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• Comments on the article: “Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy”
  Erfan Taherifard, Alireza Sadeghi
  Published on: 1 August 2022

• Published on: 1 August 2022

  Comments on the article: “Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy”

  • Erfan Taherifard, Internal medicine department Shiraz University of Medical Sciences
  • Other Contributors:
    • Alireza Sadeghi, Student research committee

  To the Editor
  We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
  The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study....

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  To the Editor
  We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
  The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study. The presence of comorbidities, smoking and ethnicity are among these factors that are associated with the response to treatment (2, 3). The participants enrolled in this study were from 21 centers from 4 countries which raises concern toward the potential for bias as ethnicity was not considered in the study. Besides, patient-reported symptoms, outcomes and true disease state have also been shown to be associated with social status of the patient, educational level, health literacy and presence of comorbidities and ethnicity (4, 5). Therefore, considering these potential confounding factors and performing appropriate techniques for adjusting of them lower the source of bias and increase the credibility of the findings in the study.
  Second, the significance level considered in this study was 10 percent. This error rate is typically considered to 5 percent, especially when the efficacy of a new drug class is being assessed in clinical studies (6). Although this high cut off for type Ⅰ error could be justified by the authors based on the intrinsic issues of the study, they should have mentioned and addressed it in the article. Third, in the protocol of this study (NCT03813199), it was mentioned that 24 centers were chosen for participants enrollment; however, in the main text of the article, the authors stated that the study was conducted in 21 centers. The detail of this issue that 2 centers in Czechia and one center in Belgium were not considered in the study should be discussed in the article to avoid any concern regarding the potential bias of selective reporting.
  Notwithstanding the foregoing, this study has provided first evidence on the efficacy and safety of this first-in-class drug in patients with moderate to severe RA nonresponding to methotrexate or anti-tumor necrosis factor-α agents. However, whether to administrate this drug or not requires further studies with larger sample size and longer duration of follow-up. Also, there is needs for conducting studies to compare efficacy and safety of this drug class with more frequently used therapeutic options in patients with RA who are not responding to first line treatments as there are other available treatment strategies in these patients.
  Authors’ contributions: Both authors contributed in all processes of the preparation of this paper.
  Acknowledgement: None.
  Conflict of Interest statement: Authors declare no conflict of interests.
  Funding: None.
  Patient and Public Involvement: Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research
  References
  1. Daien C, Krogulec M, Gineste P, Steens J-M, Desroys du Roure L, Biguenet S, et al. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study. 2022;81(8):1076-84.
  2. de Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology. 2017;57(7):1135-44.
  3. Albrecht K, Zink A. Poor prognostic factors guiding treatment decisions in rheumatoid arthritis patients: a review of data from randomized clinical trials and cohort studies. Arthritis Research & Therapy. 2017;19(1):68.
  4. Katz PP, Barton J, Trupin L, Schmajuk G, Yazdany J, Ruiz PJ, et al. Poverty, Depression, or Lost in Translation? Ethnic and Language Variation in Patient-Reported Outcomes in Rheumatoid Arthritis. Arthritis care & research. 2016;68(5):621-8.
  5. Tan Y, Buch MH. 'Difficult to treat' rheumatoid arthritis: current position and considerations for next steps. 2022;8(2):e002387.
  6. Confirmatory clinical trials : Analysis of categorical efficacy data.

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  Conflict of Interest:
  None declared.

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