The history of drug development is beset with failures, and MS therapy has provided some spectacular examples. On the basis of experiments in animals with experimental autoimmune encephalomyelitis (EAE), TNF- inhibition initially seemed to be an attractive therapeutic possibility (Probert et al. 2000). However, when a mAb against TNF- was administered to MS patients in an open phase 1 trial, the number of gadolinium-enhancing lesions, the CSF cell counts and the IgG index increased after each infusion (Van Oosten et al. 1996). This unexpected result was subsequently (and unintentionally) confirmed in a large trial with soluble TNF-a receptor (The Lenercept Multiple Sclerosis Study Group 1999): TNF neutralization resulted in an increased number of MS patients experiencing exacer bations as compared to the placebo group. Also inflammatory activity as reflected by MRI was clearly increased in the treatment groups.
The reasons for the discrepancy between the findings in EAE and MS patients are still unclear. Yet there is growing evidence that TNF is crucially involved in elimination of inflammatory T cells in the nervous system [see review in Probert et al. (2000) and Weishaupt et al. (1997)]. Interestingly, there seems to be a reciprocal relationship between MS and rheumatoid arthritis with regard to the treatment response to TNF-a. Anti-TNF- agents are clinically effective in rheumatoid arthritis, but some patients developed MS-like demye-linating lesions during treatment with anti-TNF-agents (either mAb or soluble receptor constructs) (Sicotte and Voskuhl 2001).
13.4 Adverse Reactions in Highly Efficacious Anti-a4-Integrin Therapy with Natalizumab 143
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