The anti-arthritis drug tocilizumab has proven effective in two separate trials, one involving adults, the other children. These are the conclusions of two Articles in this week's edition of The Lancet.
Rheumatoid arthritis (RA) of adults is a systemic autoimmune inflammatory disease associated with progressive joint damage, pain, fatigue, and disability; while systemic-onset juvenile idiopathic arthritis (SOJIA) is a subtype of chronic childhood arthritis of unknown cause. In both conditions, the cytokine compound interleukin 6 is involved in activation of the cells of the immune system, helping cause inflammation. The authors of both studies aimed to assess the effects on blocking the interleukin 6 receptor using tocilizumab.
In the first Article, Professor Josef Smolen, Division of Rheumatology, Medical University of Vienna, Austria, and colleagues, did the OPTION study - a phase III trial of 623 adults with moderate to severe RA. The patients were randomised to receive tocilizumab 8mg / kg body weight (205 patients), tocilizumab 4mg / kg (214) or placebo (204) intravenously every four weeks, along with the arthritis drug methotrexate at stable pre-study doses of 10-25mg per week. The primary endpoint of the study was the proportion of patients with at least 20% improvement in signs of RA according to the American College of Rheumatology criteria (ACR20 response)*.
The researchers recorded more ACR20 responses in tocilizumab patients than placebo patients. At 24 weeks, 59% of patients in the 8mg/kg group, 48% in the 4mg/kg group, and 26% in the placebo group had recorded an ACR20 response. Patients in the 8mg group were four times more likely to give an ACR20 response versus placebo, while those in the 4mg group were more than two-and-a-half times more likely to give an ACR20 response than placebo. More people receiving tocilizumab had at least one adverse event. The most common serious adverse events were serious infections, reported by six patients in the 8mg group, three in the 4mg group and two in the placebo group.
The authors conclude: "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 Article, Professor Shumpei Yokota, Department of Paediatrics, Yokohama City University School of Medicine, Japan, and colleagues did a phase III study of 56 children and young adults with SOJIA whose symptoms had not improved with conventional arthritis treatments, a common problem with this condition.
Each of the 56 patients (aged 2-19 years) was given three doses of tocilizumab 8mg./g every 2 weeks during a 6-week lead-in phase. Patients achieving an American College of Rheumatology Pediatric 30 (ACR Pedi 30)** response and a C-reactive protein*** concentration (CRP) of less than 5 mg/L were randomly assigned to receive placebo or to continue tocilizumab treatment for 12 weeks. The primary endpoint for the study was an ACR Pedi 30 response and CRP concentration of less than 15mg/L. Patients responding to tocilizumab and needing further treatment were enrolled in an extension phase for at least 48 weeks.
Of the 56 patients, 43 progressed to the randomisation stage. The researchers found 16 out of 20 patients (80%) receiving tocilizumab maintained the ACR Pedi 30 response and a CRP of less than 15 mg/L, compared with just 4 out of 23 (17%) in the placebo group. 48 patients entered the 48 week extension phase; and of these, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%) and 43 (90%) of patients respectively. Serious adverse events included gastrointestinal bleeding, bronchitis, and gastroenteritis.
The authors conclude: "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."
In an accompanying Comment, Dr Tim Bongartz, Department of Internal Medicine and Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA, says: "I am excited about the ongoing expansion of therapeutic options for rheumatoid arthritis, and especially, systemic juvenile idiopathic arthritis." However, he adds that the evidence on tocilizumab therapy for these disorders does not allow him to make a comprehensive treatment decision on the basis of comparative effectiveness and safety with other effective arthritis treatments.
Notes to editors: *ACR20 response: a composite improvement criterion based on 20% improvement in swollen and tender joint counts plus 20% improvement in 3 out of the following 5: patient's pain assessment, patient's global assessment of disease activity, physician's global assessment of disease activity, acute phase reactant levels (ESR or CRP), and physical function score
**ACR Pedi 30 response: A measurement of improvement of various symptoms, eg, number of joints with restriction of movement. The ACR Pedi 30 response means that at least 3 of 6 ACR Pedi 30 variables improved by at least 30% with no more than one variable worsening by more than 30%.
***C-reactive protein: A protein secreted by liver cells upon activation with mediators of inflammation (cytokines), in particular interleukin 6. CRP can be easily measured in peripheral blood (serum) and its levels reflect the level of inflammation ongoing in the affected tissues.
Professor Josef Smolen, Division of Rheumatology, Medical University of Vienna, Austria T) +43-1-40400-4300 E) Josef.smolen@meduniwien.ac.at / josef.smolen@wienkav.at
Professor Shumpei Yokota, Department of Paediatrics, Yokohama City University School of Medicine, Japan T) +81-45-787-2669 E) syokota@med.yokohama-cu.ac.jp
Dr Tim Bongartz, Department of Internal Medicine and Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA T) +1 507-255-5123 E) bongartz.tim@mayo.edu
PDF OF ARTICKE: http://multimedia.thelancet.com/pdf/press/arthritis.pdf
Journal
The Lancet