Rituximab In Rheumatoid Arthritis Research Articles

Rituximab: A new therapeutic alternative in rheumatoid arthritis

Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B cells, which play numerous pathogenic roles in rheumatoid arthritis (RA). This review summarises the results of three controlled studies using rituximab in RA and the data regarding tolerance and repeated treatment in 1053 patients included in the clinical studies. These studies demonstrated the efficacy of rituximab in patients with RA, including those who had been unresponsive or intolerant to one or more TNF inhibitor therapies. Rituximab was globally well-tolerated. The current informations on the efficacy and the tolerance of rituximab led us to propose recommendations for the screening of patients, the use of rituximab, and the follow-up of patients. A longer follow-up duration and data from off-trial patients, included in registries, are now required.

Safety of Biologic Therapy in Rheumatoid Arthritis and Other Autoimmune Diseases: Focus on Rituximab

To review the safety of biologic agents used to treat rheumatoid arthritis (RA) and other autoimmune diseases, with a focus on rituximab. Information was gathered from a search of the PubMed database and from major congress abstract listings through June 2007. Rituximab is approved for treating RA in patients with an inadequate response to TNF inhibitors and is under study in other indications for RA and other autoimmune disorders. The current safety profile of rituximab in RA is known from Phase II and III studies conducted preapproval, treating approximately 750 patients, as well as from long-term extension studies with repeated therapy. Clinical trials have established that the most common adverse events are infusion-associated reactions, seen in 29 to 40% of patients, most of which are mild to moderate and occur following the first rituximab infusion, with incidence and severity decreasing with subsequent infusions. Rates of infections and serious infections to date are within the range expected for RA patients treated with other biologic agents, but the longer term effects of B-cell depletion and the effects of repeated treatment on the risk of infections are uncertain. Information is limited for rituximab safety in other autoimmune disorders but current data do not suggest that there is a significant difference in adverse events from that previously reported. Rituximab is an important addition to the rheumatologist's armamentarium for the treatment of difficult RA and ongoing trials will determine its utility in other indications for RA and other autoimmune conditions. The true safety profile of rituximab will emerge as larger numbers of patients are treated in routine clinical practice.

Rituximab in rheumatoid arthritis following anti-TNF-associated tuberculosis

Rituximab in rheumatoid arthritis following anti-TNF-associated tuberculosis

Rituximab in patients with rheumatoid arthritis: systematic review

Biologic treatments are newly used in rheumatoid arthritis. Three tumornecrosis factor alfa (TNF-alpha) inhibitors--adalimumab, etanercept and infliximab--have been licensed for rheumatoid arthritis in Hungary. B-cell targeted treatment with rituximab is the next biologic treatment. Rituximab was used earlier for the treatment of non-Hodgkin's lymphoma. Rituximab was registered to be used in patients with rheumatoid arthritis who have had an inadequate response or an intolerance to one or more TNF-alpha blocking agents. Systematic review in the literature of efficacy of rituximab in rheumatoid arthritis. To assess the efficacy and safety of rituximab treatment in patients with rheumatoid arthritis. MEDLINE and Cochrane database were searched for randomized controlled trials with rituximab in rheumatoid arthritis. A meta-analysis of trial data was conducted. Three randomized controlled trials were identified including 1145 patients. 54% of patients with inadequate response to TNF-alfa inhibitors and severe disease-activity have reached American College of Rheumatology 20 criteria. This ratio is larger with 33% (95% CI, 25-41%) than without treatment, and patients have almost five times (relative risk = 4.77 95% CI, 3.12-7.31) chance to improve. Functional status represented by Health Assessment Questionnaire score improves significantly (p < 0.001) in rituximab arms (-0.4 scores) compared with placebo arms (-0.1 scores). EULAR moderate and good responses in the rituximab group were significant (p < 0.00001) compared with the placebo group, rate difference is 38% (95% CI, 32-44%). Rituximab improves also radiological symptoms of rheumatoid arthritis. New therapeutic options, rituximab is efficacious in patients with rheumatoid arthritis. Rituximab can improve symptoms of patients with inadequate response to or intolerance of TNF-alpha inhibitors.

B cell depletion therapy using anti-CD20 antibodies in rheumatoid arthritis

Some patients with rheumatoid arthritis (RA) suffer from disease that is refractory to both conventional therapy and newer biological agents such as tumor necrosis factor (TNF) inhibitors. In recent years, there has been growing interest in, and enhanced understanding of, the contribution of B cells to the immunopathogenesis of RA. Rituximab (RTX), a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, has been licensed for the treatment of malignant lymphoma for almost 10 years. Efficacy of rituximab in RA has already been demonstrated in randomized control trials, and US Food and Drug Administration has approved the combination of RTX with methotrexate for use in patients with RA, who have had an inadequate response to one or more TNF antagonist therapies. The long-term efficacy, especially about joint damage, and long-term safety need to be further investigated.

Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs

To assess safety and efficacy of repeated B-cell depletion with rituximab in patients with rheumatoid arthritis (RA). Thirty-seven patients with refractory RA entered into a programme of repeated B-lymphocyte depletion (up to 5 cycles, 89 cycles in total) with protocols based on the anti-CD20 monoclonal antibody, rituximab, have been observed over periods of >5 yrs (n = 22) or 3-5 yrs (n = 14). Twenty two subjects have been followed up for >5 yrs. Average duration of benefit per cycle was 15 months (maximum 43 months), and time to re-treatment 20 months. Nineteen patients remain on the programme. Patients were withdrawn for lack of efficacy (n = 5), hypersensitivity infusion reaction (n = 1), brevity of response (n = 8), or occurrence of adverse respiratory events (n = 1). Sixteen major lower respiratory events occurred during the 180 patient-yrs of follow-up. Of these only one had low IgG. In patients receiving rituximab +/- cyclophosphamide (cy) carcinomata have developed as follows: breast (3, +cy), ovary (1, +cy), transitional cell (1, +cy), and renal cell (1, -cy). Falls in total immunoglobulin levels to below the normal range occurred in 12 patients for IgM (undetectable levels in three after repeated cycles), seven for IgG and one for IgA, not taking into account patients who started off with low immunoglobulin levels before the first cycle. Repeated B-lymphocyte depletion over a 5-yr period appears to be an acceptable and relatively well-tolerated therapy in RA with a relatively high rate of continuation. Long-term effects on immunoglobulin levels require surveillance.

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

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.

B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus

B cells appear to have a central role in the immunopathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); both autoantibody production and B-cell anomalies are characteristic of these diseases. With the recent availability of biologic agents that can deplete B cells or block their function in vivo, it has become possible to target B cells therapeutically. Evidence strongly suggests that novel B-cell targeting agents are effective. In addition, the mechanistic specificity of B-cell targeted approaches, combined with the ability to test them in large randomized controlled trials, will provide an unprecedented opportunity to study the precise roles of B cells in the immunopathogenesis of RA and SLE. The largest volume of information is available for rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen. Information from multiple investigator-sponsored trials and from off-label use suggests efficacy of this antibody in RA, SLE, and other autoimmune syndromes. Randomized controlled trials have also provided solid evidence for the efficacy of rituximab in RA and are ongoing in SLE. Other therapeutic agents supported by controlled data include cytotoxic T-lymphocyte-associated protein 4 immunoglobulin and antibodies against the interleukin-6 receptor and the B-cell survival molecule BLyS. Additional agents and targets are in earlier stages of development. The concerns about infectious complications have so far not proven to be justified. We can reasonably expect important advances in the understanding and treatment of RA and SLE in the next 5-10 years, as B-cell targeting methods become more widespread and sophisticated.

Efficacy of B-cell-targeted therapy with rituximab in rheumatoid arthritis

Efficacy of B-cell-targeted therapy with rituximab in rheumatoid arthritis

Repeated B-cell depletion with rituximab in rheumatoid arthritis

Thirty-seven patients have been recruited to a programme of repeated B-cell depletion therapy for rheumatoid arthritis. Protocols have been based on rituximab, combined with cyclophosphamide initially. Sixty-two treatments have been given over 4.5 years. Patients were withdrawn for inadequate response (< ACR20), for successful reintroduction of disease-modifying antirheumatic drug (DMARD) or for toxicity. Twenty-five patients continue on the programme with evidence of response, and a further three patients have regained control on reintroduction of DMARD (methotrexate, sulphasalazine). All four IgM rheumatoid factor-negative patients failed to respond. One seropositive patient achieved no benefit, and two achieved benefit of 5 months or less. Two patients have been lost to follow-up. The mean period of benefit (> ACR20) was 15 months, with a maximum of 35 months. One patient showed inadequate depletion. Secondary failure of clinical response or depletion was not observed in up to four repeat treatments. Coexistent psoriasis on three patients showed no change. B-cell depletion protocols were well tolerated. Eight febrile episodes with pulmonary symptoms occurred in 85 patient-years of follow-up. All settled rapidly on antibiotic. Although most were assumed infective, at least four may have been late reactions to therapy or been disease associated. One suspected joint prosthesis infection was sterile on culture. Three patients who received rituximab in combination with cyclophosphamide have developed breast carcinoma (two patients) or carcinoma in situ (one patient), although in one case there was evidence that this predated therapy. (No increase in the incidence of carcinoma has been reported in surveillance of rituximab usage elsewhere.) In three cases who have received three courses of therapy in rapid succession, serum IgM levels have fallen to undetectable during the period of depletion. Falls in IgG levels have been modest and antibacterial antibody levels well maintained. In summary, experience with repeated B-cell depletion therapy in rheumatoid arthritis suggests that approximately 80% of seropositive patients may become susceptible to continuing control of disease, but seronegative disease appears unresponsive. Secondary resistance appears not to be a problem over 2–4 years. Susceptibility to chest infection may be increased. Cumulative effects on immunoglobulin levels may occur with frequently repeated usage.