Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study
TL;DR: 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.
Abstract: 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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Medical University of Vienna1, University of Amsterdam2, Leiden University Medical Center3, Leeds Teaching Hospitals NHS Trust4, Chapel Allerton Hospital5, Humboldt State University6, Oregon Health & Science University7, Utrecht University8, VU University Medical Center9, University of Montpellier10, University of Belgrade11, Erasmus University Rotterdam12, University of Paris-Sud13, Charles University in Prague14, Radboud University Nijmegen Medical Centre15, University of Cologne16, Weston Education Centre17, Tufts University18
TL;DR: These recommendations intend informing rheumatologists, patients, national rheumology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.
Abstract: In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at
4,730 citations
Cites background from "Comparison of tocilizumab monothera..."
...Recent data suggest that monotherapy with tocilizumab is more effective than monotherapy with DMARDs such as MTX...
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01 Jan 2011
TL;DR: Recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA based on evidence and expert opinion.
Abstract: Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
3,485 citations
Medical University of Vienna1, Maastricht University2, Leiden University3, Paris Descartes University4, University of Leeds5, Pierre-and-Marie-Curie University6, Utrecht University7, Humboldt State University8, University of Montpellier9, University of Genoa10, University of Santiago, Chile11, Autonomous University of Madrid12, University of Glasgow13, Charles University in Prague14, Radboud University Nijmegen15, King's College London16, Sapienza University of Rome17, Karolinska Institutet18, Oregon Health & Science University19, Tufts University20, Charité21
TL;DR: In this article, the authors present a set of recommendations for the treatment of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects.
Abstract: Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-a-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
1,372 citations
TL;DR: This review will discuss a wide range of evolving data leading to the current hypotheses regarding the role of immune activation and inflammation in OA onset and progression as this is the joint most well characterized by epidemiologic, imaging, and translational studies investigating the association of inflammation with OA.
Abstract: Osteoarthritis (OA) has traditionally been classified as a noninflammatory arthritis; however, the dichotomy between inflammatory and degenerative arthritis is becoming less clear with the recognition of a plethora of ongoing immune processes within the OA joint and synovium. Synovitis is defined as inflammation of the synovial membrane and is characteristic of classical inflammatory arthritidies. Increasingly recognized is the presence of synovitis in a significant proportion of patients with primary OA, and based on this observation, further studies have gone on to implicate joint inflammation and synovitis in the pathogenesis of OA. However, clinical OA is not one disease but a final common pathway secondary to many predisposing factors, most notably age, joint trauma, altered biomechanics, and obesity. How such biochemical and mechanical processes contribute to the progressive joint failure characteristic of OA is tightly linked to the interplay of joint damage, the immune response to perceived damage, and the subsequent state of chronic inflammation resulting in propagation and progression toward the phenotype recognized as clinical OA. This review will discuss a wide range of evolving data leading to our current hypotheses regarding the role of immune activation and inflammation in OA onset and progression. Although OA can affect any joint, most commonly the knee, hip, spine, and hands, this review will focus primarily on OA of the knee as this is the joint most well characterized by epidemiologic, imaging, and translational studies investigating the association of inflammation with OA.
754 citations
TL;DR: All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases.
Abstract: IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6-sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.
675 citations
References
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TL;DR: The Modified DAS that included 28-joint counts were able to discriminate between high and low disease activity (as indicated by clinical decisions of rheumatologists) and are as valid as disease activity scores that include more comprehensive joint counts.
Abstract: Objective. The development and validation of Modified Disease Activity Scores (DAS) that include different 28-joint counts.
Methods. These scores were developed by canonical discriminant analyses and validated for criterion, correlational, and construct validity. The influence of disease duration on the composition of the DAS was also investigated.
Results. No influence of disease duration was found. The Modified DAS that included 28-joint counts were able to discriminate between high and low disease activity (as indicated by clinical decisions of rheumatologists).
Conclusion. The Modified DAS are as valid as disease activity scores that include more comprehensive joint counts.
5,718 citations
Boston University1, American College of Rheumatology2, University of Toronto3, Virginia Mason Medical Center4, McMaster University5, Food and Drug Administration6, University of Kentucky7, University of California, Los Angeles8, Stanford University9, Brigham and Women's Hospital10, University of Utah11
TL;DR: The results suggest that the definition of improvement presented is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved, which the authors hope will be used widely in RA trials.
Abstract: Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.
2,593 citations
"Comparison of tocilizumab monothera..." refers background in this paper
...The primary end point was the proportion of patients with an ACR20 response at week 24....
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TL;DR: Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.
2,411 citations
TL;DR: Current slow-acting antirheumatic drugs have limited efficacy and many side effects and do not improve the long-term prognosis of rheumatoid arthritis.
Abstract: Rheumatoid arthritis is a common chronic inflammatory and destructive arthropathy that cannot be cured and that has substantial personal, social, and economic costs. The long-term prognosis is poor: 80 percent of affected patients are disabled after 20 years,1 and life expectancy is reduced by an average of 3 to 18 years.2 The medical cost of rheumatoid arthritis averages $5,919 per case per year in the United States3 and approximately £2,600 per case per year in the United Kingdom.4 Current slow-acting antirheumatic drugs have limited efficacy and many side effects. Moreover, they do not improve the long-term prognosis of rheumatoid arthritis. . . .
2,180 citations
"Comparison of tocilizumab monothera..." refers background in this paper
...Rheumatoid arthritis (RA) is a systemic inflammatory disease characterised by joint pain, stiffness and swelling due to synovial inflammation, as well as fatigue and limitations in physical function, and increased morbidity and mortality....
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TL;DR: Subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.
Abstract: Background Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. Methods We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. Results As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, ...
1,789 citations
"Comparison of tocilizumab monothera..." refers background in this paper
...To date, there is limited evidence that monotherapy with other treatments is better than methotrexate, as neither etanercept nor adalimumab monotherapy were statistically better than methotrexate in standard clinical efficacy parameters at 24 weeks in the ERA, TEMPO, and PREMIER trials....
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