Interleukin‐6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease‐modifying antirheumatic drugs: The tocilizumab in combination with traditional disease‐modifying antirheumatic drug therapy study

Abstract

Objective. To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional diseasemodifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA).Methods. A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebocontrolled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.Results. At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P < 0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28 <2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients ClinicalTrials.gov identifier: NCT00106574.

Targeting Interleukin-6 in Rheumatoid Arthritis

“…Combination therapy with methotrexate at least at the start of the treatment, is still the preferred choice of administration to the patients due to better numerical values in the study results in terms of clinical efficacy. Combination with other sDMARDs such as hydroxychloroquine, sulfasalazine and leflunomide was also effective without notable differences [51,79]. Combination therapy however is associated with an increased risk of elevated transaminases.…”

“…Mycobacterium avium intracellulare after found to have an abnormality on a chest xray [51]. The main safety profiles are summarised in Table 3.…”

Anti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases

“…Seven Phase III clinical trials of tocilizumab carried out in Japan and worldwide revealed its efficacy both as monotherapy or combined with disease modifying anti-rheumatic drugs (DMARDs) for adult patients with moderate to severe RA [36][37][38][39][40][41][42]. Moreover, the SAMURAI [36] and LITHE studies [41] proved that radiological damage of joints was significantly inhibited by tocilizumab treatment.…”

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

“…As an intravenous (IV) formulation, TCZ has already been approved in Japan for the indications of RA, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, and Castleman's disease. In monotherapy and combination therapy with methotrexate or other disease‐modifying antirheumatic drugs (DMARDs), TCZ‐IV is clinically effective, prevents structural joint damage, and improves physical function 2, 3, 4, 5, 6, 7, 8.…”