Two studies published in the March 22, 2008 issue of The Lancet indicate that the anti-arthritis drug tocilizumab can be effective in adults or children.

Adult rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the patient systemically. It is associated with progressive joint damage, pain, fatigue, and disability. Systemic-onset juvenile idiopathic arthritis (SOJIA) is a more specific type of childhood diabetes with an unknown cause. Both conditions are related to the activity of the cytokine compound interleukin 6, which is involved in the activation of cells in the inflammatory response. These studies both attempted to examine the effects of interleukin 6 receptor inhibition using the drug tocilizumab.

In the first of the two investigations, Professor Josef Smolen, Division of Rheumatology, Medical University of Vienna, Austria, and colleagues, performed a phase III trial of 623 adults with moderate to severe rheumatoid arthritis. The patients were randomly assigned to receive tocilizumab intravenously every four weeks at one of the following doses: 8 mg/kg body weight (205 patients), 4 mg/kg (214 patients) or a placebo (204). This was paired in all groups with 10-25 mg doses each week of methotrexate, an arthritis drug that has shown to be stable before the study at these concentrations. The primary endpoint of the study was the proportion of patients maintaining 20% improvement in symptoms of RA, according to criteria set forward by the American College of Rheumatology, also referred to as an ACR20 response.

More ACR 20 responses were recorded in tocilizumab patients than in the placebo group. That is, at 24 weeks, this was true for 59% of the patients given 8 mg/kg, 48% given 4 mg/kg, and 26% given the placebo. Patients in the 8 mg/kg were four times more likely to give an ACR20 response than the placebo, and patients in the 4 mg/kg group were more than two and a half time more likely than a placebo.

The researchers also reported the instances of many types of adverse events ranging from  headache or rash to exacerbation of the condition. There were more instances of tocilizumab users experiencing at least one adverse event of some type, usually serious infections, which were reported by 6 patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group.

The authors of this first Article conclude with optimistic thoughts for the drug. “These data provide evidence that inhibition of interleukin-6-mediated proinflammatory effects significantly and rapidly improves the signs and symptoms of rheumatoid arthritis. Thus tocilizumab could be an effective agent for the treatment of patients with moderate to severe rheumatoid arthritis.”

In the second investigation, children and young adults with systemic-onset juvenile idiopathic arthritis were examined. Professor Shumpei Yokota, Department of Paediatrics, Yokohama City University School of Medicine, Japan, and colleagues performed a phase III study of 56 patients aged 2-19 years whose symptoms had not improved under the standard arthritis treatment regimen, which is very common for this condition.

In the study, each of the subjects was administered three doses of tocilizumab at 8 mg/kg every two weeks for a six week lead in period. At this point, selection was made for those patients who achieved an American College of Rheumatology Pediatric 30 (ACR Pedi 30) response while displaying a concentration of the acute phase marker C-reactive protein (CRP) of less than 15 mg/L. These patients were then randomly assigned to receive a placebo or to continue the regimen of tocilizumab treatment for 12 weeks. The primary endpoint for the study was an ACR Pedi 30 response and CRP concentrations of less than 15 mg/L. Patients who responded to tocilizumab who needed further treatment were enrolled in an extension phase for a minimum of 48 weeks.

Of the 56 original patients, 43 were selected for the stage of randomization. Of the group receiving tocilizumab, 80% (16 out of 20) maintained the ACR Pedi 30 response and a CRP of less than 15 mg/L. In contrast, 17% achieved this in the placebo group. The 48 week extension phase was entered by 48 patients, and of these, ACR Pedi 30, 50, and 70 responses were achieved by a cumulative 98% (47 patients), 94% (45 patients), and 90% (43 patients) respectively. Serious adverse events reported included gastrointestinal bleeding, bronchitis, and gastroenteritis.

This study’s authors conclude with conservatively optimistic comments about the drug. “The results of this placebo-controlled and open-label extension study with tocilizumab in children with systemic-onset juvenile idiopathic arthritis show a sustained clinical improvement and a favourable risk-benefit profile. The findings of this study might represent a step forward in the control of a disease that has previously proved to be difficult to manage.”

Dr Tim Bongartz, Department of Internal Medicine and Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA, contributed a comment accompanying both of these articles in the same issue of The Lancet, in which he expressed more hopeful sentiments. “I am excited about the ongoing expansion of therapeutic options for rheumatoid arthritis, and especially, systemic juvenile idiopathic arthritis.” He does point out, however, that the tocilizumab therapy tests for these disorders do not yet provide enough information for a comprehensive treatment decision based on comparison with other effective arthritis treatments.

Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial

Josef S Smolen, Andre Beaulieu, Andrea Rubbert-Roth, Cesar Ramos-Remus, Josef Rovensky, Emma Alecock, Thasia Woodworth, Rieke Alten, for the OPTION Investigators
The Lancet, Vol 371, March 22, 2008
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Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial
Shumpei Yokota, Tomoyuki Imagawa, Masaaki Mori, Takako Miyamae, Yukoh Aihara, Shuji Takei, Naomi Iwata, Hiroaki Umebayashi, Takuji Murata, Mari Miyoshi, Minako Tomiita, Norihiro Nishimoto, Tadamitsu Kishimoto
The Lancet, Vol 371, March 22, 2008
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Tocilizumab for rheumatoid and juvenile idiopathic arthritis
Tim Bongartz
The Lancet, Vol 371, March 22, 2008
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Written by Anna Sophia McKenney