Treatment of Rheumatoid Arthritis with Biological AgentsHiroaki Matsuno1[1] Matsuno Clinic for Rheumatic Diseases, Japan1.
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial.
Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.
Golimumab, a human antibody to tumour necrosis factor ? given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study.
Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.

Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial.
Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Tocilizumab (TCZ) monotherapy is superior to adalimumab (ADA) monotherapy in reducing disease activity in patients with rheumatoid arthritis (RA): 24-week data from the phase 4 ADACTA trial. Treatment of rheumatoid synovitis with anti-reshaping human interleukin-6 receptor monoclonal antibody: use of rheumatoid arthritis tissue implants in the SCID mouse model.
Types of Cytokine Inhibitors (Biological Agents) and their effects on Rheumatoid ArthritisCytokine inhibitors used in the treatment of rheumatoid arthritis are inhibitors of IL-1 (anakinra), TNF (infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol), and IL-6 (tocilizumab). Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.
In addition, biological agents other than cytokine inhibitors used in the treatment of rheumatoid arthritis include abatacept, which inhibits the action of T-cell co-stimulatory molecules CD80 and CD86, and rituximab, which targets CD20.These drugs each have a stronger effect than methotrexate(MTX), which is considered to be most effective taken orally, and each has strong action to suppress bone and joint destruction (Figure 3, Figure.

When such an antibody is used as a therapeutic agent in humans, it causes a strong anaphylactic reaction.
Recommendations for the Use of Biological AgentsOpinion is divided on which biological agent should be used to start with when active rheumatoid arthritis is diagnosed.
Among typical rankings for the use of biological agents, there is the 2012 recommendation of the American College of Rheumatology (Figure 5) [20].According to this recommendation, in the United States the first biological agent (1st Bio) recommended for treatment of early rheumatoid arthritis with disease duration of less than 6 months is a TNF inhibitor. Selecting Biological Agents by Efficacy and SafetyAmong TNF inhibitors, there are several biological agents to choose from, with no strict standards for which biological agent to use first in either the United States or the United Kingdom.
Recently however, data has begun to accumulate suggesting which usage is best.Regarding efficacy, there is data indicating that etanercept is more effective than infliximab for active rheumatoid arthritis with high levels of anti-cyclic citrullinated peptide antibodies and rheumatoid factor [28]. In addition, among infliximab, adalimumab, and etanercept, it is reported that etanercept shows the highest efficacy in patients with high levels of anti-SS-A antibody [29].With respect to adverse reactions, the occurrence of tuberculosis among patients treated with anti TNF agents has been shown to be low for the fusion protein preparation etanercept and high for the antibody preparations infliximab and adalimumab. Therefore, from the point of view of adverse reactions, etanercept may be the best choice for rheumatoid arthritis patients with a risk of tuberculosis.The same could possibly be considered for tocilizumab, an IL-6 inhibitor which does not directly suppress macrophage function.

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