Management of inadequate response to TNF-α antagonist therapy in rheumatoid arthritis: what are the options?

摘要

The advent of tumor necrosis factor (TNF)-α antagonists for the treatment of rheumatoid arthritis (RA) has led to considerable improvements in effective disease management in patients with an inadequate response to traditional disease-modifying antirheumatic drugs. However, the available TNF-α antagonists have yet to meet the needs of all patients with RA; some patients may have an inadequate clinical response, lose their responsiveness over time, experience unacceptable side effects or have medical issues precluding the use of these medications. An inadequate response is generally determined in the context of a deteriorating clinical state, although there is no standardized definition. This review evaluates the role of two newly available biologic therapies - rituximab and abatacept - within the challenging treatment context of patients who fail to have an adequate response to TNF-α antagonists. Both medications downregulate the immune inflammatory reaction, albeit via different mechanisms, and have been shown to impede the progression of joint deterioration, providing potential options for these difficult-to-treat patients. Editorial support for this manuscript was funded by Bristol-Myers Squibb Introduction The success of biologic disease-modifying antirheumatic drugs (DMARDs) targeting tumor necrosis factor (TNF)-α has dramatically raised therapeutic expectations in rheumatoid arthritis (RA). Outcomes that previously were seldom achieved are now realistic treatment goals. Three drugs of this class have received United States (US) Food and Drug Administration approval for use in patients who have previously demonstrated an inadequate or failing response to traditional DMARDs, such as methotrexate (MTX), etanercept (Enbrel?, Amgen, Thousand Oaks, CA), infliximab (Remicade?, Centrocor, Malvern, PA) and adalimumab (HUMIRA?, Abbott Laboratories, Chicago, IL) (1,2,3,4).Despite the proven efficacy of TNF-α antagonists, these agents have yet to meet the needs of all patients (5). A significant number of patients fail to respond satisfactorily to TNF-α antagonists, do not respond at all (3,4,6), or show an initial improvement but lose responsiveness over time (7). In some patients, this may be the result of antibody formation against the biologic therapy, thereby mitigating its efficacy (8). Other patients are ineligible for TNF-α antagonists treatments due to injection/infusion reactions (5) or the development of adverse toxicity issues, such as recurring infections or various skin conditions (7,9). Moreover, the presence of comorbid conditions, such as significant congestive heart failure, recurring/chronic infections and demyelinating diseases, precludes the use of these biologic agents (10). Until recently, treating patients who experienced an inadequate response to TNF-α antagonists posed a significant problem to the rheumatologist, as there were limited alternatives. This left a treatment void in a patient population that typically has active and/or unremitting disease despite the fact that they have progressed a substantial way through the RA treatment paradigm.The purpose of this review is to evaluate strategies for treating patients with an inadequate response to TNF-α antagonist therapy, for whom there exists an unmet treatment need. Defining an adequate response to treatment There is no clear consensus on what constitutes an inadequate response to TNF-α antagonist therapy. It is generally anticipated that using maximum dosing regimens of TNF-α antagonists should lead to significant, durable improvements in clinical manifestations and laboratory parameters within 12 weeks (11,12). When this is not achieved, the decision to escalate a current therapy, prescribe an additional DMARD or switch to another medication is frequently challenging.Since RA is a heterogeneous disease, responses to a particular medication can vary markedly from patient to patient. Individual patients often exhibit differences in their response to stan