To describe six patients with relapsing-remitting multiple sclerosis (MS) treated with fingolimod that experienced MS exacerbations after being transitioned to dimethyl fumarate.

Fingolimod is a potent oral immunomodulatory agent approved for the treatment of relapsing MS. It modulates S1P receptors blocking the egression of activated lymphocytes from lymph nodes with resultant lymphopenia, predominantly decreasing CD4 cells. 

In the last years, several cases of progressive multifocal leukoencephalopathy (PML) have been reported in MS patients treated with fingolimod, without a clear association with lymphopenia. No specific guidelines for the monitoring of lymphocyte subsets of MS patients on fingolimod are currently available. This issue has raised concerns for long-term management, and in some cases prompting the switch in therapy to an alternative agent with a different mechanism of action.

All patients were clinically and radiologically stable on fingolimod from 1-5 years. The switch of therapy was due to significantly low peripheral CD4 lymphocyte count ≤ 61 cells/ul (normal range 359-1519 cells/ul). The patients were transitioned to dimethyl fumarate after a wash out period of 5-11 weeks to allow the increase of absolute lymphocyte count to 500 cells/ul or higher.

Patients experienced MS relapses with several enhancing lesions in the brain and/or spinal cord during the first six months following the discontinuation of fingolimod, and between 1-18 weeks after starting dimethyl fumarate treatment. One of the patients experienced two relapses within four months of treatment with dimethyl fumarate.

Additional studies are needed to develop guidelines for long term surveillance of MS treatments associated with lymphopenia and some risk of opportunistic infections including PML. When a switch in therapy is a consideration, due to the unpredictable individual response of MS patients to disease modifying therapies, close monitoring is essential during the first months of the transition to evaluate the new treatment’s efficacy.