(For unclear reasons, the change from baseline to 16 weeks did not correlate with clinical response). respond. Future challenges for the further development of rituximab for intractable RA will be discussed. values 0.001) (see Table 1). Table 1 Clinical response in the REFLEX trial 0.0001).22 An unanswered question is whether the high dose steroids used in REFLEX plays any role in protection from radiographic damage, ie, would rituximab without such high dose steroids be as effective? Table 2 Structural damage in the REFLEX trial value 0.0009 and 0.0001, respectively). In open trials rheumatoid factor and anti-CCP antibodies were found to decrease with rituximab NESP therapy.23,24 A moderate decrease in autoantibodies has been confirmed in randomized trials, ie, comparing baseline to 24-week titers in the REFLEX trial RF levels decreased by 55% in rituximab-treated patient and increased 37% in placebo-treated patients.19 Re-treatment with rituximab The safety and efficacy of re-treatment with rituximab for RA has not been established. The original trials leading to the approval of rituximab for RA do not provide controlled data on re-treatment. However, many patients in those clinical trials joined into open-label extension trials. Patients in the REFLEX trial were eligible for an open-label trial with repeated dosing. The patients who received placebo were allowed to go on rituximab as part of Bupropion morpholinol D6 this open label extension. Data for 179 patients receiving at least 3 courses indicates continued efficacy.25 Of course, this group of patients was undoubtedly biased because patients who did poorly could opt out of further treatment. Nevertheless, it is interesting to note that Bupropion morpholinol D6 there was a subset of patients who continued to respond to repeated courses of rituximab and that in this group the proportion of patients with very good responses increased over time, ie, for 179 patients who received 3 courses of rituximab and experienced ACR responses assessed at 24 weeks post each infusion, the proportion of patients with an ACR70 increased from 14.0% after the first Bupropion morpholinol D6 course to 25.7% after the third infusion (= 0.0049). Similarly, for the 170 patients treated with 3 courses and assessed with European League Against Rheumatism (EULAR) scores, 17.1% had low disease activity (DAS28 3.2) (DAS, Disease Activity Score in Rheumatoid Arthritis) after the first infusion, 25.9% had low disease activity after the second infusion and 34.1% had low disease activity after the third infusion ( 0.05 for 1st vs 2nd course; 0.00001 for first vs third course). There have been two publications that provide some preliminary data on what to do for patients who do not respond to the first course of rituximab. A publication from Amsterdam reported on re-treatment of 6 patients who Bupropion morpholinol D6 were nonresponders to the initial course of rituximab compared to 16 patients who were responders to the initial course. Patients treated with an initial course of rituximab were re-treated after an interval of at least 6 months if they experienced a DAS28 3.2.26 All 6 non-responders to the initial treatment were non-responders to re-treatment by EULAR criteria. In contrast, of the 16 responders to initial treatment, 4 were EULAR good responders, 10 were EULAR moderate responders, and only 2 were EULAR non-responders. These data suggest that patients who do not respond to the initial course of rituximab should not receive a second course. However, Bupropion morpholinol D6 the figures are small and there was not a statistically significant difference in the proportion of responders (0 of 6 vs 14 or 16, = 0.36 by chi-squared analysis) between the two groups. A second statement on re-treatment of non-responders was recently offered.27 In 14 non-responders the DAS28 improved by only 0.75 at 16 weeks after the initial course of rituximab. At 16 weeks following re-treatment the cumulative improvement for these initial nonresponders (initial baseline to post second course) was 1.23. Anti-CCP positive patients experienced somewhat better cumulative response than anti-CCP unfavorable patients, 2.24 vs 1.14. Based on this study it appears possible that a subgroup of non-responders may improve after a second course. However, both of these studies were small. Therefore, the question of re-treating non-responders remains open and needs further study. Another question is usually whether re-treatment should be given at fixed occasions or when it is needed. Two centers, one giving rituximab every 24 weeks and one giving re-treatment as disease relapse, analyzed 48 patient is usually a.
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