To the Editor:
We thank Dr. Abeles for his interest1 in our article2. Our analysis extends earlier observations of sustained inhibition of progressive joint damage3.
As stated in our article, the study was a posthoc analysis evaluating patients with an initial response [≥ 20% reduction in both swollen joint count (SJC) and tender joint count (TJC)] to rituximab (RTX) and who were eligible to receive repeat treatment courses based on the physician’s determination of clinical need and evidence of active disease (defined as both SJC and TJC ≥ 8). The minimum re-treatment interval was 24 weeks following course 1 and 16 weeks for course 2 and all subsequent courses although, as mentioned in the article, median treatment intervals among patients with repeat courses were 0.98 years (courses 1–2; n = 317), 1.06 years (courses 2–3; n = 259), 1.02 years (courses 3–4; n = 195), and 0.91 years (courses 4–5; n = 122). Therefore, interpretation of data from course 2 onward should take biases introduced with this study design into consideration.
From course 2 onward, the dropout rate was about 10% for all subsequent courses, a value consistent with that reported for other biologic therapies4,5,6. We agree with Dr. Abeles that knowing the number of dropouts due to insufficient response is important. Unfortunately, withdrawal reasons were not reported in granular detail in the REFLEX study. All reasons other than adverse events were simply classified as “other.”
To address Dr. Abeles’s comment about efficacy in patients who withdrew from the study or were not re-treated for other reasons, we conducted a posthoc analysis of the mean change in Disease Activity Score-erythrocyte sedimentation rate (DAS-ESR) at Week 24 after courses 2–4 for those patients who received further courses of RTX versus those who did not. Data are shown as observed and compare clinical efficacy responses of patients with (W) or without (W/O) receipt of subsequent courses, to evaluate the potential selection bias. We found that the mean change in DAS-ESR was comparable at Week 24 after courses 2–4 for those patients who received a subsequent RTX treatment versus those who did not (Table 1). Thus those patients who had not received a subsequent course were not necessarily nonresponders. Some patients had withdrawn for “other reasons” while others remained in their current treatment course beyond 24 weeks, without the need for subsequent treatment at that time [one might assume that for these patients the reason for not getting re-treatment may in part have been due to reaching stable disease/control of rheumatoid arthritis (RA) symptoms]. These observations were confirmed by a last observation carried forward sensitivity analysis. When the last DAS value for dropouts was included, the overall change in RA disease activity of those who did not receive a subsequent course was comparable to those who were re-treated (data not shown).
Similarly, a “within-patient within-visit” sensitivity analysis of patients who did receive all 5 courses of treatment and had 24-week data available after each course demonstrated a continual improvement in DAS LDA and remission out to course 5, accompanied by sustained American College of Rheumatology/European League Against Rheumatology responses.
Our data reflect real-life clinical practice, where a physician would not actively re-treat nonresponders or those with an insufficient therapeutic response, but would treat patients demonstrating response to previous treatment. This is particularly true of RTX where a course of treatment has an effect over the subsequent 6-month period.
Acknowledging the limitations inherent in a retrospective efficacy analysis of an open-label study, these data confirm RTX as an effective longterm treatment option in a refractory RA population and are helpful to clinicians.
REFERENCES
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