Time to talk about timing--when to start, stop and change anti-migratory drugs in MS.

MULTIPLE SCLEROSIS MSJ JOURNAL Multiple sclerosis (MS) is an inflammatory disease, and the relapsing–remitting form of MS (RRMS) is widely considered to be the most inflammatory phenotype of MS. There are currently eight approved therapies for patients with RRMS. Not surprisingly, all of these medications are anti-inflammatory. The mechanisms of action of agents that were approved in the 1990s are not completely understood. Newer drugs, including fingolimod and natalizumab, are the result of rational drug design that targets specific molecules. Fingolimod is a structural analog and a functional antagonist of sphingosine-1-phosphate (S1P), which mediates the egress of lymphocytes from the lymph nodes. 1 Natalizumab is a recombinant humanized monoclonal anti-body that targets α4-integrin, which is part of several heter-odimeric adhesion molecules that promote leukocyte adhesion to blood vessels and extracellular matrix molecules. 2 Both agents are very effective in decreasing the number of MS relapses and in diminishing the number and volume of new disease lesions on magnetic resonance imaging (MRI). 3–6 There is no evidence that either agent alters the etiological factors that cause MS disease activity. Instead, both agents appear to sequester some of the autore-active lymphocytes out of the brain and spinal cord. One question of great clinical relevance is whether sequential therapy of natalizumab and fingolimod results in stable disease activity and clinical improvement, or whether there is worsening of MS signs and symptoms. In the current issue of this journal, several investigators address this issue and present data from case reports and small case series. Hakiki and colleagues 7 describe six patients with MS who had previously been treated with fingolimod, and who experience disease reactivation on cessation of therapy. One patient described by Hakiki et al. 7 appeared to have developed disease rebound after fingolimod had been discontinued for three months. Thus, it has to be assumed that fingolimod was completely washed out at that point. Results from a case series by Rinaldi et al. 8 published in this issue support the observations by Hakiki and colleagues. Here, 22 JC virus (JCV)-positive natalizumab-treated RRMS patients who were shifted to fingolimod after a three-month washout were assessed. In the nine-month-follow up period, MS reactivation was observed in 11/22 patients, and a possible disease rebound was observed in three patients. As the natalizumab experience has taught us, disease rebound is very difficult to verify. In a clinical setting the documentation of disease activity prior to the …