Regaining adequate treatment responses in patients with psoriasis who discontinued dose reduction of adalimumab, etanercept or ustekinumab
Funding sources: BioCAPTURE was funded by the University Medical Center St Radboud Foundation. This foundation received funding from Pfizer, Janssen, Novartis, LEO Pharma, AbbVie, Almirall, UCB and Eli Lilly. All decisions concerning the design and execution of this study, data collection, data management, data analysis, interpretation of the data, manuscript preparation, manuscript review or manuscript approval were made independently from industrial contributions.
Conflicts of interest: L.S.vdS. carries out clinical trials for Janssen and Novartis and has received speaking fees from Janssen and Eli Lilly. All funding is not personal but goes to the independent research fund of the Department of Dermatology of the Radboudumc, Nijmegen, the Netherlands. M.E.O. has acted as a consultant for Eli Lilly. J.M.P.A.vdR. has carried out clinical trials for AbbVie, Celgene and Janssen; has received speaking fees from or attended advisory boards for AbbVie, Janssen, BMS, Almirall, LEO Pharma, Novartis, UCB and Eli Lilly; and has received reimbursement for attending a symposium from Janssen, Pfizer, Celgene and AbbVie. All funding is not personal but goes to the independent research fund of the Department of Dermatology of Radboudumc. E.M.G.J.dJ. has received research grants for the independent research fund of the Department of Dermatology of the Radboudumc from AbbVie, BMS, Janssen Pharmaceuticals, LEO Pharma, Novartis and UCB for research on psoriasis; has acted as a consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis or eczema including AbbVie, Amgen, Almirall, Celgene, Galapagos, Janssen Pharmaceuticals, Lilly, Novartis, LEO Pharma, Sanofi and UCB. All funding is not personal but goes to the independent research fund of the Department of Dermatology of Radboudumc. The other authors declare they have no conflicts of interest.
Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Dear Editor, Previous studies showed that dose reduction (DR) of adalimumab, etanercept and ustekinumab is successful in a substantial number of patients with psoriasis with low disease activity and results in cost savings.1-3 However, the question of whether adequate treatment responses can be regained when patients discontinue DR and resume the standard maintenance dose can be a concern for patients and clinicians. Therefore, the aim of the current study was to evaluate the effectiveness of re-treatment with the standard maintenance dose in patients who discontinued DR of adalimumab, etanercept or ustekinumab.
We performed an observational cohort study at the Radboud University Medical Center (Nijmegen, the Netherlands), consisting of a follow-up analysis of patients included in two previous DR studies (randomized controlled trial and daily practice cohort).2, 4 In both studies, DR was guided by disease activity (Psoriasis Area and Severity Index, PASI) and impact on quality of life (Dermatology Life Quality Index, DLQI). Patients resumed the standard dose in case of PASI and/or DLQI > 5, or at the patients’ own request despite low PASI or DLQI. In the trial, DR schedules consisted of two steps by means of interval prolongation: first to 67% of the standard dose, and in the case of 3 months with DLQI and PASI ≤ 5, further to 50%.2 Within the daily practice evaluation, only the first DR step to 67% was performed.4 Those results are described elsewhere.2, 4
The current analysis focused on patients from these studies who resumed the standard maintenance dose after DR of adalimumab, etanercept or ustekinumab. Inherent to the used strategy, patients resumed the standard dose in case of PASI and/or DLQI > 5 or at the patients’ request. Included patients were prospectively followed within the BioCAPTURE registry for 2 years after DR discontinuation.5 BioCAPTURE was approved by the local ethical committee (Arnhem-Nijmegen) in compliance with the Declaration of Helsinki 2008 and local regulations. All patients gave written informed consent.
Outcomes were disease activity scores (PASI) at the start of DR (baseline), at the moment of DR discontinuation, and at 6 and 12 months after DR discontinuation. For PASI scores at month 6 and 12, a range of ± 90 days was chosen in order to evaluate short- and long-term effects. Proportions of patients with PASI ≤ 5 and PASI ≤ 3, and absolute PASI differences between the different timepoints were calculated. Descriptive statistics were used to summarize outcomes. The time needed to reach PASI ≤ 5 was analysed by Kaplan–Meier survival analysis. Patients were censored when follow-up ended. In the case of loss to follow-up or treatment interruptions of > 90 days, available data until the end of follow-up were used (as-treated analysis). Missing data were not imputed. Analysis was performed using SPSS Statistics 25 (IBM, Armonk, NY, USA).
In total, 119 patients from previous DR studies were included, of whom 58 patients (49%) continued DR and 61 (51%) discontinued DR and resumed the standard maintenance dose. The latter group was followed for 2 years after stopping DR. Two patients were lost to follow-up. Patient characteristics and PASI scores after DR discontinuation are presented in Table 1. At baseline (DR start), PASI scores were low [median 2·4, interquartile range (IQR) 1·5–3·0]. At the moment of DR discontinuation, PASI scores had increased to a median 4·1 (IQR 2·4–6·2). Six months after stopping DR and resuming the standard dose, PASI scores had decreased (median 2·7, IQR 2·0–4·0) and the absolute difference from the baseline PASI was small (median difference 0·6, IQR −0·5–1·8). At month 12 after DR discontinuation, most patients had achieved a comparable PASI to that before the start of DR: median difference 0 (IQR −0·8–0·7) and 0·3 (IQR −1·0–2·0) for patients who resumed the standard dose at their own request (n = 19) vs. according to protocol (n = 40). Of 17 patients with PASI > 5 at the time of stopping DR, 15 (88%) reached PASI ≤ 5 again after a median time of 4 months (95% confidence interval 2·3–5·7).
| Characteristics | Total (n = 59) |
|---|---|
| Demographic characteristics at baseline (start of DR) | |
| Sex (male) | 39 (66) |
| Age (years), median (IQR) | 52·0 (43–60) |
| Body mass index (kg m−2), median (IQR) | 28·3 (24–33)a |
| Treatment | |
| Adalimumab | 23 (39) |
| Ustekinumab | 20 (3) |
| Etanercept | 16 (27) |
| Psoriatic arthritis (yes) | 17 (29) |
| Concomitant methotrexate or acitretin | 1 (2) |
| Disease activity measures | |
| PASI score at start DR, median (IQR) | 2·4 (1·5–3·0) |
| PASI ≤ 5 | 59 (100) |
| PASI > 5 | 0 |
| PASI ≤ 3 | 47 (80) |
| PASI > 3 | 12 (20) |
| PASI at stop DR, median (IQR) | 4·1 (2·4–6·2)b |
| PASI ≤ 5 | 37 (69) |
| PASI > 5 | 17 (31) |
| PASI ≤ 3 | 17 (32) |
| PASI > 3 | 37 (68) |
| Change in PASI: start DR − stop DR, median (IQR) | 1·6 (0·4–3·5) |
| PASI 6 months after stopping DR, median (IQR) | 2·7 (2·0–4·0)c |
| PASI ≤ 5 | 43 (88) |
| PASI > 5 | 6 (12) |
| PASI ≤ 3 | 30 (61) |
| PASI > 3 | 19 (39) |
| Change in PASI: start DR – 6 months after stop DR, median (IQR) | 0·6 (−0·5–1·8) |
| PASI 12 months after stop DR, median (IQR) | 2·4 (1·0–3·9)d |
| PASI ≤ 5 | 41 (84) |
| PASI > 5 | 8 (16) |
| PASI ≤ 3 | 29 (59) |
| PASI > 3 | 20 (41) |
| Change in PASI: start DR − 12 months after stop DR, median (IQR) | 0·0 (−0·8–1·5) |
- Data are presented as n (%) unless otherwise indicated. IQR, interquartile range; PASI, Psoriasis Area and Severity Index. Missing data (n): a2, b5, c11, d10.
Strengths of our study are the detailed follow-up of patients from prospective studies specifically designed to investigate DR effects. Limitations are the modest sample size and the lack of a control group. Inherent to the design of the previous studies, the included biologics were studied as one group and no subanalyses were performed on each biologic. In two smaller, retrospective studies on DR of adalimumab and etanercept, regaining adequate responses after resumption of the standard dose was also reported.6, 7 In previous withdrawal studies, regaining adequate treatment responses after re-treatment was also reported.8 Future studies are needed to provide results on DR of the newer biologics (e.g. interleukin-17 and interleukin-23 inhibitors).
In conclusion, the results of this prospective evaluation of patients with psoriasis who resumed the standard maintenance dose after DR of adalimumab, etanercept or ustekinumab showed that most patients reached low disease activity again. Therefore, by following a controlled DR strategy, timely dose adjustments lead to restoration of adequate treatment responses, hence limiting long-term safety risks. These findings are reassuring for patients and clinicians who initiate DR of adalimumab, etanercept or ustekinumab.
Acknowledgments
We would like to thank Mascha Eilander, Department of Dermatology, Radboud University Medical Center, for her contributions to our dose reduction studies.
Author contributions
Lara S. van der Schoot: Conceptualization (equal); formal analysis (lead); investigation (equal); writing – original draft (lead); writing – review and editing (lead). Selma Atalay: Conceptualization (equal); investigation (equal); writing – review and editing (equal). Marisol E. Otero: Investigation (equal); writing – review and editing (equal). Wietske Kievit: Conceptualization (equal); writing – review and editing (equal). Juul M.P.A. van den Reek: Conceptualization (equal); formal analysis (supporting); writing – review and editing (equal). Elke M.G.J. de Jong: Conceptualization (equal); writing – review and editing (equal).
