The apparent dissociation between inflammation, demyelination, and axonal injury are supported by clinical studies. Four trials of interferon beta (IFN-p) have been published in SPMS (77-80). Although all of these demonstrated a benefit on relapses and MRI activity, the results on disability progression differed among the trials. In the European Interferon Beta (IFN-p)-lb study (IFN-p), treatment slowed worsening on the Kurtzke expanded EDSS, whereas in the other three, no benefit was seen on this endpoint. A metanalysis of the four trials revealed that patients with recent relapses and rapid decline were more likely to benefit from (IFN-p) treatment, with slowing of disability progression, than patients with remote relapses and slow gradual progression.
Relapse frequency in the early phase of the disease influences time to onset of progression; however, once a threshold of disability is reached, rate of progression of disability is not affected by relapses either before the onset of the progressive phase or during this phase (81,82). During the progressive phase, the rate of clinical deterioration is similar between SPMS and PPMS patients (81,82). The absence of a relation between relapses and irreversible disability suggests a dissociation at the biologic level between recurrent acute focal inflammatory demyelination and progressive CNS degeneration. This apparent paradox is consistent with the persistence of disability progression in MS patients, despite infection with HIV (83) or suppression of cerebral inflammation after treatment with a potent antileukocyte monoclonal antibody (84). It is also in keeping with the refractory state of progressive MS to anti-inflammatory therapies (85,86). These findings imply that therapeutic agents that have a short-term effect on MS relapses may not necessarily delay the development of long-term disability. Therefore, a combination of both inflammatory and noninflammatory factors likely contribute to disability in MS.
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