Strategies after the failure of the first anti-tumor necrosis factor α agent in rheumatoid arthritis

Abstract

During the last two decades fundamental changes have taken place in the treatment of patients with rheumatoid arthritis (RA). The effective establishment of methotrexate as the anchor drug and the introduction of new drugs, in particular anti-tumor necrosis factor (TNF) α blockers and the novel biologics have made the goal of remission feasible for plenty of RA patients. However, almost 14–38% of patients do not respond to first-line anti-TNF-α treatment at all and as many as 40% discontinue these drugs within a year and 50% within 2 years. Currently, no recommendations exist as regards the treatment of RA patients after TNF-α-antagonist failure. In this review the issue of anti-TNF-α therapy failure is discussed. Further, the various options for overcoming the apparent failure are explored according to evidence from the published literature.

Introduction

Rheumatoid arthritis (RA) is a chronic disease affecting almost 0.5–1% of the population [1]. Through chronic synovial inflammation, it causes destructive changes to articular cartilage and bone leading to various deformities, while it is often accompanied by extra-articular features, such as rheumatoid nodules, pleuritis, ocular inflammation, generalized osteoporosis, cardiovascular disease and amyloidosis. The patients experience pain, distress, loss of function in daily living, permanent disability and an increase in overall morbidity and mortality compared to the general population [2], [3]. Given the considerable burden of the disease, both on the individual and the community level, a great deal of scientific work during the past 30 years has fundamentally changed the way the disease is regarded and treated. One should distinguish three crossroads in this pursuit, each often being the starting point for the other: the advances in basic research have deciphered to a significant depth the pathogenesis of the disease, putting various players (genes, environment, cells, cytokines, receptors etc) and their sophisticated interactions down on a complex pathogenetic map. Once the suspects had been identified and with the aid of advances in pharmacology, new treatment options rose leading to the era of targeted therapies, like anti-tumor necrosis factor (TNF) α, anti-B-cell therapies etc. Finally, clinical trials and long-term observations on thousands of patients have helped forge treatment strategies in RA.

Indeed, based on the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recent recommendations [4], [5], in every patient with inflammatory polyarthritis treatment should be initiated as early as possible, even if the ACR criteria for RA classification are not fulfilled. Treatment should aim for remission and should always include a disease-modifying anti-rheumatic drug (DMARD), with methotrexate (MTX) as the anchor drug. If the patient does not respond adequately to DMARD monotherapy, then a modification of the DMARD dose should be made or another drug should be added in combination, the latter drug being another DMARD or a biologic agent. So far, it is the TNF-α blockers that have almost universally been used as the first biologic agent in RA. Although abatacept has also been approved in the United States for treating RA as the first biologic drug and tocilizumab has recently been approved in the European Union for use after first DMARD failure, the largest experience with a biological agent in this setting still concerns the three TNF-α blockers, infliximab, etanercept and adalimumab. However, there are no recommendations regarding how to treat patients after the first anti-TNF-α drug has failed.