The GENDER ATTENTION Observational Study: Gender and Hormonal Status Differences in the Incidence of Adverse Events During Cyclosporine Treatment in Psoriatic Patients

Abstract

Introduction: Female sex has been shown to be a risk factor for the development of adverse drug reactions; however, this has not been studied for cyclosporine (CsA). The aim of this study was to investigate, in Italian dermatological practice, the influence of gender and menopause and related hormones on the incidence of adverse events (AEs) during CsA treatment in psoriatic patients.

Methods: Multicenter, prospective, observational study conducted from May 2011 to June 2013. Patients with plaque psoriasis, undergoing a new CsA administration course, or about to start it, were enrolled in the outpatient clinics of Italian dermatological centers. During the 2-6 months of study duration, patients had to note all AEs that occurred in a diary that was reviewed by the investigators at the follow-up visit. Sex hormone levels were measured within 7 days from the start date of a menstrual cycle.

Results: A total of 969 adult psoriatic patients were enrolled in the study, divided into four cohorts: fertile women and corresponding age-matched men; postmenopausal women and corresponding age-matched men. A significant difference in the percentage of patients with AEs was observed between fertile and postmenopausal women, but not between women and age-matched men. AE incidence rate was about 37% higher in fertile women than in age-matched men and about 18% higher in postmenopausal women than in age-matched men, but differences were not statistically significant. Incidence rate ratio of fertile vs. postmenopausal women was 0.67, reaching statistical significance. AEs were mild or moderate in severity in the great majority of patients of all cohorts and postmenopausal women had significantly less grade 1-2 AEs compared to fertile women, but more grade 3-4 AEs. FSH levels were significantly higher in postmenopausal women reporting no AEs, and DHEA sulfate levels were about 10% higher in men with no AEs, compared to those reporting at least one AE. Cortisol levels were slightly though significantly higher in postmenopausal women with no AE.

Conclusions: A better understanding of sex- and hormone-related influences on drug responses may help to improve drug safety and efficacy, by permitting one to tailor pharmacological treatments to individual subjects or defined patient cohorts.

Funding: Novartis Farma S.p.A., Italy.

Keywords: Adverse drug reaction; Cyclosporine; Dermatology; Female; Gender; Psoriasis.

Fig. 1

Patient disposition. The figure shows the number of patients considered for the analysis and who dropped out. Reasons for non-evaluability or dropout could be multiple

Fig. 2

Proportion of patients with at least one adverse event by patient cohort, overall, and by system organ class (the most frequent ones are displayed). For each cohort, proportions are computed as the ratio between the number of patients experiencing at least one adverse event during the exposure period and the total number of evaluable patients. The number of evaluable patients was 336 for fertile women (cohort 1), 253 for age-matched men (cohort 2), 182 for postmenopausal women (cohort 3), and 118 for age-matched men (cohort 4). The p value of the Chi-squared test between female cohort (fertile/postmenopausal) and experience of adverse events (yes/no) is shown as well

Fig. 3

Cortisol levels in postmenopausal women with and without adverse events. The box plot of cortisol level (mg/dL) in postmenopausal women who experienced at least one adverse event (N = 66) and who did not experience any adverse events (N = 88) during the exposure period is shown. The upper and lower edges of the box represent the 75th and the 25th percentile, respectively. The line and the plus symbol inside the box correspond to the median and mean value, respectively. Whiskers are limited by the maximum observation below upper fence (upper limit) and the minimum observation (lower limit). Small squares above the upper edge of the whiskers represent observations beyond the upper fence, defined as 1.5 (interquartile range) above the 75th percentile