Multiple Sclerosis Patients with Treatment Failure: Agressive Disease, Switching Treatment, Combination Therapies

Abstract

A reasonable portion of multiple sclerosis patients develop remarkable disability during early in the disease course despite first line immunomodulatory treatment like beta interferons or glatiramer acetate. In such patients, demyelinating attacks continue to appear without any change in their frequency in addition to cumulative disability. A challenging problem in these patients is how and when to define treatment failures. The positive effect of immunomodulatory drugs in the early years of treatment has shown to be ineffective on the cumulative disability in the later phases of the disease. The most effective factors on sustained disability in the late phase are the level of disability at the disease onset and the rate of progression in the following years. The patients with ongoing severe attacks despite reasonable treatment; continuing marked magnetic resonance imaging activity with contrast enhancement; and increasing sustained disability should be regarded as treatment non-responders and different treatment strategies must be considered. Like immunomodulatory drugs, the second line treatments are also more effective in the earlier phase of the disease when inflammatory activity dominates. In that context, the choises are to switch to a different class of immunomodulatory drugs; natalizumab as monotherapy; intense immunosuppression; or combination of an immunomodulatory drug with an immunosuppressive drug like mitoxantrone or cyclophosphamide. Although no well-planned class I study on combination therapies exist in the relevant literature, various combinations have been widely used in clinical practise. At present safety is t he most important issue for drug combinations. Autologous hematopoetic stem celi transplantation is usually reserved as the last choice applied in specialized centers experimentally. Regarding stem cell transplantation there are many problematic issues on application, toxicity, adverse reactions; and the results in the long term are not distinct.