Background Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad eff ects on immune and inflammatory responses. Our aim was to assess the therapeutic eff ects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis.

Methods In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratifi ed by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10–25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was off ered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20%
improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria(ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov,number NCT00106548.

Findings The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4·0 [95% CI 2·6–6·1], p<0·0001 for 8 mg/kg vs placebo; and 2·6 [1·7–3·9], p<0·0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the
placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group.

Interpretation Tocilizumab could be an eff ective therapeutic approach in patients with moderate to severe active rheumatoid arthritis.

Tocilizumab is the new kid on the block with regards to biologic agents for rheumatoid arthritis. It has been recently licensed for use by the FDA in moderate to severe RA in those who have failed at least one anti TNF agents. It has yet to be licensed in Malaysia although it will only be a matter of time.

Several concerns were brought about by this paper. In particular was the increase in risk of infection, which was directly proportional to the dose given. Although the absolute numbers were small for significant severe infections, it remains a concern.

The levels of cholesterol were noted to increase after the administration of tocilizumab highlighting the role of cytokines in cholesterol metabolism. It fortunately did not translate into a higher incidence of cardiovascular events. Could this effect be due to its potent anti-inflammatory actions?

However, Tocilizumab is a useful agent for the treatment of rheumatoid arthritis with improvements in the ACR scores, which includes the number of tender and swollen joints; the patient’s and doctor’s assessment of how well the patient is doing; the amount of pain present; ability to perform physical activities; and results of blood tests that monitor inflammation (e.g., CRP).

It also appears not to have an effect on reactivation of Tuberculosis due to its inhibition of IL6, which is thought to be an important cytokine in TB reactivation.

The cost remains an issue and we will be awaiting earnestly for Roche to announce the drug price in the near future.