + UVA phototherapy Efalizumab Alefacept
1569 1509 1241 919 616 248 136 78 64 46 28
(24.3) (23.4) (19.2) (14.2) (9.5) (3.8) (2.1) (1.2) (1) (0.7) (0.4)
Percentages do not add up to 100 because patients could have received multiple therapies.
Discussion In this retrospective study, those with psoriasis are at higher risk for MI. The traditional MI risk factors were also generally associated with a higher risk for MI. Our results are similar to recent findings in Canadian patients by Levesque et al. (10), who demonstrated a significantly higher risk of MI in mild psoriasis patients versus control [HR ¼ 1.18 (95% CI: 1.05, 1.33)], but they did not find the same elevated risk with severe psoriasis patients versus control [HR ¼ 1.16 (95% CI: 0.94, 1.60)]. The increased MI risk in those with severe psoriasis in our study is lower than the reported MI risk [HR ¼ 7.08 (95% CI: 3.06, 16.36)] in Gelfand et al. (5). This could be related to the fact that this population was given TNF inhibitors, which we have reported in the past to be associated with a significant reduction in MI risk when compared to patients treated only with topical therapy (11). There are a few important differences to note between this study and Gelfand et al. (5). They used only one diagnosis code for psoriasis. It is possible a high number of psoriasis patients were misclassified (12). Since a primary care physician, not a dermatologist, made most of the diagnoses, the likelihood of Table 4. Univariate and multivariable Cox proportional hazard regression models of the risk of MI in patients with mild and severe psoriasis compared with control patients. Characteristics Psoriasis (unadjusted) Severe versus control Mild versus control Severe versus mild Psoriasis (adjusted) Severe versus control Mild versus control Severe versus mild Age (years) 45–54 versus 545 55–64 versus 545 65 + versus 545 Male versus female Hypertension (yes versus no) Dyslipidemia (yes versus no) Diabetes (yes versus no) Hypertension therapy (yes versus no) Statin (yes versus no) Beta blocker (yes versus no) Diabetic medication (yes versus no)
HR (95% CI)
p value
1.35 (1.08, 1.69) 1.37 (1.19, 1.58) 0.76 (0.60, 0.97)
0.01 50.001 0.02
1.28 (1.02, 1.60) 1.31 (1.14, 1.51) 0.98 (0.77, 1.24)
0.03 50.001 0.84
2.28 3.42 6.27 2.02 1.25 1.27 1.19 1.29 1.11 1.58 1.32
50.001 50.001 50.001 50.001 50.01 50.001 0.07 50.01 0.13 50.001 50.01
(1.67, (2.54, (4.66, (1.82, (1.06, (1.10, (0.98, (1.07, (0.97, (1.41, (1.09,
3.11) 4.61) 8.42) 2.25) 1.48) 1.46) 1.43) 1.56) 1.28) 1.78) 1.60)
The p value indicates the significance of the effect in predicting MI.
Table 3. Incidence rates and PAR of cohorts. Study group Mild Characteristics Follow-up time Mean (SD) Median Q1, Q3 No. of person-years No. of new MI cases (%) Incidence per 1000 person-years Age 45–54 years PAR (95% CI) Age 55–64 years PAR (95% CI) Age 65 + years PAR (95%)
3
Severe
Controls (N ¼ 50 865) Psoriasis (N ¼ 10 173) Controls (N ¼ 19 205) Psoriasis (N ¼ 3841) 3.5 (2.00) 3.5 1.9, 4.9 179 790 880 (1.7) 4.9
3.5 (2.0) 3.5 1.9, 4.9 35 738 240 (2.4) 6.7
5.0 (2.21) 5.2 3.4, 6.9 96 059 359 (1.9) 3.7
5.0 (2.23) 5.2 3.4, 6.9 19 200 97 (2.5) 5.1
NA
13.2 (4.5, 18.3)
NA
11.8 (7.2, 19.2)
NA
6.8 (0.0, 11.1)
NA
8.0 (2.2, 13.1)
NA
2.9 (0.3, 5.2)
NA
1.2 (8.2, 5.8)
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
4
J. J. Wu et al.
J Dermatolog Treat, Early Online: 1–5
Figure 1. Kaplan–Meier curve for cumulative incidence of MI.
misclassification may have been further increased (13,14). They also did not match respective controls to mild psoriasis and severe psoriasis (i.e. they used one large group of control patients for comparison). Finally, only 3% of the total psoriasis population was deemed as having severe disease, which is much lower than other estimates of 12.4% (15) (based on BSA involvement of 410%) to a high of 79.3% (16) (BSA involvement of410% or a PASI score of 410). The PAR indicates that younger patients with psoriasis (mild or severe) tended to have a higher risk of MI due to psoriasis compared to the older counterparts. This is similar to Gelfand et al (5) in that adjusted relative risk was highest in young patients with severe psoriasis. Likely, eliminating psoriasis has a larger relative impact on the risk of MI in younger patients compared to older patients, who generally have an increased number of other cardiac risk factors. However, some studies show that patients with psoriasis do not have an increased risk for MI. Maradit-Kremers et al. (6) studied a population-based incidence cohort of patients from Olmsted County, Minnesota population with psoriasis first diagnosed between 1 January 1970 and 1 January 2000. Psoriasis was associated with an elevated risk of MI based on diagnostic codes [HR ¼ 1.26 (95% CI: 1.01, 1.58)], but not when the analyses were restricted to validated MI [HR ¼ 1.18 (95% CI: 0.80, 1.74)]. However, this study had limited power in cohort analyses due to the relatively younger age of the cohort and low incidence of cardiovascular events, and they did not adjust for traditional cardiovascular risk factors when comparing the risk of MI. Further, this is a narrow population that may not be generalizable to the rest of the population. This study has several strengths: KPSC has a stable membership with a large number of psoriasis, and there is accurate
diagnosis coding of these diseases as well as other medical co-morbidities. This allowed a substantial collection of cumulative longitudinal follow-up, giving the study adequate power to capture differences in MI incidence. Prescription drug use among the study cohort was very well documented, since 490% of all prescriptions of KPSC members are filled in a health plan pharmacy (internal records). Based on internal documentation for the KPSC database, the accuracy and completeness for all of the variables were in the mid-90% range and above. The study results may be generalizable to other patients who are from an insured and ethnically diverse population. There are some limitations to this study. Cause of death was not obtained, so a fatal MI may not have been captured with an ICD9 code for MI. Standardized measurements such as body surface area (BSA) or psoriasis area and severity index (PASI) are not generally entered by community dermatologists. Thus, it is possible that patients with severe psoriasis as based on BSA (usually defined as 10% or more) or PASI (usually defined as 10–12 or more) were not given any systemic therapy or phototherapy and thus were placed in the mild psoriasis group.
Conclusion Those with psoriasis are at higher risk for MI compared to their respective controls. Long-term prospective studies are needed to determine whether systemic therapy may reduce this risk of MI in psoriasis patients.
Acknowledgements We would like to acknowledge Tony S. Yiu, Department of Research and Evaluation, KPSC, Pasadena, CA, USA, for his assistance in creating the data set that was used for all the analyses.
Myocardial infarction in psoriasis
DOI: 10.3109/09546634.2014.952609
Declaration of interest Dr. Wu received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Merck, and Pfizer; he is a consultant for AbbVie, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. This publication was made possible by a KPSC Regional Research Committee grant which is partially supported by the Southern California Permanente Medical Group’s Department of Research and Evaluation and Direct Community Benefit Investment funds. J.J.W. received research funding from Abbott Laboratories, AbbVie, Amgen, Eli Lilly, Merck and Pfizer, which were not directly related to this study.
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
References 1. Channual J, Wu JJ, Dann FJ. Effects of TNF-alpha blockade on metabolic syndrome in psoriasis: lessons learned from rheumatoid arthritis and psoriatic arthritis. Dermatol Ther. 2009;22:61–73. 2. Xiao J, Chen LH, Tu YT, et al. Prevalence of myocardial infarction in patients with psoriasis in central China. J Eur Acad Dermatol Venereol. 2009;23:1311–15. 3. Lin HW, Wang KH, Lin HC, et al. Increased risk of acute myocardial infarction in patients with psoriasis: a 5-year populationbased study in Taiwan. J Am Acad Dermatol. 2011;64:495–501. 4. Kaye JA, Li L, Jick SS. Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis. Br J Dermatol. 2008;159:895–902. 5. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735–41. 6. Maradit-Kremers H, Dierkhising RA, Crowson CS, et al. Risk and predictors of cardiovascular disease in psoriasis: a population-based study. Int J Dermatol. 2013;52:32–40. 7. Wakkee M, Herings RM, Nijsten T. Psoriasis may not be an independent risk factor for acute ischemic heart disease
8.
9.
10.
11.
12.
13.
14.
15.
16.
5
hospitalizations: results of a large population-based Dutch cohort. J Invest Dermatol. 2010;130:962–7. Schmitt J, Ford DE. Psoriasis is independently associated with psychiatric morbidity and adverse cardiovascular risk factors, but not with cardiovascular events in a population-based sample. J Eur Acad Dermatol Venereol. 2010;24:885–92. Brauchli YB, Jick SS, Miret M, et al. Psoriasis and risk of incident myocardial infarction, stroke or transient ischaemic attack: an inception cohort study with a nested case-control analysis. Br J Dermatol. 2009;160:1048–56. Levesque A, Lachaine J, Bissonnette R. Risk of myocardial infarction in canadian patients with psoriasis: a retrospective cohort study. J Cutan Med Surg. 2013;17:398–403. Wu JJ, Poon KT, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148: 1244–50. Icen M, Crowson CS, McEvoy MT, et al. Potential misclassification of patients with psoriasis in electronic databases. J Am Acad Dermatol. 2008;59:981–5. Asgari MM, Wu JJ, Gelfand JM, et al. Validity of diagnostic codes and prevalence of psoriasis and psoriatic arthritis in a managed care population, 1996–2009. Pharmacoepidemiol Drug Saf. 2013;22: 842–9. Wu JJ, Helen Black M, Smith N, et al. Low prevalence of psoriasis among children and adolescents in a large multiethnic cohort in southern California. J Am Acad Dermatol. 2011;65:957–64. Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. Garcı´a-Diez A, Foraster CF, Sebastia´n FV, et al. What characterizes the severity of psoriasis? Results from an epidemiological study of over 3,300 patients in the Iberian region. Dermatology. 2008;216: 137–51.
ORIGINAL ARTICLE
Risk of myocardial infarction in psoriasis patients: a retrospective cohort study Jashin J. Wu1 Young M. Choi2, and Judith D. Bebchuk3 Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and 3Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
1
Abstract
Keywords
Background: Psoriasis may or may not be associated with a higher risk for myocardial infarction (MI). We sought to assess differences in MI incidence between control, mild psoriasis and severe psoriasis patients. Methods: We performed a retrospective cohort study of Kaiser Permanente Southern California members with psoriasis between 1 January 2004 and 30 June 2012, assessing the risk and incidence rates of MI. Results: There were 50 865 control patients matched to 10 173 patients with mild psoriasis and 19 205 control patients matched to 3841 patients with severe psoriasis. The MI incidence per 1000 person-years for mild psoriasis controls, mild psoriasis, severe psoriasis controls and severe psoriasis were 4.9, 6.7, 3.7 and 5.1, respectively. Upon multivariable analysis, mild psoriasis patients had a significantly higher risk of MI compared to matched control patients {hazard ratio (HR) ¼ 1.31 [95% confidence interval (CI): 1.14, 1.51]} and severe psoriasis patients had a significantly higher risk of MI compared to matched control patients [HR ¼ 1.28 (95% CI: 1.02, 1.60)]. Conclusion: Patients with psoriasis are at higher risk for MI compared to control patients.
Biologics, cardiovascular, inflammation History Received 14 May 2014 Accepted 2 August 2014 Published online 26 August 2014
Introduction
Study population and data source
Psoriasis is a chronic skin condition affecting 2–3% of the population (1), which is 125 million of the world population and 7.5 million of the US population. Many recent studies have suggested that psoriasis is associated with a higher prevalence of myocardial infarction (MI) when compared to the general population (2–5), and that those with more severe psoriasis are at higher risk compared to those with mild psoriasis (5). However, other studies have not found psoriasis patients to have a higher incidence or risk of MI compared to the general population (6–9). The primary objective of this study was to assess differences in MI incidence between control, mild psoriasis and severe psoriasis.
KPSC is a large integrated health maintenance organization that has served 3.6 million members as of 31 December 2012. KPSC comprises 15% of the region’s population. The membership in KPSC spans the geographic area from Bakersfield in the lower California Central Valley to San Diego on the Mexican border. Attrition averages 10% per year. Membership demographics, socioeconomic status and ethnicity composition are representative of California. Health plan members receive the majority of their health care at KPSC-owned facilities, including medical centers and offices. However, the health plan is also financially responsible for KPSC members’ emergency medical care received at non-plan facilities. More than 92% of members have prescription drug benefits and obtain their prescription medication from a KPSC pharmacy. All patients have blood chemistry and other laboratory test benefits. All the data were extracted from HealthConnect, the electronic databases of KPSC clinic and hospital systems. The local Institutional Review Board at KPSC approved the study protocol.
Methods Design overview This retrospective cohort study was conducted within the Kaiser Permanente Southern California (KPSC) Health Plan. The study period was from 1 January 2004 to 30 June 2012. We evaluated the MI incidence rates in those with no psoriasis (control), mild psoriasis (those with no systemic therapy or phototherapy) and severe psoriasis (those with any use of systemic therapy or phototherapy).
Correspondence: Dr Jashin J Wu, MD, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Avenue, 5th Floor, Los Angeles, CA 90027, USA. Tel: +1(323)783-4171. Fax: +1(323)783-1629. E-mail: [email protected]
Inclusion/exclusion criteria Inclusion criteria: (i) all patients had been continuously enrolled (30-day gaps allowed) for at least 1 year before and 1 year after the index date (third psoriasis diagnosis date); (ii) patients had a medical encounter at least every 2 years between index date and 30 June 2012. Patients who had a prior MI (ICD9 410 or 412) anytime before the index date or were 518 years old at the index date were excluded from the study.
2
J. J. Wu et al.
J Dermatolog Treat, Early Online: 1–5
To form the psoriasis cohorts, we included KPSC members with at least three recorded diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification) of psoriasis (696.1) on three different dates between 1 January 2004 and 30 June 2012. A physician in a hospital or clinic setting performed all the coding. Patients with psoriasis who received one of the following therapies during the study period were considered to have severe psoriasis: UVB phototherapy, PUVA, methotrexate, acitretin, cyclosporine, etanercept, adalimumab, infliximab, ustekinumab, efalizumab or alefacept. Patients with psoriasis who did not receive one of the above therapies during the study period were considered to have mild psoriasis. Controls were excluded if they ever had psoriasis or psoriatic arthritis (696.0) diagnosis. Two separate control groups were matched by age and gender to patients with mild psoriasis or with severe psoriasis.
variables and t-test for continuous variables. All statistical tests were two tailed. The rates of MI in the mild and severe psoriasis groups were compared with the rate of MI in the control group using an unadjusted Cox proportional hazards model. The rates were then adjusted for age, sex, diabetes, dyslipidemia, hypertension, diabetes therapy, statin therapy, hypertension therapy and betablocker therapy. Body mass index and smoking were not included in the model as they were only recorded for 73 and 70% of the patients respectively. Each dichotomous variable in the model was checked for proportionality while adjusting for the other covariates in the model by examining diagnostic log–log survival plots. All statistical analyses were performed using SAS Enterprise Guide version 4.3 (SAS Institute Inc., Cary, NC). All p values are two-sided and p50.05 was considered statistically significant.
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
Results Outcomes and follow-up The primary outcome was acute MI as defined as any ICD9 code for 410.xx after diagnosis of psoriasis. Follow-up ended (censored) with the first occurrence of any of the following: (i) MI, (ii) death during the study period, (iii) disenrollment from KPSC or (iv) end of study on 30 June 2012. For patients who did not experience any of these events, the last visit before the end of the study period was used as that patient’s end date to minimize information bias. Potential confounding variables We evaluated the potential confounding effects of patient level demographics, comorbidities and concomitant medications. Potential confounding variables were collected within 12 months prior to the index date. We evaluated the following demographics and comorbidities: age, gender, diabetes, hypertension and dyslipidemia. We also evaluated the potential confounding effects of the following medications during the baseline exposure window: anti-diabetic drugs, cholesterol lowering drugs, antihypertensive medications, and statins and beta-blockers in particular due to their known function to lower MI risk. Statistical analysis Categorical variables were summarized as counts and percentages and continuous variables were summarized as mean and standard deviation. Associations between the presence of psoriasis and various covariates were tested using v2 test for categorical
There were 50 865 control patients matched to 10 173 patients with mild psoriasis and 19 205 control patients matched to 3841 patients with severe psoriasis (Table 1). Diabetes was present in 9000 (17.7%) control matched to mild psoriasis, 2102 (20.7%) with mild psoriasis, 2760 (14.4%) controls matched to severe psoriasis and 697 (18.1%) with severe psoriasis. Dyslipidemia was present in 24 820 (48.8%) controls matched to mild psoriasis, 5326 (52.4%) with mild psoriasis, 7268 (37.8%) controls matched to severe psoriasis and 1514 (39.4%) with severe psoriasis. Hypertension was present in 25 233 (49.6%) controls matched to mild psoriasis, 5439 (53.5%) with mild psoriasis, 7686 (40%) controls matched to severe psoriasis and 1862 (48.5%) with severe psoriasis. When compared with their respective controls, those with mild psoriasis were more likely to be younger, to have diabetes, dyslipidemia, hypertension and to be on therapy for diabetes, dyslipidemia, hypertension and on a beta-blocker or statin. When compared with their respective controls, those with severe psoriasis were more likely to be younger, to have diabetes, hypertension and to be on therapy for diabetes, dyslipidemia and on a beta-blocker or statin. For those with severe psoriasis, UVB phototherapy was most commonly prescribed for 1569 (24.3%) patients (Table 2). Methotrexate was the most commonly prescribed systemic therapy for 1509 (23.4%) patients. Etanercept was the most commonly prescribed biological therapy for 1241 (19.2%) patients. The MI incidence per 1000 person-years for controls matched to mild psoriasis, mild psoriasis, control matched to severe
Table 1. Cohort characteristics. Study group Mild Characteristics Age at diagnosis, mean (SD) Male, n (%)* Non-Hispanic White, n (%) Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Lipid medication, n (%) Hypertension medication, n (%) Statin, n (%) Beta blocker, n (%) Diabetic medication, n (%)
Controls (N ¼ 50865) 57.7 23 965 23 685 25 233 24 820 9000 19 636 27 871 19 592 14 973 7682
(14.87) (47.1) (48.4) (49.6) (48.8) (17.7) (38.6) (54.8) (38.5) (29.4) (15.1)
p value Severe
Psoriasis (N ¼ 10173)
Controls (N ¼ 19205)
57.2 4793 5869 5439 5326 2102 4209 5942 4203 3322 1824
52.9 9660 8647 7686 7268 2760 5579 8763 5572 4436 2404
(14.87) (47.1) (59.8) (53.5) (52.4) (20.7) (41.4) (58.4) (41.3) (32.7) (17.9)
(13.70) (50.3) (46.9) (40) (37.8) (14.4) (29) (45.6) (29) (23.1) (12.5)
Psoriasis (N ¼ 3841) 52.4 1932 2041 1862 1514 697 1223 2031 1217 1086 640
(13.69) (50.3) (55) (48.5) (39.4) (18.1) (31.8) (52.9) (31.7) (28.3) (16.7)
*The study groups were matched on gender so it is not appropriate to calculate a p value for the comparison.
Mild psoriasis versus control
Severe psoriasis versus control
0.003
0.042
50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001
50.001 50.001 0.067 50.001 50.001 50.001 50.001 50.001 50.001
Myocardial infarction in psoriasis
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
DOI: 10.3109/09546634.2014.952609
psoriasis and severe psoriasis was 4.9, 6.7, 3.7 and 5.1, respectively (Table 3). The population attributable risk (PAR) indicates the number of MI that would not occur if the psoriasis were not present. In mild psoriasis, for those in the 45–54 years, 55–64 years and 65 years age groups, the PAR (%) is 13.2 [95% confidence interval (CI): 4.5, 18.3], 6.8 (95% CI: 0.0, 11.1) and 2.9 (95% CI: 0.3, 5.2), respectively. In severe psoriasis, for those in the 45–54 years, 55–64 years and 65 years age groups, the PAR (%) is 11.8 (7.2, 19.2), 8.0 (2.2, 13.1) and 1.2 (8.2, 5.8), respectively. Since BMI and smoking status was missing for 20 and 25% of the cohort, respectively, these variables were not included in the multivariable analysis (Table 4). After adjusting for other comorbidities, patients with mild psoriasis were significantly more likely to develop an MI compared to their respective controls [hazard ratio (HR) ¼ 1.31 (95% CI: 1.14, 1.51)]. After adjusting for other co-morbidities, patients with severe psoriasis were significantly more likely to develop an MI compared to their respective controls [HR ¼ 1.28 (95% CI: 1.02, 1.60)]. The traditional MI comorbidities were associated with an increased MI risk: older age [65 + versus 545 years: HR ¼ 6.27 (95% CI: 4.66, 8.42)], male versus female [HR ¼ 2.02 (95% CI: 1.82, 2.25)], dyslipidemia [yes versus no: HR ¼ 1.27 (95% CI: 1.10, 1.46)] and hypertension [yes versus no: HR ¼ 1.25 (95% CI: 1.06, 1.48)]. Diabetes was not significantly associated with MI risk [yes versus no: HR ¼ 1.19 (95% CI: 0.98, 1.43)]. The cumulative incidence of MI by age of the four groups is illustrated in Figure 1.
Table 2. Prescribed therapies for severe psoriasis. No. of patients (%) with severe psoriasis (N ¼ 3841)
Treatment UVB phototherapy Methotrexate Etanercept Acitretin Adalimumab Cyclosporine Infliximab Ustekinumab Methoxsalen + UVA phototherapy Efalizumab Alefacept
1569 1509 1241 919 616 248 136 78 64 46 28
(24.3) (23.4) (19.2) (14.2) (9.5) (3.8) (2.1) (1.2) (1) (0.7) (0.4)
Percentages do not add up to 100 because patients could have received multiple therapies.
Discussion In this retrospective study, those with psoriasis are at higher risk for MI. The traditional MI risk factors were also generally associated with a higher risk for MI. Our results are similar to recent findings in Canadian patients by Levesque et al. (10), who demonstrated a significantly higher risk of MI in mild psoriasis patients versus control [HR ¼ 1.18 (95% CI: 1.05, 1.33)], but they did not find the same elevated risk with severe psoriasis patients versus control [HR ¼ 1.16 (95% CI: 0.94, 1.60)]. The increased MI risk in those with severe psoriasis in our study is lower than the reported MI risk [HR ¼ 7.08 (95% CI: 3.06, 16.36)] in Gelfand et al. (5). This could be related to the fact that this population was given TNF inhibitors, which we have reported in the past to be associated with a significant reduction in MI risk when compared to patients treated only with topical therapy (11). There are a few important differences to note between this study and Gelfand et al. (5). They used only one diagnosis code for psoriasis. It is possible a high number of psoriasis patients were misclassified (12). Since a primary care physician, not a dermatologist, made most of the diagnoses, the likelihood of Table 4. Univariate and multivariable Cox proportional hazard regression models of the risk of MI in patients with mild and severe psoriasis compared with control patients. Characteristics Psoriasis (unadjusted) Severe versus control Mild versus control Severe versus mild Psoriasis (adjusted) Severe versus control Mild versus control Severe versus mild Age (years) 45–54 versus 545 55–64 versus 545 65 + versus 545 Male versus female Hypertension (yes versus no) Dyslipidemia (yes versus no) Diabetes (yes versus no) Hypertension therapy (yes versus no) Statin (yes versus no) Beta blocker (yes versus no) Diabetic medication (yes versus no)
HR (95% CI)
p value
1.35 (1.08, 1.69) 1.37 (1.19, 1.58) 0.76 (0.60, 0.97)
0.01 50.001 0.02
1.28 (1.02, 1.60) 1.31 (1.14, 1.51) 0.98 (0.77, 1.24)
0.03 50.001 0.84
2.28 3.42 6.27 2.02 1.25 1.27 1.19 1.29 1.11 1.58 1.32
50.001 50.001 50.001 50.001 50.01 50.001 0.07 50.01 0.13 50.001 50.01
(1.67, (2.54, (4.66, (1.82, (1.06, (1.10, (0.98, (1.07, (0.97, (1.41, (1.09,
3.11) 4.61) 8.42) 2.25) 1.48) 1.46) 1.43) 1.56) 1.28) 1.78) 1.60)
The p value indicates the significance of the effect in predicting MI.
Table 3. Incidence rates and PAR of cohorts. Study group Mild Characteristics Follow-up time Mean (SD) Median Q1, Q3 No. of person-years No. of new MI cases (%) Incidence per 1000 person-years Age 45–54 years PAR (95% CI) Age 55–64 years PAR (95% CI) Age 65 + years PAR (95%)
3
Severe
Controls (N ¼ 50 865) Psoriasis (N ¼ 10 173) Controls (N ¼ 19 205) Psoriasis (N ¼ 3841) 3.5 (2.00) 3.5 1.9, 4.9 179 790 880 (1.7) 4.9
3.5 (2.0) 3.5 1.9, 4.9 35 738 240 (2.4) 6.7
5.0 (2.21) 5.2 3.4, 6.9 96 059 359 (1.9) 3.7
5.0 (2.23) 5.2 3.4, 6.9 19 200 97 (2.5) 5.1
NA
13.2 (4.5, 18.3)
NA
11.8 (7.2, 19.2)
NA
6.8 (0.0, 11.1)
NA
8.0 (2.2, 13.1)
NA
2.9 (0.3, 5.2)
NA
1.2 (8.2, 5.8)
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
4
J. J. Wu et al.
J Dermatolog Treat, Early Online: 1–5
Figure 1. Kaplan–Meier curve for cumulative incidence of MI.
misclassification may have been further increased (13,14). They also did not match respective controls to mild psoriasis and severe psoriasis (i.e. they used one large group of control patients for comparison). Finally, only 3% of the total psoriasis population was deemed as having severe disease, which is much lower than other estimates of 12.4% (15) (based on BSA involvement of 410%) to a high of 79.3% (16) (BSA involvement of410% or a PASI score of 410). The PAR indicates that younger patients with psoriasis (mild or severe) tended to have a higher risk of MI due to psoriasis compared to the older counterparts. This is similar to Gelfand et al (5) in that adjusted relative risk was highest in young patients with severe psoriasis. Likely, eliminating psoriasis has a larger relative impact on the risk of MI in younger patients compared to older patients, who generally have an increased number of other cardiac risk factors. However, some studies show that patients with psoriasis do not have an increased risk for MI. Maradit-Kremers et al. (6) studied a population-based incidence cohort of patients from Olmsted County, Minnesota population with psoriasis first diagnosed between 1 January 1970 and 1 January 2000. Psoriasis was associated with an elevated risk of MI based on diagnostic codes [HR ¼ 1.26 (95% CI: 1.01, 1.58)], but not when the analyses were restricted to validated MI [HR ¼ 1.18 (95% CI: 0.80, 1.74)]. However, this study had limited power in cohort analyses due to the relatively younger age of the cohort and low incidence of cardiovascular events, and they did not adjust for traditional cardiovascular risk factors when comparing the risk of MI. Further, this is a narrow population that may not be generalizable to the rest of the population. This study has several strengths: KPSC has a stable membership with a large number of psoriasis, and there is accurate
diagnosis coding of these diseases as well as other medical co-morbidities. This allowed a substantial collection of cumulative longitudinal follow-up, giving the study adequate power to capture differences in MI incidence. Prescription drug use among the study cohort was very well documented, since 490% of all prescriptions of KPSC members are filled in a health plan pharmacy (internal records). Based on internal documentation for the KPSC database, the accuracy and completeness for all of the variables were in the mid-90% range and above. The study results may be generalizable to other patients who are from an insured and ethnically diverse population. There are some limitations to this study. Cause of death was not obtained, so a fatal MI may not have been captured with an ICD9 code for MI. Standardized measurements such as body surface area (BSA) or psoriasis area and severity index (PASI) are not generally entered by community dermatologists. Thus, it is possible that patients with severe psoriasis as based on BSA (usually defined as 10% or more) or PASI (usually defined as 10–12 or more) were not given any systemic therapy or phototherapy and thus were placed in the mild psoriasis group.
Conclusion Those with psoriasis are at higher risk for MI compared to their respective controls. Long-term prospective studies are needed to determine whether systemic therapy may reduce this risk of MI in psoriasis patients.
Acknowledgements We would like to acknowledge Tony S. Yiu, Department of Research and Evaluation, KPSC, Pasadena, CA, USA, for his assistance in creating the data set that was used for all the analyses.
Myocardial infarction in psoriasis
DOI: 10.3109/09546634.2014.952609
Declaration of interest Dr. Wu received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Merck, and Pfizer; he is a consultant for AbbVie, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. This publication was made possible by a KPSC Regional Research Committee grant which is partially supported by the Southern California Permanente Medical Group’s Department of Research and Evaluation and Direct Community Benefit Investment funds. J.J.W. received research funding from Abbott Laboratories, AbbVie, Amgen, Eli Lilly, Merck and Pfizer, which were not directly related to this study.
J Dermatolog Treat Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15 For personal use only.
References 1. Channual J, Wu JJ, Dann FJ. Effects of TNF-alpha blockade on metabolic syndrome in psoriasis: lessons learned from rheumatoid arthritis and psoriatic arthritis. Dermatol Ther. 2009;22:61–73. 2. Xiao J, Chen LH, Tu YT, et al. Prevalence of myocardial infarction in patients with psoriasis in central China. J Eur Acad Dermatol Venereol. 2009;23:1311–15. 3. Lin HW, Wang KH, Lin HC, et al. Increased risk of acute myocardial infarction in patients with psoriasis: a 5-year populationbased study in Taiwan. J Am Acad Dermatol. 2011;64:495–501. 4. Kaye JA, Li L, Jick SS. Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis. Br J Dermatol. 2008;159:895–902. 5. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735–41. 6. Maradit-Kremers H, Dierkhising RA, Crowson CS, et al. Risk and predictors of cardiovascular disease in psoriasis: a population-based study. Int J Dermatol. 2013;52:32–40. 7. Wakkee M, Herings RM, Nijsten T. Psoriasis may not be an independent risk factor for acute ischemic heart disease
8.
9.
10.
11.
12.
13.
14.
15.
16.
5
hospitalizations: results of a large population-based Dutch cohort. J Invest Dermatol. 2010;130:962–7. Schmitt J, Ford DE. Psoriasis is independently associated with psychiatric morbidity and adverse cardiovascular risk factors, but not with cardiovascular events in a population-based sample. J Eur Acad Dermatol Venereol. 2010;24:885–92. Brauchli YB, Jick SS, Miret M, et al. Psoriasis and risk of incident myocardial infarction, stroke or transient ischaemic attack: an inception cohort study with a nested case-control analysis. Br J Dermatol. 2009;160:1048–56. Levesque A, Lachaine J, Bissonnette R. Risk of myocardial infarction in canadian patients with psoriasis: a retrospective cohort study. J Cutan Med Surg. 2013;17:398–403. Wu JJ, Poon KT, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148: 1244–50. Icen M, Crowson CS, McEvoy MT, et al. Potential misclassification of patients with psoriasis in electronic databases. J Am Acad Dermatol. 2008;59:981–5. Asgari MM, Wu JJ, Gelfand JM, et al. Validity of diagnostic codes and prevalence of psoriasis and psoriatic arthritis in a managed care population, 1996–2009. Pharmacoepidemiol Drug Saf. 2013;22: 842–9. Wu JJ, Helen Black M, Smith N, et al. Low prevalence of psoriasis among children and adolescents in a large multiethnic cohort in southern California. J Am Acad Dermatol. 2011;65:957–64. Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. Garcı´a-Diez A, Foraster CF, Sebastia´n FV, et al. What characterizes the severity of psoriasis? Results from an epidemiological study of over 3,300 patients in the Iberian region. Dermatology. 2008;216: 137–51.
