OP0001: Inhibition of Structural Damage Progression
OP0012: 1-Year Results of the ASSURE Trial

OP0001 ABATACEPT SIGNIFICANTLY INHIBITS STRUCTURAL DAMAGE PROGRESSION AS ASSESSED BY THE GENANT-MODIFIED SHARP SCORING SYSTEM IN RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE METHOTREXATE RESPONSES
H. Genant, C. Peterfy, S. Paira, J. Gomez-Reino, Y. Miaux, C. Wu, Y. Jiang, M. Sieffert, Z. Ge, R. Aranda, J. Becker, P. Emery

The Abatacept in Inadequate responders to Methotrexate (AIM) study was a 1-year, placebo controlled Phase III trial using a fixed dose of abatacept (10mg/kg) in patients with active rheumatoid arthritis despite methotrexate (MTX) treatment. ACR response scores were highlighted previously (see prior highlights). This abstract examines the effect of abatacept on radiographic progression.

Patients were randomized to abatacept or placebo treatment on days 1, 15, 29, and every 28 days thereafter. Throughout the study, patients continued on a stable dose of MTX and one additional DMARD was allowed between 6 and 12 months. Hand and feet radiographs were taken at baseline and at one year (or before if a patient terminated the study early).

Results: The abatacept treated patients showed significantly greater inhibition of structural damage at one year compared to the placebo treated patients. The table below compares the mean scores for erosions, joint space narrowing and total score using Genant-modified Sharp scoring method.

Conclusion: Abatacept plus methotrexate inhibits radiographic progression of joint damage significantly better than placebo plus methotrexate.

Editorial comments: This is an important study to provide additional details of a disease-modifying effect of abatacept in RA patients. Data has previously been presented showing improvement in signs and symptoms in this group of patients with persistent disease activity in spite of MTX treatment. Data were briefly presented at ACR2004 showing inhibition of radiographic progression with abatacept.(see data) The study presented at EULAR provided additional details and showed a reduction in mean numbers of erosions and joint space narrowing by approximately 50% as well as in the combined total sharp score.

One caveat of this analysis is that the method used to assess radiographic progression in this study, the Genant-modified Sharp Scoring system, cannot be directly compared against radiographic outcome studies that have often used the Van der Heijde Modified Sharp Score, which records a higher number of sites for erosions and joint space narrowing with a slightly different scoring scale for erosions. The previously presented baseline characteristics of the patients in this study indicated relatively longstanding disease, but the baseline radiographic characteristics were not delineated thus making it difficult to extrapolate an anticipated rate of progression in each group. Additional information to demonstrate the proportion of patients who progressed in each group as well as probability plots showing this data in other forms will help to better place this data set in context, though direct comparisons between these results and those for other agents may be limited due to the differing methods chosen to score the films. Another confounder in the analysis of this data was the allowance of additional DMARD therapy after 6 months in the protocol. However, with all caveats aside, these data indicate that abatacept does have DMARD properties in addition to improving signs and symptoms for patients with established RA with an incomplete response to MTX.

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OP0012 SAFETY OF ABATACEPT IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS RECEIVING BACKGROUND NON-BIOLOGIC AND BIOLOGIC DMARDS: 1-YEAR RESULTS OF THE ASSURE TRIAL
M. Weinblatt, B. Combe, A. White, R. Aranda, J. Becker, E. Keystone

Abatacept has been shown to be efficacious in a similar patient group both in the AIM trial and in the ATTAIN trial. The purpose of the ASSURE (Abatacept Study of Safety in Use with other Rheumatoid arthritis therapies) trial is to assess the safety of combination therapy with abatacept and approved biologic and non-biologic DMARDs in patients with active rheumatoid arthritis.

In this study, patients were randomized to receive abatacept 10 mg/kg or placebo for one year in addition to either non-biologic or biologic background DMARDs. Medically stable co-morbidities were allowed.

Results: 1441 patients were enrolled. Among the co-morbidities were Type 1 or 2 diabetes (7%), asthma (6%), chronic obstructive pulmonary disease (4%), and congestive heart failure (1%). The drop-out rate was greatest in the placebo-treated patients compared to the abatacept-treated patients, 12.8% vs 19.2%, respectively. Adverse events and lack of efficacy were cited as the main reasons for discontinuation, abatacept (5.3% and 2.7%) and placebo (3.9% and 9.1%).

Conclusion: Abatacept and placebo have a similar safety profile when added to background DMARD therapy in patients with active RA and possible co-morbidities. However, abatacept added with background biologic therapy showed the least favorable profile with increased incidences of adverse events and infections.

Editorial Comments: This study is important in expanding our understanding of the combination of abatacept (10 mg/kg) with other DMARD Agents. Such studies provide important relevant clinical information regarding additional side effects for combinations of new therapies with other agents besides MTX that are commonly used in clinical practice.

A more than 2-fold increased rate of infection was demonstrated in patients treated with abatacept in combination with a biologic compared to abatacept alone, biologic alone, or placebo. Similarly increased rates of serious infection were also observed with abatacept with another biologic. Of some additional concern was an increased rate of neoplasms when combination biological therapy was used. It should be noted however the numbers of patients in this study who were receiving concomitant biological therapy were far fewer than the traditional DMARD comparator groups.

In patients receiving abatacept with nonbiological DMARDS, there was not a significant increase in the rate of infectious AEs compared to comparators who received placebo or other biologics without abatacept. Data had previously been presented (ACR Highlights 2002 Abstract 464-Weinblatt et al) showing a combination of abatacept at a lower dose of 2 mg/kg with etanercept showed some additional efficacy in patients who were not responding well to etanercept. However in the current study, which allowed TNF antagonists to be combined with a higher dose of abatacept (10mg/kg), additive toxicity was seen. Whether this will be balanced with proportionate increases in efficacy remains to be determined.

Based on this data as well as the previously presented data showing increased infectious adverse events with anakinra combined with etanercept, the use of combination biological DMARD therapies should be restricted to the careful and watchful conditions of a controlled clinical trial. Longer term evaluation to determine the potential impact of multimodal targeted therapies on tumor surveillance as well as opportunistic and nonopportunistic infections is also needed.

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