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Psoriasis has been associated with diabetes and hypertension in previous cross-sectional studies
To evaluate prospectively the independent association between psoriasis and risk of diabetes and hypertension
A prospective study of female nurses followed from 1991-2005
Nurses' Health Study II, a cohort of 116,671 US women aged 27 - 44 in 1991
78,061 women who responded to a question about life-time history of physician-diagnosed psoriasis in 2005; women reporting a diagnosis of diabetes or hypertension at baseline were excluded
New diagnosis of diabetes or hypertension, obtained from biennial questionnaires.
Among the 78,061 women, 1,813 (2.3%) reported a diagnosis of psoriasis. During the 14 years of follow-up, we documented a total of 1,560 (2%) incident cases of diabetes and 15,724 (20%) incident cases of hypertension. The multivariate-adjusted relative risk (RR) of diabetes in women with psoriasis compared to women without was 1.63 (95% CI, 1.25-2.12). Women with psoriasis were also at an increased risk for developing hypertension (multivariate RR 1.17; 95% CI, 1.06-1.30). Age, body mass index and smoking did not significantly modify the association between psoriasis and risk of diabetes or hypertension (p values for interaction ≥0.07).
In this prospective analysis, psoriasis was independently associated with an increased risk of diabetes and hypertension. Future studies are needed to examine if psoriasis treatment will reduce the risk of diabetes and hypertension.
Psoriasis is a chronic inflammatory skin disease that affects between 1-3% of the population  and poses a lifelong burden . Recent studies indicate that psoriasis is associated with an increased risk of comorbidity  and mortality compared to the general population . Systemic inflammation in psoriasis and an increased prevalence of unhealthy life style factors have been independently associated with obesity, insulin resistance and an unfavorable cardiovascular risk profile .
Diabetes and hypertension are responsible for major morbidity and mortality in the United States [6-9]. Previous cross-sectional studies have demonstrated that individuals with psoriasis have a higher prevalence of obesity, diabetes and hypertension [10, 11]. Participants with mild psoriasis had a slightly, but significantly higher adjusted (for age, sex, and BMI) odds of diabetes 1.13 and hypertension 1.03 . In a case-control study from Israel, the risk of diabetes 1.27 was significantly higher in individuals with psoriasis . In a group of psoriatic individuals from Italy, diabetes mellitus occurred more frequently in those under 50 years age . Individuals with psoriasis were more likely to have cardiovascular risk factors including hypertension  and myocardial infarctions at a younger age .
More than 80% of individuals with diabetes develop hypertension, and about 20% of individuals with hypertension develop diabetes . In patients with hypertension and diabetes, the pathophysiology of cardiovascular disease is multifactorial, but recent evidence points toward the presence of a low-grade inflammatory process . Inflammatory markers (e.g. C-reactive protein) have been shown to predict development of diabetes [17-19], and hypertension .
No previous studies have prospectively evaluated the link between psoriasis and diabetes or hypertension; therefore we examined this in a cohort of US women.
The Nurses Health Study II (NHS II) is an ongoing longitudinal study of 116,671 female registered nurses from fifteen states in the US who were between the ages of 25 and 42 when they completed and returned a baseline questionnaire in 1989. The cohort is followed with biennial questionnaires and the follow-up rate exceeded 90% for each two-year period.
In 2005, NHS II participants were asked if they had ever received a physician diagnosis of psoriasis and if so, the date of diagnosis. Of the 84,039 women who responded to the psoriasis question in 2005, a total of 2,169 women reported a physician-diagnosis of psoriasis. After excluding women with diabetes or hypertension at baseline in 1991, 78,061 women remained in the analysis of whom 1,813 women reported psoriasis. Hence we excluded 356 women with psoriasis because of baseline diabetes or hypertension. For this study, we started follow-up in 1991 as this is the first year for which we have corresponding information on smoking and alcohol status.
Self-reported incident hypertension and incident diabetes cases were recorded from 1991 to 2005. We excluded women who first reported concomitant diabetes and hypertension on the same questionnaire during follow-up so that diabetes and hypertension could be evaluated as independent outcomes. Previously, medical record review confirmed a documented blood pressure >140/90 in 100% of women in the Nurses' Health Study I reporting hypertension; additionally, self-reported hypertension was predictive of subsequent cardiovascular events .
Date of birth and height were reported on the 1989 questionnaire. Participants reported their current weight on the biennial mailed questionnaires. Body mass index was calculated by dividing weight in kilograms by the square of height in meters. The baseline and biennial follow up questionnaires inquired about smoking status and alcohol intake. Physical activity was assessed as the number of metabolic equivalent hours (MET-hrs) per week, the time invested in an activity every week multiplied by the energy expenditure required by the activity.
Women accrued person-time from the return of the 1991 questionnaire until they reported a diagnosis of diabetes or hypertension or were censored at the end of the follow-up period in 2005. New psoriasis diagnoses were updated every 2 years. We used Cox proportion hazards modeling to estimate the age-adjusted and multivariate relative risks of incident diabetes and hypertension in women who had reported a physician diagnosis of psoriasis compared with those who did not. We categorized body mass index at baseline and at each questionnaire cycle into six categories: <21 kg/m2, 21-22.9 kg/m2, 23-24.9 kg/m2, 25-29.9 kg/m2, 30-34.9 kg/m2 and ≥35 kg/m2. To minimize residual confounding by BMI in categories, we also considered BMI as a continuous variable. Smoking was categorized (never, current, past), as was alcohol intake (1-4, 5-9, 10-14, 15-29, ≥30 grams per week). Physical activity was categorized in quintiles of metabolic equivalents (METS) per week. We explored potential interactions by age (<45 versus ≥45 years), BMI (<25 versus ≥25 kg/m2) and smoking (never, current, past) by testing the significance of interaction terms added to our final multivariate models. For all rate ratios, we calculated 95% confidence intervals. All statistical analyses were performed using SAS software, version 9.1 (SAS Institute Inc, Cary, NC). The Partners Health Care System institutional review board approved this study.
Over the 14-year follow-up, 1,560 incident cases of diabetes and 15,724 incident cases of hypertension occurred. There was no substantial difference in mean age between women with and without psoriasis (Table 1). Mean BMI, alcohol intake and the proportions of current smoking and past smokers were higher in the psoriasis group.
Among women with psoriasis, there were 60 (3.3%) incident cases of diabetes. Compared to women without psoriasis, the age-adjusted relative risk of diabetes in women with psoriasis was 2.08 (95% confidence interval [CI], 1.60-2.69) (Table 2). This remained significantly elevated (RR 1.63; 95% CI, 1.25-2.12) after further adjusting for BMI, smoking, alcohol intake and physical activity. None of the 60 women who reported psoriasis and diabetes had type I diabetes.
Among women with psoriasis, a total of 386 (21.3%) women developed incident hypertension. This represented an increased risk of hypertension in women with psoriasis (age-adjusted RR 1.32; 95% CI, 1.19-1.45) that was attenuated but remained significant after multivariate adjustment (RR 1.17; 95% CI, 1.06-1.30).
We also evaluated possible effect modification by age, BMI and smoking in multivariate models. The association between psoriasis and risk was not modified by BMI for diabetes (p = 0.65) or hypertension (p = 0.07). There was also no effect modification by smoking for diabetes or hypertension (p ≥ 0.50).
Because women with psoriasis may be more likely to see a physician and therefore diagnosed with diabetes or hypertension, we performed additional analyses after limiting the population to those women who had at least one physical examination during the follow-up. There was no material change in the results.
This prospective study demonstrated an increased risk of diabetes and hypertension in women with psoriasis, even after adjusting for age, BMI, alcohol intake and smoking. Hence, our study advances previous findings from cross-sectional studies and emphasizes the need to better understand the mechanisms that underlie these associations.
The risk of diabetes among individuals with psoriasis has been shown in cross-sectional studies to be elevated with RR between 1.27 and 2.48 [4, 10, 13, 14, 22-25], consistent with our prospective study. Although obesity and the metabolic syndrome had been proposed as an explanation for this increased risk , we found that the risk of diabetes was independent of BMI. Inflammation could be a biologically plausible mechanism underlying this association; insulin resistance has been attributed to inflammation previously [26, 27] and elevated C-reactive protein levels are predictive of diabetes [17, 18]. Alternatively, therapy for psoriasis may promote development of diabetes, especially if patients were treated with systemic steroids. In our study, information on psoriasis-related therapy is not available. Nonetheless, systemic steroids are not the standard of care for psoriasis in the United States and are typically avoided in psoriasis patients due to the potential for disease worsening . Topical steroids often used in psoriasis may be systemically absorbed if used on large body surface areas for extended periods of time . This could explain the observed increase in risk for diabetes, although adherence with long-term topical steroids use is generally low [30, 31].
An increased risk of hypertension of 1.2 to 2-fold has been reported in cross-sectional studies. In our study, individuals with psoriasis were at slightly increased risk for hypertension. Although psoriasis and hypertension share common risk factors such as smoking and obesity, we observed an independent association between psoriasis and hypertension after adjusting for smoking and BMI. Potential explanations for this association include systemic inflammation and psoriasis treatment. As mentioned above, psoriasis is a chronic inflammatory disease , and inflammation is a risk factor for hypertension [5, 11, 12]. In one study, although the risk for other cardiovascular risk factors was higher in severe psoriasis, a similar association between psoriasis severity and risk of hypertension was not found . Previous work has shown that elevated levels of C-reactive protein were associated with a 52% increase in the risk of developing hypertension in women . Systemic therapy for psoriasis with medications such as cyclosporine may increase risk of hypertension directly, albeit this risk is low ; we did not have data on therapy in our study but long-term cyclosporine use in psoriasis is not common . Individuals with psoriasis may also be less likely to exercise due to physical or social discomfort , hence increasing their risk for hypertension. In our study, we controlled for physical activity and found no material change in risk for hypertension.
Our study was restricted to predominantly Caucasian women. Hence we cannot generalize these results to men or other racial groups. Our study was observational; thus, we cannot rule out the possibility that unmeasured factors might contribute to the observed associations. While we observed no material change in the results that excluded those with at least one physical examination during the follow-up, we cannot eliminate potentially increased ascertainment of our outcomes among women with psoriasis. A major strength of the study was detailed collection of information on body mass index, smoking and alcohol. Similar to other epidemiologic studies of psoriasis [37-40], we did not confirm the nurses' self-reported physician-diagnosis of psoriasis clinically with an examination by a dermatologist. Previous validation studies in the Nurses Health Study I for another skin condition, i.e. basal cell carcinoma, found self-reports to be >90% accurate [21, 41]. While we expect the overall accuracy of self-reported physician-diagnosis of psoriasis to be high among registered nurses, the corresponding accuracy against a dermatologist's examination is not available. Confirming our results using more specific case definitions of psoriasis and evaluating for various psoriasis subtypes, severity, and treatment effects would be valuable.
In conclusion, our prospective study indicates that women with psoriasis have an increased risk of diabetes and hypertension, confirming the findings from previous cross-sectional studies. These data illustrate the importance of considering psoriasis a systemic disorder rather than simply a skin disease. Further research is needed to better understand the mechanisms underlying these associations and whether psoriasis therapy can reduce risk for diabetes and hypertension.
We are indebted to Elaine Coughlan-Gifford for her assistance with data analysis and programming
Funding: This work was partly supported by K07CA108978/NCI (AAQ) and CA050385/NCI
Conflict of Interest: Dr. Qureshi has been a consultant/speaker for Abbott, Amgen and Genentech