Rheumatoid Arthritis Treatments - B-Cell Inhibition
- OP0016: Impact of Rituximab on Structural Damage - REFLEX Study
- OP0017: Results of Repeat Treatment Course of Rituximab
OP0016 PREVENTION OF JOINT STRUCTURAL DAMAGE AT 1 YEAR WITH RITUXIMAB IN RHEUMATOID ARTHRITIS PATIENTS WITH AN INADEQUATE RESPONSE TO ONE OR MORE TNF INHIBITORS (REFLEX STUDY)
E. Keystone, P. Emery, C.G. Peterfy, P.P. Tak, S. Cohen, M. Genovese, S. Williams, M. Totoritis, M. Cravets, T. Shaw
Rituximab, a monoclonal antibody directed against CD20+ B cells, has been shown to be effective at reducing clinical signs and symptoms of rheumatoid arthritis (RA). Demonstration of efficacy in reducing radiographic progression of RA has only been established out to 6 months in clinical trials. Here, radiographic data extending to 1 year from the REFLEX trial are presented.
Methods: Study methods for this trial have been summarized here previously (see previous resusuts). For the 56 week radiographic data, 2 blinded assessors evaluated paired radiographs blinded to treatment allocation and sequence using the Genant modification of the Sharp scoring method (G-Sh). 56 week outcomes in subjects with missing data were linearly extrapolated from prior datapoints.
Results: Of the 517 subjects randomized, 202 rituximab treated subjects (73%) and 141 placebo treated subjects (76%) completed to 56 weeks. Baseline characteristics were balanced between treatment groups with the subjects being mostly female (76%) and Caucasian with an average age of 51 years. Baseline RA characteristics included mean tender and swollen joints counts of 33 and 23, respectively; mean DAS of 6.8; mean HAQ of 1.9; and an RA duration of 11 years. The mean G-Sh score at baseline was 48 units. Subjects had failed an average of 4.5 biologic and non-biologic DMARDs at entry. Baseline dose of weekly methotrexate was 16 mg and 60% of subjects were receiving glucocorticoids. 90% of subjects were enrolled due to inefficacy of prior TNF inhibitors rather than intolerance. The maximum number of rituximab infusions received during the study period was 3.
| Placebo + Background MTX | RTX + Background MTX | Placebo | |
| Mean change in total G-Sh Score from baseline | 2.31 + 5.28 | 1.00 + 2.76 | 0.0043 |
| Mean change in erosion score | 1.32 + 3.16 | 0.59 + 1.85 | 0.0106 |
| Mean change in Joint Space Narrowing score | 0.99 + 2.57 | 0.41 + 1.33 | 0.0007 |
53% of subjects in the rituximab group demonstrated no change in total G-Sh score over the study period compared to only 46% in the placebo treated group, however, this difference was not statistically significant. There was a significant difference in erosion non-progressors, with 61% of rituximab treated patients demonstrating no change in erosion scores over the study period, compared to 52% in the placebo treated group (p=0.0445).
Conclusion: Treatment with rituximab plus background methotrexate was associated with a significant reduction in radiographic progression at 1 year in RA patients who had previously failed treatment with a TNF inhibitor.
Editorial Comments: These are important results for defining the disease modifying properties of rituximab. However, interpretation can become complicated due to several issues. First, since the analyses are intent-to-treat, placebo treated patients who received rescue therapy with rituximab at 24 weeks are analyzed in the placebo group, possibly making the differences between the groups appear smaller. Also, the dynamics of dosing intervals on radiographic progression have not been explored; such that there may exist a differential effect of one, two, or three infusions over a given time period. Finally, as all of the enrolled subjects were previously exposed to TNF inhibitors, there may be some residual carry-over protective effect of the prior drug on radiographic damage, depending on when the last dosage was given, that may blur the results. Further analyses will likely take some of these issues into consideration in an exploratory fashion.
OP0017 LONG-TERM EFFICACY AND SAFETY OF A REPEAT TREATMENT COURSE OF RITUXIMAB IN RA PATIENTS WITH AN INADEQUATE RESPONSE TO DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS
P. Emery, D.E. Furst, G. Ferraccioli, J. Udell, R.F. Van Vollenhoven, K. Rowe, S. Agarwal, T. Shaw
The period of clinical efficacy after a treatment course of rituximab is highly variable between patients. However, repeated infusions are required in almost all patients in order to maintain clinical efficacy. Limited data from clinical trials is available on the long-term efficacy and safety of repeated courses of rituximab therapy in RA.
Methods: Subjects who received at least one treatment course of rituximab in the Phase IIa (link to EULAR 2003 abstract 0004) and Phase IIb (DANCER) (link to ACR 2005 abstract 1917) trials of rituximab were included. Subjects had to have demonstrated at least an ACR20 response in the first 24 weeks after their initial treatment course to be included. Thereafter, decisions about whether repeated treatments were needed depended on a deterioration in clinical efficacy relative to their original baseline and the direction of their treating rheumatologist.
For the analysis presented here, clinical response after each course of rituximab (measured with the ACR20/50/70 and EULAR response criteria) was compared at the 24 week time point.
Results: Data for 99 of the 145 subjects who had received 3 treatment courses (initial course plus two re-treatment courses) of rituximab were analyzed. Baseline characterisitics have been reported here previously (see links above) and were similar for the 99 subjects included in the sub-analysis presented here. Of note, 16% of subjects were seronegative for rheumatoid factor.
| Clinical response after 1st treatment course | Clinical response after 2nd treatment course (1st re-treatment) |
Clinical response after 3rd treatment course (2nd re-treatment) |
|
| ACR20 | 59% | 73% | 60% |
| ACR50 | 27% | 37% | 32% |
| ACR70 | 9% | 15% | 16% |
| EULAR remission (DAS28<2.6) | 8% | 14% | 14% |
In general, repeated treatment responses were similar, if not better than, responses achieved from prior treatment courses. Adverse events tended to be mild and did not increase with repeated treatment courses. A trend toward a greater proportion of subjects with total immunoglobulin levels below the lower limit of normal was seen as the number of re-treatments increased. However, this was not associated with an increased risk of infection within the study interval analyzed. For infusion reactions, the first infusion tended to be associated with the greatest risk of infusion reaction, with the risk decreasing rapidly with subsequent infusions.
Conclusion: In RA patients with incomplete responses to previous non-biologic DMARDs, repeated treatment courses (up to three total courses) were associated with sustained clinical efficacy and no apparent increase in toxicity.
Editorial Comments: Some of the obvious concerns about repeated infusions of rituximab, such as the possibility that clinical efficacy will diminish or that adverse events will increase over time, are not supported by this analysis. Although this is reassuring, the clinical trails data from which these results derive may not be absolutely ideal for assessing these issues. For one, subjects who remain in a clinical trial into the open-label phase are more likely to have had a favorable response and less likely to have had a serious adverse event. Thus, as the number of infusions increases, the population becomes more and more skewed towards those with the best overall responses. However, there is no better available source for this data and, until rituximab becomes more widely prescribed, data from real-world population based effectiveness studies will not be available.