Dear Editor, Results from clinical studies indicate that azathioprine (AZA) and enteric‐coated mycophenolate sodium (EC‐MPS) are safe and potent drugs for the treatment of atopic dermatitis (AD).1 2 3 4 5 However, published data from large groups of nonselected patients are nonexistent, which hampers generalization to daily practice. In addition, head‐to‐head trials in which AZA and EC‐MPS are compared have never been performed. The primary objective was to perform an analysis of drug survival for AZA and EC‐MPS in a long‐term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival. Using the Kaplan–Meier survival technique, which allows for censoring, drug survival is a reflection of daily practice and explores the time on a particular drug. Data were retrospectively collected in two tertiary referral centres in the Netherlands (University Medical Center Groningen and University Medical Center Utrecht). Patients with AD, diagnosed based on the criteria of Hanifin and Rajka,6 and of Williams et al.,7 treated in the period from 1995 (AZA) and 2004 (EC‐MPS) until data lock in December 2013, were included. Patients were treated according to the standard follow‐up protocol in order to minimize differences between physicians (AZA 150/200 mg daily; EC‐MPS 1440 mg daily). Drug survival was analysed using Kaplan–Meier survival curves. Determinants of drug survival (age, sex, oral corticosteroids used concomitantly at the moment of discontinuation and the AZA maintenance dose) were selected using a univariate Cox regression analysis and analysed with a multivariate Cox regression analysis with backward selection. Statistical analyses were performed in SPSS for Windows version 21 (IBM, Armonk, NY, U.S.A.). Drug survival of 94 patients [median duration of treatment 180 days (range 4–1095) days; 82 patient‐years] treated with AZA and of 84 patients [median duration of treatment 324 days (range 14–1095); 110 patient‐years] treated with EC‐MPS was analysed (Table 1). Twenty‐two patients were counted twice as they were treated with both AZA and EC‐MPS. Patient and treatment characteristics Data are n (%) unless otherwise indicated. AZA, azathioprine; EC‐MPS, enteric‐coated mycophenolate sodium; NA, not applicable. aIndependent sample t‐test; bPearson χ2 test; cMann–Whitney U‐test; dpercentage of total treatment episode is the duration of concomitant therapy divided by the duration of total AZA/EC‐MPS episode; edata lock in December 2013. Patient and treatment characteristics Data are n (%) unless otherwise indicated. AZA, azathioprine; EC‐MPS, enteric‐coated mycophenolate sodium; NA, not applicable. aIndependent sample t‐test; bPearson χ2 test; cMann–Whitney U‐test; dpercentage of total treatment episode is the duration of concomitant therapy divided by the duration of total AZA/EC‐MPS episode; edata lock in December 2013. In the AZA group, 24 (25%) patients were still actively treated at the moment of data lock. Ten (11%) patients had their treatment discontinued owing to controlled AD; three of these patients concomitantly used oral corticosteroids at the moment of discontinuation. Controlled AD was defined as relief of AD symptoms mentioned by the patient and a satisfactory result reported by the physician. In case of controlled AD, the dose could be gradually reduced and eventually discontinued. Side‐effects were a reason for discontinuation of AZA in 34 (36%) patients, and 18 (19%) patients were discontinued owing to ineffectiveness. Two patients (2%) discontinued AZA owing to both side‐effects and ineffectiveness. Six (6%) patients stopped AZA owing to another event. Twenty‐two (26%) patients were still actively treated with EC‐MPS at the moment of data lock and three (4%) were lost to follow‐up. Nine (11%) patients had discontinued owing to controlled AD; none of them concomitantly used oral corticosteroids or ciclosporin A at the moment of stopping. Ineffectiveness was a reason for discontinuation of EC‐MPS in 32 (38%) patients. Side‐effects were the reason for discontinuation in 12 (14%) patients. Three (4%) patients stopped EC‐MPS owing to both side‐effects and ineffectiveness, and three (4%) patients stopped owing to another event. The median overall drug survival for AZA was 201 days and for EC‐MPS it was 322 days. After 1, 2 and 3 years, the respective percentages of patients using AZA were 44%, 26% and 14%, and for EC‐MPS they were 45%, 36% and 27% (Fig. 1a). The drug survival split by reason for discontinuation is shown in Figure 1(b–d). After 1, 2 and 3 years, respectively, 6%, 21% and 44% discontinued AZA, and 6%, 15% and 28% discontinued EC‐MPS owing to controlled AD. After 1, 2 and 3 years, respectively, 40%, 44% and 47% discontinued AZA, and 20%, 20% and 23% discontinued EC‐MPS owing to side‐effects. After 1, 2 and 3 years, respectively, 23%, 36% and 41% discontinued AZA, and 40%, 47% and 51% discontinued EC‐MPS owing to ineffectiveness. Azathioprine (AZA) and enteric‐coated mycophenolate sodium (EC‐MPS) drug survival split for reasons of discontinuation. (a) Median drug survival overall [discontinuation owing to controlled atopic dermatitis (AD), side‐effects, ineffectiveness and other reasons]: AZA 201 days; EC‐MPS 322 days. The median drug survival with respect to controlled AD, side‐effects and ineffectiveness could not be estimated as > 50% of patients still used the drugs after 3 years. Overall drug survival: log rank test P = 0·04. (b) Discontinuation owing to controlled AD: curves cross; no trend towards a difference between drug survival is seen. (c) Discontinuation owing to side‐effects: log rank test P = 0·00. (d) Discontinuation owing to ineffectiveness: curves cross; after 3 months a trend towards better drug survival for AZA is seen. The overall drug survival (P = 0·04) and drug survival related to side‐effects (P = 0·01) of EC‐MPS was significantly better compared with AZA. The drug survival curves related to ineffectiveness cross with a trend towards better drug survival for AZA compared with EC‐MPS. No significant difference between the drug survival distributions was found with respect to controlled AD. Multivariate Cox regression analysis for AZA showed that concomitant oral corticosteroids at the moment of discontinuation was associated with a decreased drug survival related to side‐effects [hazard ratio (HR) 2·16, 95% confidence interval (CI) 1·07–4·34]. Older age was associated with an increased drug survival related to ineffectiveness (HR 0·81, 95% CI 0·69–0·95). Multivariate Cox regression analysis for EC‐MPS showed that concomitant oral corticosteroids at the moment of discontinuation was associated with a decreased drug survival related to side‐effects (HR 3·82, 95% CI 1·33–10·97) and a decreased drug survival related to ineffectiveness (HR 2·22, 95% CI 1·02–4·80). Male sex was associated with an increased drug survival related to ineffectiveness (HR 0·48, 95% CI 0·25–0·94). The results show that the course of overall drug survival of AZA and EC‐MPS was almost identical. Remarkably, discontinuation of treatment owing to side‐effects and/or ineffectiveness of both AZA and EC‐MPS is higher in our drug survival study than in earlier clinical trials.1 2 3 4 5 An explanation might be that patients who participate in clinical trials are often very motivated to fulfil the trial period, despite ineffectiveness or side‐effects.8 In addition, the longer treatment duration in daily practice may account for a higher discontinuation rate. A recent study by Thomsen et al. also reports a less favourable outcome in 60 patients treated with AZA in daily practice compared with those in clinical trials.9 Patients with severe AD have uncontrolled eczema, despite the use of high amounts of topical corticosteroids. Discontinuation of the oral immunosuppressive drug leads to exacerbations of AD and excessive use of topical corticosteroids, which can cause side‐effects. Therefore, in daily practice, no upper time limit exists for treatment with oral immunosuppressive drugs in AD. There are differences between clinical trials and drug survival studies. Drug survival analysis is not a study of efficacy but a reflection of daily practice. Clinical decisions made by the physician and patient together, taking into account effectiveness and side‐effects, determine the outcome instead of clinical skin scores at fixed time points. Furthermore, clinical trials use strict inclusion and exclusion criteria, while in daily practice studies all patients are included. Patient characteristics such as comorbidity, susceptibility to side‐effects and earlier treatment failure may influence treatment success. Oral corticosteroids at the moment of discontinuation of AZA or EC‐MPS treatment may influence the reason for stopping. The number of patients using concomitant oral corticosteroids at the moment of discontinuation was comparable in both groups (P = 0·59). A significant effect on drug survival in the multivariate Cox regression analysis was found for the AZA group that discontinued owing to side‐effects and for the EC‐MPS groups with respect to discontinuation owing to side‐effects and ineffectiveness. The determinants in the Cox regression model do not fully explain the outcome. Other factors, for example disease severity, physician preferences, adherence to treatment and the availability of other treatment options, may also influence the outcome. A limitation of this study might be the low explained variance of the results of the Cox regression analysis. Another limitation is the retrospective design, which is dependent on the quality of the medical records. In conclusion, drug survival of AZA is mainly limited by discontinuation owing to side‐effects, while drug survival of EC‐MPS is mainly limited by discontinuation owing to ineffectiveness. Concomitant use of oral corticosteroids in the more advanced phase of treatment has a negative effect on drug survival. Funding sources: none. Conflicts of interest: none declared.
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