Tests of TNF inhibitors for sciatica continue

Both mechanical and chemical factors contribute to development of radiculopathy associated with disk herniation, and while TNF- is part of the story, it isn’t the whole story. Dr Philippe Goupille (Hopital Trousseau, Tours, France) writes in the February 2006 issue of Annals of the Rheumatic Diseases that despite good theoretical underpinnings and excellent results in open-label pilot studies, the first controlled trial of a TNF inhibitor in sciatica did not find much treatment effect

“Although the rationale appears to be sound, there is no proof of the efficacy of such a treatment, and its use still has not been validated,” Goupille says.Disappointing RCT results raise interesting new questions Among the factors that suggested a potential benefit from use of TNF inhibitors in disk-herniation-associated radiculopathy are:- “Chemical” effects of herniated nucleus pulposus (NP) material that resemble effects of TNF-a. – Blocking of these effects by doxycycline and partial blocking by anti-TNF monoclonals. – Sensitization by TNF-a of nerve roots that have been subjected to mechanical stress. – Presence of TNF-a in neurons and Schwann cells.”TNF-a appears to be able to sensitize the nerve root to pain when the latter has previously been subjected to mechanical stress, a hypothesis that is compatible with current understanding of the physiopathology of disk-induced sciatica,” Goupille writes.Following good results in two open-label studies of infliximab (Remicade, Centocor) infusion in patients with sciatica and MRI-proven disk herniation, the first randomized, controlled, double-blind trial comparing infliximab (5 mg/kg) with placebo was undertaken by Korhonen et al.This trial, dubbed the Finnish Infliximab Related Study (FIRST II), was meant to confirm the efficacy of a single infusion of infliximab for sciatic pain. Forty patients with unilateral moderate to severe sciatic pain and MRI-verified disk herniation were randomized to a single infusion of either infliximab or placebo. The primary end point was a reduction in leg pain from baseline to 12 weeks.The investigators found significant reductions in leg pain in both groups, with no significant difference between treatment regimens. Seven patients in each group required surgery. The researchers concluded, “The results of this randomized trial do not support the use of infliximab for lumbar radicular pain in patients with disk-herniation-induced sciatica.”Goupille notes that the methodology of this study has been criticized due to its heterogeneous population, small group size, and use of only one infusion. “The response might have been influenced by the intensity of the radicular pain, the duration of evolution, or the anatomical localization of the disk herniation,” he says.”Might TNF-a be only one of the pieces in the puzzle, and might anti-TNF-a be beneficial only if used in combination with drugs blocking other cytokines? Might TNF-a have a role only in the initial stages of sciatica, and might anti-TNF-a be effective only at an early stage?” Goupille asks.Some of these questions might be answered later this year, when results of two ongoing controlled studies of adalimumab (Humira, Abbott) for treatment of sciatica are expected. (Source:1) Goupille P, Mulleman D, Valat JP. Radiculopathy associated with disc herniation. Ann Rheum Dis 2006; 65:141-143. 2) Korhonen T, Karppinen J, Paimela L, et al. The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study. Spine 2005; 30:2724-2728.Rheumawire: Joint & Bone: January 2006.)