EULAR 2006: 7th Annual European Congress of Rheumatology

2006年6月21－24日

荷兰阿姆斯特丹

June 21 - 24, 2006, Amsterdam, the Netherlands

Developments With Established Biologic Agents

Arthur Kavanaugh, MD University of California at San Diego

Introduction

At the recent 2006 European League Against Rheumatism (EULAR) meeting, a number of abstracts and presentations focused on important new information concerning the efficacy and safety of established biologic agents. Many studies described the inhibitors of the central proinflammatory tumor necrosis factor (TNF).

Update on the BeSt Trial

One of the most eagerly anticipated sets of results came from the 3-year analysis of data from the initial combination therapy with methotrexate and infliximab (BeSt) study, a trial that will surely be considered one of the landmark studies in rheumatology. It addresses the optimal treatment paradigm for patients with early rheumatoid arthritis (RA). This study, initiated in The Netherlands in April 2000, involved 508 patients with early RA (defined as < 2 years of arthritis) randomized to 1 of 4 treatment arms:

• sequential monotherapy (beginning with methotrexate [MTX]);
  
  
• step-up combination therapy (also beginning with MTX);
  
  
• initial combination therapy with MTX, sulfasalazine (SSZ), and high-dose prednisone (as was used in the earlier COBRA study); and
  
  
• initial combination therapy with MTX plus a TNF inhibitor (infliximab).

In all arms, the goal was to achieve low levels of disease activity. At their 3-monthly follow-up visits, patients not achieving this goal, defined by a disease activity score (DAS) of 2.4 or less, were required to have their treatment altered according to an algorithm specific for each group. Eventually, groups 1, 2, and 3 could end up on MTX plus a TNF inhibitor. If patients did achieve low disease activity on 2 successive visits, treatment was tapered (to a minimum of MTX 10 mg/wk over the first 2 years, and off all therapy after the second year). Data from the 12-month and 2-year analyses of this pivotal study have been presented at previous scientific meetings and also have been published.^[1] In summary, patients in groups 3 and 4 achieved low disease activity and even remission quicker than did those in groups 1 and 2, although as might have been expected given the study design with its mandatory changes in therapies, clinical efficacy was comparable across all groups by 2 years. However, the progression of joint damage measured radiographically was less in groups 3 and 4 through the first 2 years of the study.

At EULAR 2006, a number of abstracts with exiting new information from the BeSt study were presented. In one analysis, investigators assessed the effect of tight control of disease activity on radiographic progression — specifically, the association between x-ray changes and known factors that have previously been shown to predict such damage, including the presence of the major histocompatibility antigen HLA-DR4, the shared epitope (SE), rheumatoid factor (RF), and antibodies to cyclic citrullinated peptides (CCP).^[2] Of note, in all groups, tight control of disease resulted in the dissociation of risk between x-ray change and the presence of HLA-DR4 or the SE. Furthermore, in groups 3 and 4, the association between x-ray progression and the presence of RF or anti-CCP antibodies was also eliminated. This suggests that treatment using such a tight control strategy, and in particular tight control with highly effective therapeutic strategies, can be the most important determinant of outcome in early RA.

In earlier analysis of the 2-year data, it was shown that 54% of the patients in group 4, who initially began treatment with MTX plus infliximab, did so well that they were able to taper off the TNF inhibitor. A presentation at EULAR 2006 provided further follow-up of this group.^[3] Remarkably, at 3 years, 66 patients, representing 55% of the 120 early RA patients beginning treatment in group 4, remained at a low level of disease activity off the TNF inhibitor. Perhaps even more notably, 14% of the 120 patients achieved remission according to DAS criteria (DAS < 1.6) while off all therapy. Thus, in early RA, the use of MTX plus a TNF inhibitor in a tight control paradigm may be effective at inducing remission and truly altering the course of RA for a subset of patients. Results from further patient follow-up are eagerly awaited, as is additional information concerning functional status and radiographic progression. Nevertheless, the idea of tapering therapy has relevant implications for safety considerations and for pharmacoeconomic analyses.

Safety Issues

Safety issues are always of concern with immunomodulatory therapies, and there were several presentations at EULAR 2006 on this topic. The use of any agent that alters immune function raises the possibility of certain adverse effects — for example, infection and malignancy. This issue is one that has been of growing concern in rheumatology, with the introduction and study of ever-increasing numbers of biologic agents that target various components of the immune system. Interesting data from the British Society for Rheumatology Biologics Registry (BSRBR) shed some light on risk factors for cancer potentially related to the use of TNF inhibitors.^[4] In this analysis, data from 9999 RA patients who received TNF inhibitors were compared with that from 1877 RA patients who received other treatments for RA, including various disease-modifying antirheumatic drugs (DMARDs), but did not receive TNF inhibitors. The authors found that when adjusted for important risk factors, including age, sex, disease severity, and smoking history, patients who received a TNF inhibitor had a comparable — or even perhaps a lower — incidence of developing cancers compared with RA patients on DMARDs alone. However, when analysis focused on patients who had already had a cancer previously, the risk for newly developing cancer was increased among patients receiving TNF inhibitors. Of note, even though the result was statistically significant, the actual numbers were small; 6 patients with a history of cancer newly developed cancer after therapy with a TNF inhibitor. While further analysis and larger numbers of patients are needed, this suggests that a history of a previous malignancy may place RA patients receiving TNF inhibitors at greater risk for newly developing cancer.

As a side point, this study shows the usefulness of registries as a way to accrue large populations of heterogeneous patients and thereby explore important clinical associations that might never be discovered in a clinical trial. Another study also took advantage of a very large dataset to address the potential association between therapy with TNF inhibitors and a particular type of cancer, lymphoma, that is known to be more common among RA patients than the general population, particularly those with severe active RA. In this study, the authors assessed data from more than 22,000 patients with RA, and also from over 6000 persons with various noninflammatory rheumatic diseases as a control.^[5] As has been noted previously, lymphoma was more common among the RA patients, with a relative risk of 1.8. The authors then assessed whether any treatment predisposed patients to a greater risk of developing lymphoma. Of note, none of the treatments assessed, including all of the TNF inhibitors individually or combined, was associated with an increased risk for lymphoma. Thus, while clinicians caring for RA pa