Fingolimod and multiple sclerosis

Neurology 2012;79:1942–1943 Unexpected consequences arise from our incomplete knowledge of the immune system. Who, for example, would have predicted that natalizumab, a monoclonal antibody targeting 4 integrin on leukocytes, would dramatically increase the risk of developing progressive multifocal leukoencephalopathy without causing notable immunosuppression? Thus, any new immunomodulatory therapy in humans must be approached with caution. Fingolimod, the first oral drug to treat multiple sclerosis (MS), is a sphingosine 1-phosphate (S1P) receptor modulator.1 By modulating S1P receptors on lymphocytes, fingolimod inhibits egress of naive and central memory lymphocytes, but not effector memory T cells, from lymph nodes. How the resultant relative increase in effector memory T cells in blood translates to an amelioration of a putative immunopathologic response in brain is unknown. Furthermore, fingolimod may directly affect astrocytes, oligodendrocytes, microglia, endothelial cells, and neurons, since they all express sphingolipids and S1P receptors and the effect of fingolimod on these cells is uncertain. In this issue, 4 Clinical/Scientific Notes describe 2 different neurologic complications of fingolimod treatment.2–5 First, MS can paradoxically worsen after fingolimod treatment. Centonze et al.2 present 3 patients with MS who started fingolimod 3– 4 months after stopping natalizumab and experienced severe exacerbations 6–19 days later. While the MS exacerbations might have been a rebound-type increased disease activity after cessation of natalizumab,6 they could also represent a fingolimodinduced exacerbation.7 Furthermore, Visser et al.3 describe a woman who developed tumefactive MS lesions 6 months after starting fingolimod without previously receiving natalizumab. Tumefactive MS usually develops early, but not late, in the disease course. Another report of tumefactive MS associated with fingolimod8 raises the possibility that this is more than coincidence. As described by Gross et al.,4 marked exacerbation of MS also can follow cessation of fingolimod therapy, suggesting a rebound-like worsening of disease activity as described by others.9 It remains unclear whether the paradoxical effects of fingolimod were related to modulation of lymphocytes, or a direct effect on one or more brain cell types. Another possibility is that if demyelination is triggered by virus infection, fingolimod treatment could have potentiated virus activation. A different problem that appears to have arisen after fingolimod treatment is herpes zoster with its attendant neurologic complications. Zoster is characterized by dermatomal distribution pain and rash produced by varicella-zoster virus (VZV). VZV is a ubiquitous, highly neurotropic and exclusively human herpesvirus. Primary infection usually causes varicella (chicken pox), after which virus becomes latent in ganglionic neurons along the entire neuraxis. Years later, as cell-mediated immunity to VZV declines with age or immunosuppression, such as in organ transplant recipients or patients with cancer or AIDS, VZV reactivates to cause zoster. Because fingolimod modulates trafficking of lymphocytes but does not destroy them or prevent their production, the drug is believed to be an immunomodulator that causes little immunosuppression. Yet Gross et al.4 describe a patient with MS who developed zoster and polyneuritis cranialis after taking fingolimod for 42 months and Ratchford et al.5 cared for a 50-year-old patient with MS with zoster followed by VZV encephalitis and vasculopathy after taking fingolimod for 3 months. Future studies will reveal whether zoster occurs more often after fingolimod treatment than expected by chance alone. If so, prospective studies are needed to identify T-cell subsets critical for maintenance of cell-mediated immunity against VZV that the drug alters. Other future studies will focus on lymphocyte subsets that reappear in the circulation following cessation of fingolimod, particularly in those who experience a rebound-type worsening of disease. UnSeepages2000, 2002, 2004, and2006