Future of RA: building on what we know and tailoring treatment

Biologic therapies beyond conventional DMARDs The articles in this supplement examined the pathogenesis of RA; the efficacy and safety of biologic agents, with a focus on tocilizumab, either as adjunct therapy in the case of failure of conventional DMARDs or as monotherapy; and pathways to designing effective RA treatments. The availability of biologic therapies with different mechanisms of action expands the therapeutic options for patients whose disease is inadequately controlled with conventional DMARDs and allows greater ability to tailor treatment individually. The pathobiology of RA is multifaceted and involves many cell populations, such as T cells, B cells, macrophages and fibroblasts, as well as the complex interaction of many pro-inflammatory cytokines, including TNF-α and IL-6. In addition to joint symptoms, many patients experience extra-articular or systemic manifestations, or both [1], although major extra-articular manifestations have become rare. Systemic manifestations include anaemia, cardiovascular disease, osteoporosis and fatigue [2]. Conventional DMARDs, such as MTX, are the mainstay of RA treatment. They can improve clinical symptoms, reduce joint damage and allow a subset of patients to achieve remission [3]. However, MTX alone may not fully control disease activity, and it is used in combination or triple therapy regimens with other DMARDs [4, 5]. In the past decade, the introduction of biologic agents has resulted in further improvements in clinical outcomes with a better effect on disease activity, structural damage and functional capacity [6]. Biologic compounds include anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab and golimumab), a B-cell-depleting anti-CD20 antibody (rituximab), a cytotoxic T-lymphocyte antigen-4 fusion protein (abatacept) that inhibits co-stimulation, an IL-1 receptor antagonist (anakinra) and now an IL-6 receptor inhibitor (tocilizumab). More than 50% of patients who receive anti-TNF agents do not achieve substantial clinical responses and only a small proportion achieve disease remission [7]. The four non-TNF inhibitors approved for use in RA patients—abatacept, rituximab, anakinra and tocilizumab—have been studied in large, randomized placebo-controlled trials that demonstrate their clinical efficacy in reducing disease activity in patients for whom TNF inhibitor therapy fails [8]. Four randomized, double-blind trials have compared biologic agent monotherapy with MTX monotherapy. The trials evaluated the TNF inhibitors etanercept and adalimumab and the IL-6 receptor antagonist tocilizumab. Studies involving monotherapy with TNF inhibitors found no clear advantage over MTX monotherapy for clinical efficacy; in the two trials that included a TNF inhibitor and MTX combination arm, combination therapy was superior to monotherapy with either agent alone [9–11]. Although etanercept monotherapy decreased symptoms and joint damage in patients with early RA more rapidly than MTX, clinical response at 12 months did not differ significantly between patients receiving the biologic agent and those receiving MTX [9]. Adalimumab monotherapy resulted in significantly less radiographic progression than MTX monotherapy; however, combination therapy proved better in reducing radiographic progression over 2 years than either of the monotherapy arms [11]. In contrast, the tocilizumab trials showed that monotherapy with tocilizumab was superior to that with MTX/DMARDs in terms of clinical response, disease activity, remission and functionality [12, 13]. RA is defined by the interrelated triad of disease activity, joint damage and disability [14]. Disease activity leads to both joint damage and disability, although disability related to disease activity is reversible and that related to joint damage is not [14]. Therapeutic attention should, therefore, focus on the maximum possible reduction of disease activity, thus halting joint damage accrual and leading to maximum disability reversal. Treatment should be initiated early and aggressively, with frequent assessments and a goal of achieving remission as quickly as possible after treatment initiation. Tight control is associated with disease remission and decreased risk of radiographic progression [15]. Treatment should be adjusted immediately for patients who do not exhibit any improvement by 3 months, and therapy should be switched for patients who do not achieve low disease activity (or, ideally, remission) within 6 months. The emergence of biologic agents for the treatment of patients with RA has significantly improved outcomes. However, use of biologic agents is associated with safety concerns, often related to the drug’s immunomodulatory properties. Major safety issues are serious infections (including tuberculosis), lymphoma and other malignancies, demyelinating disorders, hepatotoxicity, hyperlipidaemia, cardiotoxicity, injection-site reactions and acute infusion reactions. To optimize patient safety, patients should be carefully screened and monitored. The numerous immune mediators that contribute to the pathobiology of RA suggest that many targeted therapies provide favourable clinical outcomes. Ongoing studies are aimed at further elucidating how one can tailor a particular agent to a particular patient for optimal outcomes in all patients. The authors thank ApotheCom for writing and editorial assistance, which was funded by F. Hoffmann-La Roche Ltd. Funding: This study was funded by Roche. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. Supplement: This article forms part of the supplement ‘Current Treatment Options and New Directions in the Management of Rheumatoid Arthritis’. This supplement was commissioned and funded by F. Hoffmann-La Roche Ltd. Disclosure statement: E.C.K. is a consultant for and has received grant support from Roche. J.S. is a consultant for, received honoraria and research grant/research support from Roche.

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