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New cases of central nervous system demyelination and exacerbations of pre-existing disease have been reported in patients with rheumatoid arthritis following exposure to TNF inhibitors. However, as in the case of lymphoma, any causal relationship remains controversial and unproven. In fact, TNF-a has been implicated in the pathogenesis of multiple sclerosis, and because of this there have been studies of TNF inhibitors in this disease. In a Phase I open-label study, two patients with rapidly progressing multiple sclerosis refractory to high-dose intravenous corticosteroids were treated with intravenous infliximab. Both patients were found to have an increase in the number of gadolinium-enhancing lesions on MRI, together with increases in CSF leucocyte counts after each infusion. However, these changes were not accompanied by neurological deterioration (van Oosten et al. 1996). In a Phase II multicentre study, 168 patients with relapsing-remitting and secondary progressive multiple sclerosis received monthly infusions of lenercept (a recombinant soluble TNF p55 receptor fusion protein) at three dose levels or placebo for up to 48 weeks. Although this treatment was not associated with an increase in the number of new lesions, on MRI scanning it was sufficiently associated with increased demyelination attack frequency but not duration or severity (Klinkert et al. 1997). Neurological events associated with demyelinat-ing lesions on MRI have been reported in patients treated with anti-TNF agents (Mohan et al. 2001). However, the rate of new cases of multiple sclerosis reported in post-marketing surveillance for infliximab, etanercept, and adalimumab is at or below the number of expected cases based on the background rate for society as a whole, which is approximately six new cases per 100,000 per year (Noseworthy et al. 2000). Although there is not a proven relationship between TNF inhibition and onset of a demyelinating episode, it is wisest to avoid TNF inhibitors in patients with a history of optic neuritis, transverse myelitis, or other form of CNS demyelination.

In clinical trial data, induction of anti-nuclear antibodies and antibodies to double-stranded DNA have been reported with higher frequency in patients receiv ing TNF inhibitors than in comparator groups not receiving these drugs. Although induction of antibodies to double-stranded DNA is relatively common, in the order of 10-15% of patients, the occurrence of clinical features of SLE is much less common. Sulfasalazine, widely used in the treatment of rheumatoid arthritis, is also associated with a similar pattern of autoantibody induction. In reported cases of clinical lupus following exposure to TNF inhibitors, the onset of symptoms occurs between 1% and 18 months after introduction of the anti-TNF agent, with a mean time of 4.4 months, and women are predominantly affected. The syndrome abates on cessation of the TNF inhibitor and introduction of corticosteroid therapy as appropriate (Mohan et al. 2002).

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