Psoriasis is associated with a greater risk of incident venous thromboembolism: the Iowa Women's Health Study

Abstract

Psoriasis is a common chronic skin disease, affecting approximately 2% of the US population [1Christophers E. Psoriasis – epidemiology and clinical spectrum.Clin Exp Dermatol. 2001; 26: 314-20Crossref PubMed Scopus (0) Google Scholar]. The condition is characterized by autoimmune dysregulation and systemic inflammation [2Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2158) Google Scholar]. As such, psoriasis can serve as a model for studies of mechanisms of chronic inflammation [2Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2158) Google Scholar]. Recently there has been considerable interest in whether systemic inflammation is a risk factor for venous thromboembolism (VTE), as inflammation is associated with a procoagulant state [3Levi M. van der Poll T. Büller H.R. Bidirectional relation between inflammation and coagulation.Circulation. 2004; 109: 2698-704Crossref PubMed Scopus (682) Google Scholar, 4Lippi G. Favaloro E.J. Montagnana M. Franchini M. C‐reactive protein and venous thromboembolism: causal or casual association?.Clin Chem Lab Med. 2010; 48: 1693-701Crossref PubMed Scopus (0) Google Scholar]. Most research exploring this relation has been observational, and has utilized blood markers of systemic inflammation, such as C‐reactive protein (CRP) and cytokines. Results have been mixed, but overall suggestive of a positive association between inflammatory markers and VTE [4Lippi G. Favaloro E.J. Montagnana M. Franchini M. C‐reactive protein and venous thromboembolism: causal or casual association?.Clin Chem Lab Med. 2010; 48: 1693-701Crossref PubMed Scopus (0) Google Scholar]. There has also been active inquiry into whether medical conditions characterized by chronic systemic inflammation, such as rheumatoid arthritis [5Matta F. Singala R. Yaekoub A.Y. Najjar R. Stein P.D. Risk of venous thromboembolism with rheumatoid arthritis.Thromb Haemost. 2009; 101: 134-8Crossref PubMed Scopus (106) Google Scholar, 6Ramagopalan S. Wotton C. Handel A. Yeates D. Goldacre M. Risk of venous thromboembolism in people admitted to hospital with selected immune‐mediated diseases: record‐linkage study.BMC Med. 2011; 9: 1Crossref PubMed Scopus (0) Google Scholar], psoriasis [6Ramagopalan S. Wotton C. Handel A. Yeates D. Goldacre M. Risk of venous thromboembolism in people admitted to hospital with selected immune‐mediated diseases: record‐linkage study.BMC Med. 2011; 9: 1Crossref PubMed Scopus (0) Google Scholar, 7Ahlehoff O. Gislason G.H. Lindhardsen J. Charlot M.G. Jorgensen C.H. Olesen J.B. Bretler D.M. Skov L. Torp‐Pedersen C. Hansen P.R. Psoriasis carries an increased risk of venous thromboembolism: a Danish nationwide cohort study.PLoS ONE. 2011; 6: e18125Crossref PubMed Scopus (78) Google Scholar, 8Zhao Y.X. Chen G. Zhao R.Z. Zhang X.G. Psoriasis complicated with venous thromboembolism: report of two cases and a literature review.Chin Med J. 2011; 124: 1593-6Google Scholar] and inflammatory bowel disease [9Grainge M.J. West J. Card T.R. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study.Lancet. 2010; 375: 657-63Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar, 10Saleh T. Matta F. Yaekoub A.Y. Danescu S. Stein P.D. Risk of venous thromboembolism with inflammatory bowel disease.Clin Appl Thromb Hemost. 2011; 17: 254-8Crossref PubMed Scopus (36) Google Scholar, 11Novacek G. Weltermann A. Sobala A. Tilg H. Petritsch W. Reinisch W. Mayer A. Haas T. Kaser A. Feichtenschlager T. Fuchssteiner H. Knoflach P. Vogelsang H. Miehsler W. Platzer R. Tillinger W. Jaritz B. Schmid A. Blaha B. Dejaco C. et al.Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism.Gastroenterology. 2010; 139: 779-87Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar], may be associated with elevated VTE risk. To date, studies of psoriasis and VTE include two case reports [8Zhao Y.X. Chen G. Zhao R.Z. Zhang X.G. Psoriasis complicated with venous thromboembolism: report of two cases and a literature review.Chin Med J. 2011; 124: 1593-6Google Scholar], a medical record‐linkage study based on hospital admissions and deaths [6Ramagopalan S. Wotton C. Handel A. Yeates D. Goldacre M. Risk of venous thromboembolism in people admitted to hospital with selected immune‐mediated diseases: record‐linkage study.BMC Med. 2011; 9: 1Crossref PubMed Scopus (0) Google Scholar] and a prospective cohort of the entire Danish population from 1997 to 2006 [7Ahlehoff O. Gislason G.H. Lindhardsen J. Charlot M.G. Jorgensen C.H. Olesen J.B. Bretler D.M. Skov L. Torp‐Pedersen C. Hansen P.R. Psoriasis carries an increased risk of venous thromboembolism: a Danish nationwide cohort study.PLoS ONE. 2011; 6: e18125Crossref PubMed Scopus (78) Google Scholar]. We used data from the Iowa Women’s Health Study (IWHS) to test the hypothesis that psoriasis is associated with an elevated risk of incident VTE, after adjustment for several potentially confounding variables. The IWHS cohort commenced in January 1986 when a questionnaire was mailed to 99 826 Iowa women aged 55 to 69 years, who were randomly sampled from the State driver’s list. The 41 836 women who responded to this initial questionnaire constitute the IWHS cohort. The questionnaire collected information on characteristics such as age, educational attainment, smoking habits, height, weight, diabetes status and hormone replacement therapy (HRT) use. Information on behaviors and physiologic characteristics were queried again in 1992. As detailed previously [12Lutsey P.L. Virnig B.A. Durham S.B. Steffen L.M. Hirsch A.T. Jacobs Jr, D.R. Folsom A.R. Correlates and consequences of venous thromboembolism: the Iowa Women’s Health Study.Am J Public Health. 2010; 100: 1506-13Crossref PubMed Scopus (0) Google Scholar, 13Prizment A. Alonso A. Folsom A. Ahmed R. Virnig B. Warshaw E. Anderson K. Association between psoriasis and incident cancer: the iowa’s women’s health study.Cancer Causes Control. 2011; 22: 1003-10Crossref PubMed Scopus (21) Google Scholar], the IWHS data were linked to Centers for Medicare Services (CMS) enrollment and health care utilization data from 1986 to 2004. Medicare provides payment for all or part of health care for most US residents aged 65 years and older [14Gornick M.E. Warren J.L. Eggers P.W. Lubitz J.D. De Lew N. Davis M.H. Cooper B.S. Thirty years of medicare: impact on the covered population.Health Care Financ Rev. 1996; 18: 179-237PubMed Google Scholar, 15Virnig B.A. Marshall McBean A. Kind S. Dholakia R. Hospice use before death: variability across cancer diagnoses.Med Care. 2002; 40: 73-8Crossref PubMed Scopus (71) Google Scholar], and data stemming from the payment of Medicare bills is now used widely as a population‐based data source for clinical occurrences [16Virnig B.A. McBean M. Administrative data for public health surveillance and planning.Annu Rev Public Health. 2001; 22: 213-30Crossref PubMed Scopus (191) Google Scholar]. Of IWHS cohort members surviving to 65 years, 98% (40 377 of 40 997) met our CMS inclusion criteria and were therefore followed for incident VTE events [12Lutsey P.L. Virnig B.A. Durham S.B. Steffen L.M. Hirsch A.T. Jacobs Jr, D.R. Folsom A.R. Correlates and consequences of venous thromboembolism: the Iowa Women’s Health Study.Am J Public Health. 2010; 100: 1506-13Crossref PubMed Scopus (0) Google Scholar]. Information about Medicare enrollees was collected from four files (Denominator, MedPar, Carrier and Outpatient). Information about Medicare enrollment and inpatient services, including discharge codes, has been available since 1986, whereas data about outpatient services, including diagnosis codes, have been available since 1991 (Outpatient and Carrier files). Psoriasis diagnoses were identified using the International Classification of Diseases (ICD‐9) diagnosis code 696.1 in Medicare claims data [13Prizment A. Alonso A. Folsom A. Ahmed R. Virnig B. Warshaw E. Anderson K. Association between psoriasis and incident cancer: the iowa’s women’s health study.Cancer Causes Control. 2011; 22: 1003-10Crossref PubMed Scopus (21) Google Scholar]. Psoriasis was defined as ≥ 1 claim from a dermatologist or ≥ 2 claims from any Medicare file. IWHS participants were considered to have had a VTE if any of the following VTE ICD‐9 codes occurred on their Medicare MedPAR (hospitalization) discharge diagnosis records [12Lutsey P.L. Virnig B.A. Durham S.B. Steffen L.M. Hirsch A.T. Jacobs Jr, D.R. Folsom A.R. Correlates and consequences of venous thromboembolism: the Iowa Women’s Health Study.Am J Public Health. 2010; 100: 1506-13Crossref PubMed Scopus (0) Google Scholar]: 415.1x, 451.1x, 451.2, 451.81, 451.9, 453.0, 453.1, 453.2, 453.3, 453.4x, 453.8, 453.9. Psoriasis is typically treated in an outpatient setting, and most psoriasis claims are found in the Medicare Carrier file available from 1991–2004. Thus, our analytical sample included only participants who, since 1991, were enrolled in at least 1 month of fee‐for‐service Part A and Part B Medicare coverage after reaching 65 years (n = 38 608). Person‐years accumulated from the date participants met the enrollment criteria until the occurrence of VTE, death, fee‐for‐service part A or B disenrollment, or the end of December 2004. Characteristics of women with and without psoriasis were described using means and proportions. Body mass index (BMI) was calculated as weight over height squared (kg m−2). Cox’s proportional hazards regression models were used to evaluate the relation between psoriasis and incident VTE, with psoriasis modeled as a time‐dependent covariate. Our first model adjusted only for age (continuous). Model 2 additionally adjusted for characteristics which have been associated with both psoriasis and VTE in previous analyzes of the IWHS cohort [12Lutsey P.L. Virnig B.A. Durham S.B. Steffen L.M. Hirsch A.T. Jacobs Jr, D.R. Folsom A.R. Correlates and consequences of venous thromboembolism: the Iowa Women’s Health Study.Am J Public Health. 2010; 100: 1506-13Crossref PubMed Scopus (0) Google Scholar, 13Prizment A. Alonso A. Folsom A. Ahmed R. Virnig B. Warshaw E. Anderson K. Association between psoriasis and incident cancer: the iowa’s women’s health study.Cancer Causes Control. 2011; 22: 1003-10Crossref PubMed Scopus (21) Google Scholar]: age, education (< high school, high school or > high school), smoking status (current, former or never), BMI (continuous), diabetes (yes or no) and HRT use (current, former or never). Covariate information collected in 1992 was utilized. In instances of missing values, data from the baseline (1986) survey was carried forward. In sensitivity analyzes, results were similar when baseline data was not carried forward. Our analytic cohort included 38 608 women who were followed for a median of 11.3 years (maximum: 14.0 years). At baseline, the women were on average 68.1 years old (min: 65.0, max: 84.6), and were almost exclusively Caucasian. Through follow‐up, 859 women, who constitute 2.2% of the cohort, were diagnosed with psoriasis. Women who developed psoriasis were more likely to be younger, more highly educated, smokers, have a higher BMI, have diabetes and be HRT users (Table S1). A total of 1825 incident VTE events occurred over 435 065 person‐years of follow‐up. Thirty‐seven of these VTEs were preceded by psoriasis. In time‐dependent analyzes, the age‐adjusted hazard ratio (HR) for VTE among individuals who developed psoriasis was 1.40 (95% confidence interval [CI]: 1.00, 1.94) vs. those who did not develop psoriasis (Table S2). The association was similar (HR: 1.39 [1.00, 1.93]) after additional adjustment for education, smoking status, BMI, diabetes and HRT use. A diagnosis of psoriasis was associated with a 40% increased risk of incident VTE in this prospective, population‐based study of nearly 40 000 older women. These results corroborate recent work which has suggested that psoriasis is associated with increased VTE risk. Among the three manuscripts exploring the relation between psoriasis and VTE, all of which were published in 2011 [6Ramagopalan S. Wotton C. Handel A. Yeates D. Goldacre M. Risk of venous thromboembolism in people admitted to hospital with selected immune‐mediated diseases: record‐linkage study.BMC Med. 2011; 9: 1Crossref PubMed Scopus (0) Google Scholar, 7Ahlehoff O. Gislason G.H. Lindhardsen J. Charlot M.G. Jorgensen C.H. Olesen J.B. Bretler D.M. Skov L. Torp‐Pedersen C. Hansen P.R. Psoriasis carries an increased risk of venous thromboembolism: a Danish nationwide cohort study.PLoS ONE. 2011; 6: e18125Crossref PubMed Scopus (78) Google Scholar, 8Zhao Y.X. Chen G. Zhao R.Z. Zhang X.G. Psoriasis complicated with venous thromboembolism: report of two cases and a literature review.Chin Med J. 2011; 124: 1593-6Google Scholar], the Danish manuscript has the strongest study design [7Ahlehoff O. Gislason G.H. Lindhardsen J. Charlot M.G. Jorgensen C.H. Olesen J.B. Bretler D.M. Skov L. Torp‐Pedersen C. Hansen P.R. Psoriasis carries an increased risk of venous thromboembolism: a Danish nationwide cohort study.PLoS ONE. 2011; 6: e18125Crossref PubMed Scopus (78) Google Scholar]; however, it too was limited in that it was unable to adjust for lifestyle characteristics and anthropometrics. These characteristics, particularly obesity, are associated with both psoriasis and VTE, and may have confounded the previous study’s observed associations. Furthermore, psoriasis was defined on the basis of psoriasis hospitalizations and claims for prescriptions for vitamin D derivatives. The authors were, therefore, unable to identify outpatients treated with topical corticosteroids alone, the most common topical medication for psoriasis. The IWHS associations we observed were similar in magnitude to the Danish study’s. Further, our results extend previous work in that we were able to control for lifestyle and anthropometrics, and identify outpatient psoriasis cases. The implications of this research are two‐fold. Our findings contribute to ongoing discussions about whether chronic systemic inflammation causes VTE [4Lippi G. Favaloro E.J. Montagnana M. Franchini M. C‐reactive protein and venous thromboembolism: causal or casual association?.Clin Chem Lab Med. 2010; 48: 1693-701Crossref PubMed Scopus (0) Google Scholar]. Notably, a genome‐wide association scan recently identified as a susceptibility locus for VTE HIVEP1 on chromosome 6p24.1, which codes for a protein that participates in the transcriptional regulation of inflammatory target genes [17Morange P.‐.E. Bezemer I. Saut N. Bare L. Burgos G. Brocheton J. Durand H. Biron‐Andreani C. Schved J.F. Pernod G. Galan P. Drouet L. Zelenika D. Germain M. Nicaud V. Heath S. Ninio E. Delluc A. Münzel T. Zeller T. et al.A follow‐up study of a genome‐wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1.Am J Hum Genet. 2010; 86: 592-5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Additionally, the JUPITER trial showed that statins, whose pleiotropic effects include reducing levels of CRP, reduced VTE risk [18Glynn R.J. Danielson E. Fonseca F.A.H. Genest J. Gotto A.M. Kastelein J.J.P. Koenig W. Libby P. Lorenzatti A.J. MacFadyen J.G. Nordestgaard B.G. Shepherd J. Willerson J.T. Ridker P.M. A randomized trial of rosuvastatin in the prevention of venous thromboembolism.N Engl J Med. 2009; 360: 1851-61Crossref PubMed Scopus (604) Google Scholar]. From a clinical perspective, the present findings suggest that psoriasis patients may be at an elevated, albeit modestly, risk of VTE. Given the modest HR and the relatively low incidence of VTE a diagnosis of psoriasis would not justify special VTE prevention. Individuals with moderate and severe psoriasis are also at an elevated risk of atherosclerotic cardiovascular disease [19Friedewald V.E. Cather J.C. Gelfand J.M. Gordon K.B. Gibbons G.H. Grundy S.M. Jarratt M.T. Krueger J.G. Ridker P.M. Stone N. Roberts W.C. Ajc editor’s consensus: psoriasis and coronary artery disease.Am J Cardiol. 2008; 102: 1631-43Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 20Mehta N.N. Yu Y. Pinnelas R. Krishnamoorthy P. Shin D.B. Troxel A.B. Gelfand J.M. Attributable risk estimate of severe psoriasis on major cardiovascular events.Am J Med. 2011; 124: 775Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar]. Thus, psoriasis patients may already be targeted for cardiopreventive therapies, such as weight loss and statins, which may also lower the VTE risk. Strengths of this analysis are the population‐based sample, prospective design, identification of outpatient psoriasis cases, and ability to adjust for behavioral characteristics and obesity. There are also several limitations. First, we did not validate cases of psoriasis or VTE. However, validation studies comparing Medicare data to medical records for other autoimmune conditions [21Katz J.N. Barrett J. Liang M.H. Bacon A.M. Kaplan H. Kieval R.I. Lindsey S.M. Roberts W.N. Sheff D.M. Spencer R.T. Weaver A.L. Baron J.A. Sensitivity and positive predictive value of medicare part b physician claims for rheumatologic diagnoses and procedures.Arthritis Rheum. 1997; 40: 1594-600Crossref PubMed Scopus (128) Google Scholar] and VTE [22Cushman M. Tsai A.W. White R.H. Heckbert S.R. Rosamond W.D. Enright P. Folsom A.R. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.The American Journal of Medicine. 2004; 117: 19Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 23White R.H. Zhou H. Romano P.S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in california.Ann Intern Med. 1998; 128: 737-40Crossref PubMed Google Scholar, 24Heckbert S.R. Kooperberg C. Safford M.M. Psaty B.M. Hsia J. McTiernan A. Gaziano J.M. Frishman W.H. Curb J.D. Comparison of self‐report, hospital discharge codes, and adjudication of cardiovascular events in the women’s health initiative.Am J Epidemiol. 2004; 160: 1152-8Crossref PubMed Scopus (0) Google Scholar, 25Kniffin Jr, W.D. Baron J.A. Barrett J. Birkmeyer J.D. Anderson Jr, F.A. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly.Arch Intern Med. 1994; 154: 861-6Crossref PubMed Google Scholar, 26Birman‐Deych E. Waterman A.D. Yan Y. Nilasena D.S. Radford M.J. Gage B.F. Accuracy of icd‐9‐cm codes for identifying cardiovascular and stroke risk factors.Med Care. 2005; 43: 480-5Crossref PubMed Scopus (0) Google Scholar] have shown high positive predictive values. Furthermore, as we have reported previously, rates of both psoriasis [13Prizment A. Alonso A. Folsom A. Ahmed R. Virnig B. Warshaw E. Anderson K. Association between psoriasis and incident cancer: the iowa’s women’s health study.Cancer Causes Control. 2011; 22: 1003-10Crossref PubMed Scopus (21) Google Scholar] and venous thromboembolism [12Lutsey P.L. Virnig B.A. Durham S.B. Steffen L.M. Hirsch A.T. Jacobs Jr, D.R. Folsom A.R. Correlates and consequences of venous thromboembolism: the Iowa Women’s Health Study.Am J Public Health. 2010; 100: 1506-13Crossref PubMed Scopus (0) Google Scholar] were in accordance with what one would expect in the general population. Related, the precise date of psoriasis onset is unknown. Second, as we were looking at interrelations between two relatively rare conditions stratifying by psoriasis severity or VTE type (i.e. provoked vs. unprovoked) was not viable. Lastly, the generalizability of our finding may be limited, as the present study was conducted among elderly women living in Iowa. To conclude, the present study compliments existing work suggesting a relation between chronic, systemic inflammation and risk of VTE, and suggests that patients with even mild‐to‐moderate psoriasis may be at an elevated risk of a VTE event. The authors state that they have no conflict of interest. This Iowa Women’s Health Study was supported by the National Cancer Institute (grant R01 CA39742). We thank the other investigators, the staff and the participants in the Iowa Women’s Health Study for their valuable contributions. Table S1. Selected characteristics stratifiedaccording to psoriasis diagnosis: The Iowa Women’s HealthStudy. Table S2. Relation of psoriasis to incidentvenous thromboembolism: The Iowa Women’s Health Study,1991–2004. Download .doc (.04 MB) Help with doc files Supporting info item