Posted: August 27 2008 at 10:10pm

September, 2008 - CRA Journal Club: Review by Dr. HY TANNENBAUM   Lovell et coll.  NEJM 2008:359:810-20 - ADALIMUMAB WITH OR WITHOUT METHOTREXATE IN JUVENILE RHEUMATOID ARTHRITIS   Synthèse par le Dr. HY TANNENBAUM   LEARNING OBJECTIVES 1. ADALIMUMAB IS AN EFFECTIVE THERAPY IN THE MANAGEMENT OF POLYARTICULAR JUVENILE RHEUMATOID ARTHRITIS 2. CHILDREN TREATED WITH ADALIMUMAB HAVE FEWER FLARE UPS THAN THOSE WHO RECIVED PLACEBO IN THE DOUBLE BLIND PHASE OF THIS STUDY 3. CHILDREN RECEIVING ADALIMUMAB PLUS METHOTREXATE RESPONDED BETTER THAT THE GROUP TREATED WITH ADALIMUMAB MONOTHERAPY   4. RESPONSE TO ADALIMUMAB WAS COMPARABLE IF PATIENTS PREVIOULSY HAD BEEN TREATED WITH METHOTREXATE OR WERE METHOTREXATE NAIVE   This is the second paper published by Lovell et al  in the NEJM,  which demonstrates that anti-TNF therapy is effective in polyarticular JRA.  In 2002,  Lovell et al previously demonstrated that etanercept was efficacious in a similar cohort of patients and the present study extends this finding  to  adalimumab Conducting placebo-controlled trial in pediatric populations requires special consideration of the ethical issues associated with denying active treatment during a double-blind phase. The FDA  and the study designers agreed that the blinded, randomized MEDICATION-WITHDRAWAL DESIGN provided acceptable scientific rigor while minimizing exposure to placebo and the primary endpoint should be a comparison, in the no-methotrexate  stratum, between the percentage of patients with disease flares in the group receiving adalimumab and the group receiving placebo during the double-blind phase.   STUDY DESIGN : This was a randomized. double blind, placebo controlled trial  conducted in patients between the ages of 4 to 17 with polyarticular JRA who were unresponsive to NSAID’s.  Patients were at the outset stratified to those previously not treated with MTX or those previously  receiving MTX.  This was a medication withdrawal study with  a 16 week open label lead in phase in which all children received adalimumab every other week . a 32 week double blind withdrawal phase and an open label extension phase for up to 2 years.   RESULTS:   At week 16, upon completion of the open label phase, patients treated with adalimumab plus methotrexate  had a superior response in the ACR Pedi 30 score than those receiving adalimumab monotherapy (94% versus 74%). During the double-blind phase, in  patients concomitantly on  MTX,   up to 65%  on placebo and 37% on adalimumab had disease flares.  Those results were very similar if patients had  not been received MTX.  During the 2 years of adalimumab treatment in the open label extension phase, the ACR Pedi responses were sustained  including achievement of the ACR Pedi 100 responses by 40% of the patients.   Serious adverse events included 7 serious infections among which were pneumonias and herpes simplex and herpes zoster infections..     CONCLUSIONS:  Adalimumab administered with or without MTX, improved signs and symptoms in children with polyarticular JRA. Disease flares were significantly less frequent in children receiving adalimumab than among those receiving placebo Patients  previously treated or non treated with MTX had comparable frequency of flare ups in the double-blind withdrawal phase of the trial. Click HERE Full Text Article (PDF) ABSTRACT Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis Daniel J. Lovell, M.D., M.P.H., Nicolino Ruperto, M.D., M.P.H., Steven Goodman, M.D., Andreas Reiff, M.D., Lawrence Jung, M.D., Katerina Jarosova, M.U.Dr., Dana Nemcova, M.D., Richard Mouy, M.D., Christy Sandborg, M.D., John Bohnsack, M.D., Dirk Elewaut, M.D., Ph.D., Ivan Foeldvari, M.D., Valeria Gerloni, M.D., Jozef Rovensky, M.D., Ph.D., Kirsten Minden, M.D., Richard K. Vehe, M.D., L. Wagner Weiner, M.D., Gerd Horneff, M.D., Hans-Iko Huppertz, M.D., Nancy Y. Olson, M.D., John R. Medich, Ph.D., Roberto Carcereri-De-Prati, M.D., Melissa J. McIlraith, Ph.D., Edward H. Giannini, M.Sc., Dr.P.H., Alberto Martini, M.D., for the Pediatric Rheumatology Collaborative Study Group and the Pediatric Rheumatology International Trials Organisation ABSTRACT Background Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. Methods Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. Results Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. Conclusions Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542 [ClinicalTrials.gov] .) Source Information The authors' affiliations are listed in the Appendix. Drs. Lovell and Ruperto contributed equally to this article. Address reprint requests to Dr. Lovell at Cincinnati Children's Hospital Medical Center, Division of Rheumatology, Location E, Rm. 2-129, MLC 4010, 3333 Burnet Ave., Cincinnati, OH 45229-3039, or at daniel.lovell@cchmc.org.