LA JOLLA, California – Somewhat disappointing results from several trials in rheumatoid arthritis (RA) of mitogen-activated protein (MAP) kinase inhibitors are likely the result in part of a feature meant to make the new drugs safer—a structural design that keeps them out of the central nervous system (CNS). Gary S. Firestein, MD, Chief of the Division of Rheumatology, Allergy, and Immunology at the University of California San Diego School of Medicine in La Jolla, reports that in animal studies, p38 MAP kinase inhibitors are much more effective against inflammatory arthritis when injected into the spinal cord than when administered systemically, and that the tumor necrosis factor (TNF) inhibitor etanercept is, as well.1
Dr. Firestein also found that inhibiting p38 in the spinal cord decreased synovial inflammation and radiographic evidence of bone and cartilage destruction in an animal model of RA. Dr. Firestein collaborated with Drs. David L. Boyle and Linda Sorkin on these studies of how the spinal cord regulates peripheral inflammation, and their work is reported online in Public Library of Science – Medicine.1
Analgesics Also Have Anti-Inflammatory Activity If Administered to the Spinal Cord
The work with p38 and TNF-α grew out of this group's earlier studies of adenosine agonists in the CNS, where they both cause analgesia and reduce inflammatory responses. The p38 inhibitor SB203580 used in this study administered intrathecally (IT) to the spinal cord of rats with adjuvant arthritis "markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction," the investigators report. The same dose of SB203580 given systemically had no effect, and systemic administration required a dose about 1000 times higher to have an anti-inflammatory effect.
Dr. Firestein found that the p38-mediated activity within the spinal cord could be prevented using IT doses of etanercept (Enbrel®) to inhibit the activity of TNF-α. Again, the etanercept dose required for efficacy against inflammatory arthritis was about three times higher with systemic administration than with IT dosing. He contends that the p38 inhibitor results suggest that other small molecules that are analgesic with systemic dosing might also have anti-inflammatory effects if administered intrathecally. He also thinks that this dual effect might account for the very early sense of improved well-being reported by many patients treated with TNF inhibitors, which typically occurs before anti-inflammatory efficacy is apparent.
"The fact that TNF-α within the CNS is also playing a role in regulating peripheral inflammation was unexpected," Dr. Firestein said. "The way TNF-α gets into the spinal cord also is complicated. Some is produced locally, but some is transported up axons from the periphery, which appears to be one of the ways the CNS and the periphery communicate."
The bottom line is that researchers should not just focus on the target tissue or the site of inflammation. "The CNS and other influences are equal to or more important than target tissues, such as the synovium, in inflammatory arthritis," Dr. Firestein said. "Those designing new p38 inhibitors or similar small-molecule compounds should not be designing them to completely avoid the CNS, or they will lose part of the potential anti-inflammatory effect."
Dr. Firestein thinks that this CNS-peripheral inflammation connection also is likely to explain some aspects of the placebo effect and may partially explain why stress can exacerbate inflammatory diseases such as RA.
Reference
1. Boyle DL, Jones TL, Hammaker D, et al. Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 2006;3:e338. Available at http://medicine.plosjournals.org/perlserv/?request=getocument&doi=10.1371%2Fjournal.pmed.0030338. Accessed September 11, 2006.