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      Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

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          Abstract

          ObjectivesThis phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment.MethodsPatients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48.ResultsAt week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48.ConclusionsRituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

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          Most cited references 10

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          Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation.

          A number of studies have computed the minimally important difference (MID) for health-related quality of life instruments. To determine whether there is consistency in the magnitude of MID estimates from different instruments. We conducted a systematic review of the literature to identify studies that computed an MID and contained sufficient information to compute an effect size (ES). Thirty-eight studies fulfilled the criteria, resulting in 62 ESs. For all but 6 studies, the MID estimates were close to one half a SD (mean = 0.495, SD = 0.155). There was no consistent relationship with factors such as disease-specific or generic instrument or the number of response options. Negative changes were not associated with larger ESs. Population-based estimation procedures and brief follow-up were associated with smaller ESs, and acute conditions with larger ESs. An explanation for this consistency is that research in psychology has shown that the limit of people's ability to discriminate over a wide range of tasks is approximately 1 part in 7, which is very close to half a SD. In most circumstances, the threshold of discrimination for changes in health-related quality of life for chronic diseases appears to be approximately half a SD.
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            Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.

            An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48. Copyright 2004 Massachusetts Medical Society
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              Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.

               ,  Mark Genovese,  M Totoritis (2006)
              To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti-tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population. We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks. Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group. At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.
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                Author and article information

                Affiliations
                [1 ]Section of Musculoskeletal Disease, Leeds University, Leeds, UK
                [2 ]Oregon Health & Science University, Portland, Oregon, USA
                [3 ]Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA
                [4 ]Newcastle University, Newcastle upon Tyne, UK
                [5 ]Lapeyronie Hospital, Montpellier, France
                [6 ]Department of Internal Medicine and Osteoarthrology, Bialystok Regional Hospital, Bialystok, Poland
                [7 ]Kansas University Medical Center, Kansas City, Kansas, USA
                [8 ]Hospital Central and Faculty of Medicine, University of San Luis Potosí, San Luis Potosí, México
                [9 ]Wydz Fizjoterapii, WSSP im W. Pola, Lublin, Poland
                [10 ]Advanced Musculoskeletal Institute, Kalamazoo, Michigan, USA
                [11 ]Genentech Inc, South San Francisco, California, USA
                [12 ]Roche Products, Welwyn Garden City, UK
                Author notes
                Correspondence to Paul Emery, Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK; p.emery@ 123456leeds.ac.uk
                Journal
                Ann Rheum Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                1 September 2010
                1 September 2010
                : 69
                : 9
                : 1629-1635
                2938895
                20488885
                annrheumdis119933
                10.1136/ard.2009.119933
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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                Clinical and Epidemiological Research
                1506
                Extended report
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                Immunology

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