The FDA has approved ponesimod (Ponvory – Janssen), a sphingosine 1-phosphate (S1P) receptor modulator, for treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (initial neurological episode), relapsing-remitting disease, and active secondary progressive MS (SPMS). Ponesimod is the fourth oral S1P receptor modulator to be approved in the US for once-daily treatment of relapsing forms of MS; ozanimod (Zeposia) and siponimod (Mayzent) are also approved for use in adults, and fingolimod (Gilenya) is indicated for use in patients ≥10 years old.

Most patients with multiple sclerosis (MS) present with the relapsing-remitting form of the disease. Pharmacologic treatment usually includes a disease-modifying drug, corticosteroids for acute exacerbations, and other drugs for managing symptoms such as fatigue, depression, and pain. Early use of disease-modifying therapy has improved clinical outcomes.

The FDA has approved ozanimod (Zeposia – Celgene), a sphingosine 1-phosphate (S1P) receptor modulator, for treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (initial neurological episode), relapsing-remitting disease, and active secondary progressive MS (SPMS). It is the third oral S1P receptor modulator to be approved in the US for treatment of relapsing forms of MS; siponimod (Mayzent) is also indicated for use in adults, and fingolimod (Gilenya) is approved for use in patients ≥10 years old.

The FDA has approved cladribine (Mavenclad – EMD Serono), a purine antimetabolite, for oral treatment of adults with relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive MS (SPMS), who cannot tolerate or have had an inadequate response to other drugs indicated for treatment of MS. It is not recommended for use in patients with clinically isolated syndrome (CIS). IV cladribine, which is FDA-approved for treatment of hairy cell leukemia, has been used off-label for treatment of MS.

The FDA has approved siponimod (Mayzent – Novartis), a sphingosine 1-phosphate (S1P) receptor modulator, for oral treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (initial neurological episode), relapsing-remitting disease, and active secondary progressive MS (SPMS). Siponimod is the second S1P receptor modulator to be approved in the US; fingolimod (Gilenya), which is approved for oral treatment of relapsing forms of MS in patients ≥10 years old, was the first. The purine antimetabolite cladribine (Mavenclad) was also recently approved for oral treatment of relapsing forms of MS and will be reviewed in a future issue.

The FDA has warned that the antiepileptic and mood-stabilizing drug lamotrigine (Lamictal, and generics) can rarely cause hemophagocytic lymphohistiocytosis (HLH), a serious and potentially fatal immune-related reaction.1

HLH, which can be familial, occurs most often in infants, but can occur at any age. Often induced by Epstein-Barr Virus infection (HIV infection and non-Hodgkin's lymphoma are other common triggers), HLH is characterized by an unremitting activation of CD8+ T cells and macrophages.2 If untreated, it causes organ damage, particularly in the liver, bone marrow, and CNS; organ failure and death occur within months after onset.3 Clinical features can include fever and rash, splenomegaly, hepatitis, cytopenias, elevated triglyceride levels or low fibrinogen levels, hyperferritinemia, hemophagocytosis, decreased or absent natural killer cell activity, and elevated blood CD25 levels.4

The optimal treatment for drug-induced HLH is unclear. Treatment of HLH generally involves use of corticosteroids and blood products, sometimes augmented by aggressive immunosuppression with the cytotoxic drug etoposide (Toposar, and generics). The anti-CD52 antibody alemtuzumab (Lemtrada) can be added in refractory HLH cases,5 and allogeneic hematopoietic cell transplantation has been used in genetic cases.

Since lamotrigine first became available in 1994, five confirmed and three suspected cases of HLH associated with its use have been reported. All of these cases occurred within 24 days of starting treatment and required hospitalization. One death was reported; in the other cases, improvement occurred after discontinuation of lamotrigine and treatment of HLH. Because initial signs and symptoms of HLH are nonspecific, the condition can be confused with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), another potentially fatal, multiorgan, immune-related adverse reaction associated with lamotrigine use.1,6

Patients being treated successfully with lamotrigine should continue taking it. Clinicians should monitor patients taking lamotrigine for signs and symptoms of HLH, especially during the first few weeks after starting the drug.

1. FDA Drug Safety Communication: FDA warns of serious immune system reaction with seizure and mental health medicine lamotrigine (Lamictal). Available at: www.fda.gov. Accessed June 7, 2018.
2. M Ramos-Casals et al. Adult haemophagocytic syndrome. Lancet 2014; 383:1503.
3. SA Parikh et al. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc 2014; 89:484.
4. JI Henter et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
5. RA Marsh et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 2013; 60:101.
6. SH Kardaun et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013; 169:1071.

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The FDA has approved ocrelizumab (Ocrevus – Genentech), a humanized anti-CD20 monoclonal antibody, for treatment of adults with primary progressive or relapsing multiple sclerosis (MS). It is the first anti-CD20 monoclonal antibody to be approved for treatment of MS and the first disease-modifying drug to be approved in the US for primary progressive MS.

The FDA has approved daclizumab (Zinbryta – Biogen/Abbvie), an interleukin-2 (IL-2) receptor blocking monoclonal antibody, for treatment of adults with relapsing forms of multiple sclerosis (MS). It is the first subcutaneously injected monoclonal antibody to be approved for treatment of MS.

Most patients with multiple sclerosis (MS) present with the relapsing-remitting form of the disease. Treatment usually includes disease-modifying drugs, various other drugs for managing symptoms such as fatigue, depression, and pain, and corticosteroids for acute exacerbations.

The FDA has approved a pegylated form of interferon beta-1a (Plegridy – Biogen) for biweekly treatment of patients with relapsing multiple sclerosis (MS).