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Norihiro Nishimoto - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Tocilizumab in patients with refractory takayasu arteritis results from a randomised double blind placebo controlled phase 3 trial in japan the takt study
Annals of the Rheumatic Diseases, 2018Co-Authors: Yoshikazu Nakaoka, Yoshiya Tanaka, Mitsuaki Isobe, Syuji Takei, Tomonori Ishii, Shumpei Yokota, Akira Nomura, Seitaro Yoshida, Norihiro NishimotoAbstract:Objective To investigate the efficacy and safety of the interleukin-6 receptor antibody Tocilizumab in patients with Takayasu arteritis (TAK). Methods Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly Tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms. Results The intent-to-treat and safety populations included 18 Tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 Tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight Tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr’s definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one Tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths. Conclusion Although the primary endpoint was not met, the results suggest favour for Tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of Tocilizumab in patients with refractory TAK. Trial registration number JapicCTI-142616.
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study of active controlled Tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate satori significant reduction in disease activity and serum vascular endothelial growth factor by il 6 receptor inhibition
Modern Rheumatology, 2009Co-Authors: Norihiro Nishimoto, Tsutomu Takeuchi, Nobuyuki Miyasaka, Kazuhiko Yamamoto, Shinichi Kawai, Junichi Azuma, Tadamitsu KishimotoAbstract:We investigated the clinical efficacy and safety of Tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either Tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (Tocilizumab group) or Tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the Tocilizumab group achieved ACR20 response. The Tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by Tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the Tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
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mechanisms and pathologic significances in increase in serum interleukin 6 il 6 and soluble il 6 receptor after administration of an anti il 6 receptor antibody Tocilizumab in patients with rheumatoid arthritis and castleman disease
Blood, 2008Co-Authors: Norihiro Nishimoto, Kimio Terao, Toru Mima, Hideko Nakahara, Nobuhiro Takagi, Takahiro KakehiAbstract:Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), Tocilizumab (a humanized anti–IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including C-reactive protein (CRP). We found that Tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with Tocilizumab after Tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after Tocilizumab administration in both RA and Castleman disease. As long as free Tocilizumab was detectable, sIL-6R was saturated with Tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of Tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R–mediated consumption of IL-6 was inhibited by the unavailability of Tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during Tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity.
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Tocilizumab for the treatment of rheumatoid arthritis
Expert Review of Clinical Immunology, 2008Co-Authors: Toru Mima, Norihiro NishimotoAbstract:Tocilizumab is a humanized anti-human IL-6 receptor antibody that specifically inhibits the biological activity of IL-6 by competitively inhibiting the binding of IL-6 to the IL-6 receptor. Clinical trials have shown that Tocilizumab 8 mg/kg administered by monthly infusion not only improves clinical signs and symptoms of refractory rheumatoid arthritis but also suppresses radiographic progression. In regard to safety, the most common adverse event was nonsevere infection, such as nasopharyngitis, although the incident rate of adverse events was slightly higher than that of disease-modifying antirheumatic drug treatment. Studies have shown that there is no specific infection or prolongation of infection related to Tocilizumab treatment. Tocilizumab is a promising therapeutic agent with statisfactory efficacy and safety for rheumatoid arthritis.
Tadamitsu Kishimoto - One of the best experts on this subject based on the ideXlab platform.
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Immunotherapy of Tocilizumab for Rheumatoid Arthritis
Journal of clinical & cellular immunology, 2013Co-Authors: Toshio Tanaka, Tadamitsu KishimotoAbstract:Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by persistent joint inflammation, systemic inflammation and immunological abnormalities. Because IL-6 plays a major role in the development of these characteristics, IL-6 blockade may reasonably be expected to constitute a novel therapeutic strategy for the treatment of RA. Phase III clinical trials of a humanized anti-human IL-6 receptor monoclonal antibody, Tocilizumab, have demonstrated its outstanding clinical efficacy, either as monotherapy or in combination with disease-modifying antirheumatic drugs, for moderate to severe active RA patients. Although Tocilizumab is currently recommended as a second-line biologic for RA patients whose response to one or more of TNF inhibitors is inadequate, further clinical studies including head-to-head comparative studies, and clarification of the mechanisms through which Tocilizumab exerts its clinical effects are sure to identify RA patients who should be treated with Tocilizumab as a first line biologic.
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study of active controlled Tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate satori significant reduction in disease activity and serum vascular endothelial growth factor by il 6 receptor inhibition
Modern Rheumatology, 2009Co-Authors: Norihiro Nishimoto, Tsutomu Takeuchi, Nobuyuki Miyasaka, Kazuhiko Yamamoto, Shinichi Kawai, Junichi Azuma, Tadamitsu KishimotoAbstract:We investigated the clinical efficacy and safety of Tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either Tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (Tocilizumab group) or Tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the Tocilizumab group achieved ACR20 response. The Tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by Tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the Tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
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humanized antihuman il 6 receptor antibody Tocilizumab
Handbook of experimental pharmacology, 2008Co-Authors: N Nishimoto, Tadamitsu KishimotoAbstract:Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune responses and inflammatory reactions. Overproduction of IL-6 has been shown to play a role in inflammatory autoimmune diseases such as rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA) and, therefore, an agent blocking IL-6 actions can be a therapy of these diseases. IL-6 belongs to a cytokine family, which shares the cytokine receptor subunit glycoprotein (gp) 130. This family also includes IL-11, oncostatin-M, and leukemia inhibitory factor (LIF). In the IL-6 receptor (IL-6R) system, both a membrane-bound IL-6R and a soluble form of IL-6R are able to mediate IL-6 signals into the cells through the interaction of gpl30. Tocilizumab is a humanized antihuman IL-6 receptor antibody designed using genetic engineering technology. Tocilizumab recognizes both the membrane-bound and the soluble form IL-6R and specifically blocks IL-6 actions. Tocilizumab is expected to ameliorate the autoimmune inflammatory diseases with IL-6 overproduction and has been clinically developed as a therapeutic agent for RA, systemic-onset and articular types of JIA, Crohn's disease, etc. Tocilizumab has been shown to be effective not only for improving signs and symptoms but also for preventing joint destruction of RA. Immunopharmacology and clinical benefit of Tocilizumab in RA is addressed.
Thasia G Woodworth - One of the best experts on this subject based on the ideXlab platform.
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early rheumatoid arthritis treated with Tocilizumab methotrexate or their combination u act early a multicentre randomised double blind double dummy strategy trial
The Lancet, 2016Co-Authors: Johannes W J Bijlsma, Paco M J Welsing, Thasia G Woodworth, Leonie Middelink, Attila Pethoschramm, Corrado Bernasconi, Michelle E A Borm, Cornelis H Wortel, Evert Jan Ter Borg, Nazira Z JahangierAbstract:Summary Background For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody Tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. Methods We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start Tocilizumab plus methotrexate (the Tocilizumab plus methotrexate arm), or Tocilizumab plus placebo-methotrexate (the Tocilizumab arm), or methotrexate plus placebo-Tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the Tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then Tocilizumab (and placebo-Tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 Findings Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the Tocilizumab plus methotrexate arm, 103 to the Tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72–78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the Tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the Tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59–2·51 for Tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48–2·32 for Tocilizumab vs methotrexate, p vs methotrexate, 1·14, 1·01–1·29, p=0·0356 for Tocilizumab vs methotrexate, and p=0·59 for Tocilizumab plus methotrexate vs Tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the Tocilizumab plus methotrexate arm, 40 (39%) of 103 in the Tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the Tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the Tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. Interpretation For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of Tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. Funding Roche Nederland BV.
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Population Pharmacokinetic Analysis of Tocilizumab in Patients With Rheumatoid Arthritis
The Journal of Clinical Pharmacology, 2010Co-Authors: Nicolas Frey, Susan Grange, Thasia G WoodworthAbstract:Abstract Tocilizumab is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that has demonstrated efficacy in the treatment of rheumatoid arthritis (RA). A population pharmacokinetic (PK) model was developed using nonlinear mixed effect modeling to describe the PK profile of Tocilizumab and used to estimate interindividual variability and assess the influence of covariates on PK parameters. The model was constructed based on data collected from 1793 patients with moderate to severe RA who received Tocilizumab (4 or 8 mg/kg), via intravenous infusion every 4 weeks, during 4 phase III clinical trials. Serum concentration-time profiles of Tocilizumab were adequately described by a 2-compartment disposition model with parallel linear and nonlinear elimination kinetics. The 8-mg/kg dose of Tocilizumab, compared with the 4-mg/kg dose, resulted in a more pronounced saturation of the nonlinear clearance pathway over the dosing interval, and this nonlinear clearance was representative of target-mediated elimination due to Tocilizumab binding to the IL-6 receptor.
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comparison of Tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis the ambition study
Annals of the Rheumatic Diseases, 2010Co-Authors: Graeme Jones, Anthony Sebba, Emma Alecock, Juan J Gomezreino, Jieruo Gu, Mitchell B Lowenstein, Armando Calvo, Daniel Siri, Matija Tomsic, Thasia G WoodworthAbstract:Background: The anti-interleukin (IL) 6 receptor antibody Tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. Objective: To evaluate through the AMBITION study the efficacy and safety of Tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either Tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by Tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. Results: The intention-to-treat analysis demonstrated that Tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p 3×– Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed. Trial registration number: NCT00109408
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interleukin 6 receptor inhibition with Tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease modifying antirheumatic drugs the Tocilizumab in combination with traditional disease modifying antirheumatic drug
Arthritis & Rheumatism, 2008Co-Authors: Mark C Genovese, Thasia G Woodworth, James D Mckay, E L Nasonov, Eduardo Mysler, Nilzio A Da Silva, Emma Alecock, Juan J GomezreinoAbstract:Objective To examine the efficacy and safety of the humanized anti–interleukin-6 receptor antibody Tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). Methods A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received Tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. Results At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the Tocilizumab plus DMARD group than in the control group (61% versus 25%; P 3-fold the upper limit of normal, occurred in 4% of patients in the Tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving Tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. Conclusion Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.
Tsutomu Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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Tocilizumab in isolated polymyalgia rheumatica: A systematic literature review.
Seminars in Arthritis and Rheumatism, 2020Co-Authors: Mitsuhiro Akiyama, Yuko Kaneko, Tsutomu TakeuchiAbstract:ABSTRACT OBJECTIVE : We investigated the effectiveness of Tocilizumab (an anti-interleukin-6 receptor antibody) in patients with polymyalgia rheumatica (PMR). METHODS : We performed a systematic literature review from the inception dates until August 7, 2019 for articles reporting Tocilizumab administration to treat isolated PMR. RESULTS : We identified 59 patients with isolated PMR treated with Tocilizumab. All studies used intravenously administered Tocilizumab at a dose of 8 mg/kg monthly. Tocilizumab monotherapy was administered to 24 and combination therapy (Tocilizumab + glucocorticoid) to 35 patients. Tocilizumab monotherapy achieved low disease activity scores in only 17% of patients at week 4 and in only 71% patients even at week 12. Compared to glucocorticoid monotherapy, the reduction in the cumulative glucocorticoid dose was between 58% and 70% using a combination of Tocilizumab and glucocorticoids, and 33–100% of the patients eventually showed glucocorticoid-free remission. All relapses occurred in patients administered Tocilizumab monotherapy. No new safety event was reported. CONCLUSION : Tocilizumab is effective in cases of isolated PMR, particularly in combination with glucocorticoids. In addition to its glucocorticoid-sparing effect, it achieves glucocorticoid-free remission and reduces relapse rates. Tocilizumab monotherapy is not recommended.
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Tocilizumab in patients with adult onset still s disease refractory to glucocorticoid treatment a randomised double blind placebo controlled phase iii trial
Annals of the Rheumatic Diseases, 2018Co-Authors: Yuko Kaneko, Hideto Kameda, Kei Ikeda, Tomonoti Ishii, Kosaku Murakami, Hyota Takamatsu, Yoshiya Tanaka, Tsutomu TakeuchiAbstract:Objective To evaluate the efficacy and safety of Tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still’s disease. Methods In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still’s disease refractory to glucocorticoids were randomised to Tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label Tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point. Results In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the Tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were –4.1 in the Tocilizumab group and –2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the Tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of Tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still’s disease, drug eruption and anaphylactic shock. Conclusion The study suggests that Tocilizumab is effective in adult-onset Still’s disease, although the primary endpoint was not met and solid conclusion was not drawn.
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clinical radiographic and functional effectiveness of Tocilizumab for rheumatoid arthritis patients reaction 52 week study
Rheumatology, 2011Co-Authors: Tsutomu Takeuchi, Yuko Kaneko, Yoshiya Tanaka, Koichi Amano, D Hoshi, Masao Nawata, Hayato Nagasawa, Eri Sato, Kazuyoshi Saito, Shunsuke FukuyoAbstract:Objectives. To evaluate the effectiveness and safety of Tocilizumab in RA patients in clinical practice. Methods. We observed 232 consecutive RA patients who began Tocilizumab in three rheumatology centres in Japan for 52 weeks. Clinical, radiographic and functional status and safety were evaluated. Results. Mean age of the 232 patients was 59.1 years, mean duration of disease was 12.4 years and average DAS using the 28-joint count (DAS-28) was 5.6. Although 62.8% of the patients had been treated previously with anti-TNF biologics, clinical remission at Week 52 was achieved in 43.7%, radiographic non-progression in 62.8% and functional remission in 26.4%. Retention rate at Week 52 was 71.1%, and the same for those with or without previous anti-TNF treatment. Adverse drug reactions leading to Tocilizumab discontinuation were observed in 15.5% of patients, the most frequent adverse drug reaction being pneumonia in eight cases. On multivariate logistic regression analysis, DAS-28, HAQ-disability index (HAQ-DI), concomitant MTX and concomitant glucocorticoids (GCs) were predictive variables for clinical remission at Week 52 of Tocilizumab treatment. In particular, HAQ-DI was found to be a predictive variable for remission of all three types—clinical, radiographic and functional—at Week 52 of Tocilizumab treatment. Conclusions. In daily clinical practice, Tocilizumab exhibited excellent effectiveness in established RA patients, some of whom had failed to respond to previous anti-TNF treatment. Although further detailed safety findings are required, this study provides valuable real-world findings on the management of RA with Tocilizumab.
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study of active controlled Tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate satori significant reduction in disease activity and serum vascular endothelial growth factor by il 6 receptor inhibition
Modern Rheumatology, 2009Co-Authors: Norihiro Nishimoto, Tsutomu Takeuchi, Nobuyuki Miyasaka, Kazuhiko Yamamoto, Shinichi Kawai, Junichi Azuma, Tadamitsu KishimotoAbstract:We investigated the clinical efficacy and safety of Tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either Tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (Tocilizumab group) or Tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the Tocilizumab group achieved ACR20 response. The Tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by Tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the Tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
Josef S Smolen - One of the best experts on this subject based on the ideXlab platform.
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interleukin 6 receptor inhibition with Tocilizumab and attainment of disease remission in rheumatoid arthritis the role of acute phase reactants
Arthritis & Rheumatism, 2011Co-Authors: Josef S Smolen, Daniel AletahaAbstract:Objective To determine the effects of Tocilizumab on rheumatoid arthritis (RA) disease activity and remission assessment, using measures that do or do not comprise acute-phase reactants. Methods Simplified Disease Activity Index (SDAI) scores, Clinical Disease Activity Index (CDAI) scores, and the Disease Activity Score in 28 joints (DAS28) were calculated using data from Tocilizumab trials in patients with RA in whom disease had remained active despite treatment with disease-modifying antirheumatic drugs. The CDAI does not contain an acute-phase reactant component. Disease activity states, including remission, were defined using established cut points; for the DAS28, an alternative cut point of <2.4 was also used. Results Changes in the DAS28, the SDAI score, and the CDAI score among patients receiving Tocilizumab were significantly higher than those among patients receiving placebo, and the magnitude of these changes was similar for the SDAI and the CDAI. Among patients who achieved 50% improvement in disease activity according to the American College of Rheumatology criteria, only ∼20% required a reduction in acute-phase reactant values in order to fulfill the criteria. However, DAS28 remission rates were higher (even when using the lower cut point) than the SDAI and CDAI remission rates. Only a minority of Tocilizumab-treated patients with DAS28 remission also had disease remission according to the SDAI (26%) or CDAI (∼21%). With infliximab treatment, SDAI and CDAI remission rates were of the same magnitude as those observed with Tocilizumab treatment, and DAS28 remission rates were lower. Tocilizumab-treated patients with DAS28 remission but without CDAI remission had significantly higher swollen joint counts but lower erythrocyte sedimentation rates (ESRs) compared with patients with SDAI or CDAI remission. Conclusion Disease activity in RA is reduced by Tocilizumab treatment, irrespective of the type of composite measure used to evaluate disease activity. Remission rates were much higher using the DAS28 compared with the SDAI and CDAI, due to the high weight of the ESR in the DAS28 and the effect of Tocilizumab on the ESR. Using the stringent SDAI and CDAI criteria, however, remission rates in patients treated with Tocilizumab were in the same range as those seen in patients treated with tumor necrosis factor inhibitors.
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double blind randomized controlled clinical trial of the interleukin 6 receptor antagonist Tocilizumab in european patients with rheumatoid arthritis who had an incomplete response to methotrexate
Arthritis & Rheumatism, 2006Co-Authors: Ravinder N Maini, K Pavelka, Peter C Taylor, J Szechinski, J Broll, G Balint, Paul Emery, F Raemen, Jorgen Holm Petersen, Josef S SmolenAbstract:Objective To establish the safety and efficacy of repeat infusions of Tocilizumab (previously known as MRA), a humanized anti–interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). Methods The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: Tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. Results A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of Tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of Tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of Tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of Tocilizumab. In the majority of patients who received 8 mg/kg of Tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of Tocilizumab plus MTX. Conclusion These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.
