Genovese_edit.qxp 1/5/07 11:58 am Page 21
New Therapies for Rheumatoid Arthritis – Abatacept and Rituximab
most events being of a respiratory nature including cough, dyspnoea placebo in conjunction with methotrexate (10–25mg weekly).
11
All patients
and COPD exacerbation. enrolled in REFLEX had radiograph-proven erosive disease and inadequate
responses to methotrexate plus a three-month or longer trial of any of the
Just as the efficacy of abatacept highlights the importance of T-cells in three commercially available TNF inhibitors. The primary end-point of ACR
RA, recent data on rituximab, a monoclonal antibody that targets B-cells, 20 response at 24 weeks in patients receiving rituximab was 51% versus
solidifies a role for the latter as well. Initial studies of rituximab in RA were 18% in placebo. There was also a non-significant trend towards slowing of
performed in patients with long-standing seropositive disease and radiographic progression with rituximab over this relatively short study
inadequate control with methotrexate.
9
One hundred and sixty-one period. Preliminary 56-week data from European League Against
patients were divided into four groups who received the combinations of Rheumatism (EULAR) 2006 and ACR 2006 suggest continued slowing of
methotrexate (≥10mg weekly) + placebo, rituximab + placebo, rituximab radiographic progression that achieved statistical significance.
12
+ cyclophosphamide, and methotrexate (≥10mg weekly) + rituximab.
Rituximab was given as two 1,000mg IV infusions on days one and 15, Given the rapid and complete depletion of peripheral B-cells that is seen in
and cyclophosphamide was given as two 750mg IV infusions on days response to rituximab, the possibility of subsequent infection risk is a
three and 17. In addition, all patients received 100mg concern. Similar rates of serious infection were similar between patients
methylprednisolone IV prior to rituximab infusions as well as high-dose receiving rituximab versus placebo in both Edwards et al. (3% versus 2.5%)
9
daily oral steroids through this two-week period. The primary end-point and DANCER (2% versus 1%). In REFLEX, however, patients receiving the
of an ACR 50 response at 24 weeks was met for groups receiving active drug experienced a slightly higher rate of serious infection at a rate of
rituximab in conjunction with either cyclophosphamide (41% of patients) 5.7 per 100 patient-years compared with 3.7 for placebo. Importantly,
or methotrexate (43%) compared with methotrexate alone (13%). serious infections were those typically encountered in routine medical
practice, including upper/lower respiratory tract, sepsis, septic arthritis, and
The Dose-Ranging Assessment: International Clinical Evaluation of pyelonephritis. There were no reported cases of opportunistic infections.
Rituximab in RA (DANCER) study sought to determine the efficacy of two
doses of rituximab in conjunction with methotrexate but without Infusion-related symptoms and signs constituted a portion of the AEs
concurrent cyclophosphamide.
10
DANCER also aimed to isolate the effect reported in all rituximab trials. These reactions included pruritus,
of daily steroids in the regimen, as 465 patients with methotrexate- urticaria/rash, headache, transient hypotension, cough, bronchospasm,
refractory disease were divided into nine groups who were administered fever, chills and rigours, and were slightly more frequent in the groups
methotrexate (10–25mg weekly) plus one of two rituximab doses (2 x receiving rituximab than placebo (23–32% of patients receiving rituximab
500mg or 2 x 1,000mg) or placebo as well as one of three different steroid versus 17% receiving placebo in DANCER, and 23% of patients receiving
regimens (IV pre-medication + daily oral doses, IV pre-medication only, or rituximab versus 18% receiving placebo in REFLEX). Although IV steroid
placebo). Patients receiving either rituximab dose achieved the primary pre-medication had no impact on the efficacy of rituximab in DANCER, it
end-point of ACR 20 response at 24 weeks (roughly 55% compared with did reduce the probability of having an infusion reaction.
28% for placebo), and the probability of achieving this response was the
same among patients receiving any of the three steroid regimens. The clinical trials of abatacept and rituximab in RA described here have
Percentages of patients achieving ACR 50 (roughly 33%) and 70 (roughly led to the addition of two new agents to the therapies available to
15%) criteria were also significantly greater than those receiving placebo clinicians in the management of this disease. Thus far both drugs appear
(13% and 5%, respectively). Some measures showed a trend towards to reduce the symptoms and signs, improve function, reduce disability
better response with the higher rituximab dose, but the differences were and slow radiographic progression in patients with RA. Perhaps their
relatively small and the study was not powered to assess their significance. greatest advantage is their effectiveness in those patients who have had
an inadequate response to TNF-inhibition as this serves a large unmet
The issue of efficacy in the TNF inadequate responder population was need. Outstanding issues to be addressed include their long-term efficacy
specifically addressed in the Randomized Evaluation of Long-Term Efficacy as well as the long-term safety of their continued use. Close study of
of Rituximab in RA (REFLEX) trial, in which 520 patients with inadequate additional safety data as more patients receive the drug is warranted, as
responses to TNF inhibition received rituximab (two 1,000mg infusions) or would be expected from any new therapies. ■
1. Kremer JM, Westhovens R, Leon M, et al., Treatment of 5. Genant HK, Peterfy C, Westhovens R, et al., Non-progression of arthritis, N Engl J Med, 2004;350:2572–81.
rheumatoid arthritis by selective inhibition of T-cell activation structural damage over 2 years with abatacept in rheumatoid 10. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al., The
with fusion protein CTLA4Ig, N Engl J Med, 2003;349: arthritis patients with an inadequate response to methotrexate efficacy and safety of rituximab in patients with active
1907–15. in the AIM trial (abstract), Arthritis Rheum, 2006;54:S408. rheumatoid arthritis despite methotrexate treatment: results of
2. Kremer JM, Genant HK, Moreland LW, et al., Effects of 6. Genovese MC, Becker JC, Schiff M, et al., Abatacept for a phase IIB randomized, double-blind, placebo-controlled, dose-
abatacept in patients with methotrexate-resistant active rheumatoid arthritis refractory to tumor necrosis factor alpha ranging trial, Arthritis Rheum, 2006;54:1390–400.
rheumatoid arthritis: a randomized trial, Ann Intern Med, inhibition, N Engl J Med, 2005;353:1114–23. 11. Cohen SB, Emery P, Greenwald MW, et al., Rituximab for
2006;144:865–876. 7. Genovese MC, Schiff M, Luggen M, et al., Sustained efficacy rheumatoid arthritis refractory to anti-tumor necrosis factor
3. Luggen M, Emery P, Li T, et al., Abatacept provided clinically and safety through 2 years in patients with rheumatoid arthritis therapy: Results of a multicenter, randomized, double-blind,
meaningful improvements in multiple aspects of health related (RA) in the long-term extension of the ATTAIN trial (abstract), placebo-controlled, phase III trial evaluating primary efficacy
quality of life (HRQoL) and physical function through 2 years of Arthritis Rheum, 2006;54:S244. and safety at twenty-four weeks, Arthritis Rheum, 2006;54:
treatment in patients with active rheumatoid arthritis (RA): 8. Weinblatt M, Combe B, Covucci A, et al., Safety of the selective 2793–806.
results from the AIM and ATTAIN trials (abstract), Arthritis costimulation modulator abatacept in rheumatoid arthritis 12. Keystone E, Emery P, Peterfy, et al., Inhibition of joint structural
Rheum, 2006;54:S422. patients receiving background biologic and nonbiologic disease- damage with rituximab is not dependent on clinical response in
4. Kremer J, Westhovens R, Russell A, et al., Long-term efficacy of modifying antirheumatic drugs: a one-year randomized, rheumatoid arthritis patients with an inadequate response to
abatacept through 2 years of treatment in rheumatoid arthritis placebo-controlled study, Arthritis Rheum, 2006;54: 2807–16. one or more TNF inhibitors (REFLEX study) (abstract), Arthritis
patients in the AIM trial (abstract), Arthritis Rheum, 2006;54: 9. Edwards JC, Szczepanski L, Szechinski J, et al., Efficacy of B- Rheum, 2006;54:S542.
S247. cell-targeted therapy with rituximab in patients with rheumatoid
EUROPEAN MUSCULOSKELETAL REVIEW 2007 21
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100