Washington, DC—The days when rheumatoid arthritis (RA) was thought to be a T-cell mediated disease seemed far distant at the 2006 American College of Rheumatology meeting, where many RA studies  focused on the B-cell depleting anti-CD20 antibody rituximab (Rituxan®, MabThera® [Genentech/Biogen-Idec]).

Joint protection not dependent on clinical response

Expanding on data first presented at EULAR, Edward Keystone, MD, and investigators from the REFLEX trial reported that rituximab's ability to inhibit structural joint damage is not dependent on clinical response.¹ By week 56, patients who were ACR20 nonresponders at week 24 had protection against joint deterioration nearly as great as that for patients who had ACR20 responses at week 24 [Table].

Using data from REFLEX, patients who had been randomized to placebo/MTX and crossed over to rescue therapy with rituximab/MTX plus IV-only or IV plus oral glucocorticoids between weeks 16 and 24, Ruderman et al concluded that adding oral steroids neither reduced the incidence of rituximab acute infusion reactions nor improved efficacy and so "add[s] no major additional value to the rituximab treatment."²

Repeat courses maintain efficacy

Repeated courses of rituximab produce "a comparable or improved degree of sustained efficacy relative to original baseline" in patients with active RA and inadequate response to disease-modifying anti-rheumatic drugs (DMARDs)³ or to TNF inhibitors⁴ without causing new safety problems. Repeat treatment "can lead to a continued improvement in patients' physical function and an enhanced improvement in both mental and physical components of patients' quality of life,⁵ but time may be of the essence for getting the most benefit from this drug.

Mease et al found that patients who respond to an initial course of rituximab will do better if a second course is given before disease activity levels worsen. "Taking into account a patient's DAS28 after course 1, every point (1.0) that DAS28 was allowed to increase (worsen) before repeating treatment resulted in a 0.28 ± 0.09 point higher DAS28 after course 2," they reported.⁶

Fortunately, as had been seen previously with rituximab in cancer patients, the risk of infusion reactions decreased with additional courses of rituximab.⁷

The relationship between return of B cells and increased RA disease activity remains murky. Emery et al reported that the return of peripheral B cells doubled the risk of losing response but that B-cell return is too variable and generally too distant (median: 32 weeks) from loss of response to rituximab to be clinically useful as a guide to repeat treatment.⁸

Ability to respond to vaccination maintained

The effect of new biologicals on patients' ability to respond to vaccination has been a concern, but Ori Elkayam, MD, and colleagues at Tel Aviv Medical Center, in Israel, reported that patients treated with rituximab were still able to mount a robust humoral response to influenza virus vaccine, despite B-cell depletion.⁹ "A substantial proportion of patients treated with rituximab respond to vaccination despite absence of detectable B cells, and we believe they should be vaccinated," Dr. Elkayam said.

Most of the rituximab studies have involved patients previously treated with DMARDs and/or TNF inhibitors. Genovese et al reported that no additional risk appears to be attached to the opposite sequence. A pilot study of 78 patients with active RA who had withdrawn from clinical trials after receiving rituximab and then been treated with etanercept, infliximab, or adalimumab found no increased risk of serious infections and no increase in the overall incidence of adverse events in these patients compared with patients treated with TNF inhibitors alone.¹⁰

B-cell depletion appears to be only part of the story behind rituximab's efficacy in RA, however. Tak et al found that patients who were seronegative for both rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) had significant benefits from rituximab in terms of ACR20 response but were less likely than patients with one or both autoantibodies to have higher-level ACR50 or ACR70 responses. "This suggests that other mechanisms (eg, antigen presentation, T-cell co-stimulation, and cytokine release) may account for low levels of response, with higher responses to rituximab therapy mediated primarily by suppression of pathogenic autoantibodies," they concluded.¹¹

Table 1: Rituximab Inhibits Joint Damage Even Without ACR20 Response

ACR20 Response at Week 24 Nonresponders	Placebo + MTX at 56 Weeks (n = 151)	Rituximb + MTX at 56 Weeks (n = 125)
Mean change in total Genant-Sharp score	2.39	0.93 (P = .0271)
Mean change in erosion score	1.46	0.49 (P = .0396)
Mean change in joint space narrowing	0.93	0.44 (P = .0126)

Source: Keystone E ,et al. ACR 2006. Abstract 1307.

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References

1. Keystone E, Emery P, Peterfy CG, et al. Inhibition of joint structural damage with rituximab is not dependent on clinical response in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors (REFLEX study). Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 1307.
2. Ruderman EM, Burmester GR, Durez P, et al. Oral glucocorticoids have no impact on the efficacy or safety profile of rituximab in rheumatoid arthritis patients with inadequate response to TNF inhibitors (REFLEX study). Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 454.
3. Emery P, Furst DE, Ferraccioli G, et al. 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. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 458.
4. Keystone E, Fleischmann RM, Emery P, et al. Long-term efficacy and safety of a repeat treatment course of rituximab in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 725.
5. Tak PP, Mease PJ, Bombardieri S, et al. Repeat treatment with rituximab improves physical function and quality of life in patients with rheumatoid arthritis and an inadequate response to TNF inhibitors. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 926.
6. Mease P, Keystone E, Kaell A, et al. Recent disease activity affects outcome of second course of rituximab for RA. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 479.
7. Fleischmann R, van Vollenhoven R Udell J, et al. Infusion-associated events decrease with repeat courses of rituximab in patients with active rheumatoid arthritis. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 483.
8. Emery P, Breedveld F, Martin-Mola E, et al. Relationship between peripheral B cell return and loss of EULAR response in RA patients treated with rituximab. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 5.
9. Oren C, Mendelbaum M, Paran D, et al. Vaccination against influenza in rheumatoid arthritis: the effect of rituximab on the humoral response. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 1234.
10. Genovese M, Breedveld FC, Emery P, et al. TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 726.
11. Tak PP, Cohen S, Emery P, et al. Baseline autoantibody status (RA, anti-CCP) and clinical response following the first treatment course with rituximab. Presented at: American College of Rheumatology Meeting; November 10–15, 2006; Washington, DC. Abstract 833.