Safety considerations when choosing the appropriate treatment for patients with multiple sclerosis

Keywords::

• dimethyl fumarate
• fingolimod
• multiple sclerosis
• safety
• teriflunomide

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that commonly affects young adults. The actual therapeutic armamentarium includes a large number of disease-modifying drugs (DMDs), with 10 drugs already approved in Europe and 9 in the US, making the choice of therapy more complex. This requires an accurate evaluation of the benefits and risks provided by the different treatment options [1].

In the July issue of Expert Opinion on Drug Safety, we can read a thorough review on the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod, the first approved oral multiple sclerosis therapy [2]. Fingolimod is an effective treatment for relapsing MS and a suitable first- or second-line DMD for patients without cardiovascular risk factors [3], although in Europe it is only approved as a second-line therapy. How does fingolimod compare to the other two available oral DMDs: teriflunomide and dimethyl-fumarate (DMF)? As no head-to-head studies comparing the oral DMDs are available, tolerability and safety emerge as important points in making a decision on therapy (Table 1). DMF is a twice-daily therapy, whereas fingolimod and teriflunomide are taken only once daily, which increases the likelihood of adherence.

Table 1. Adverse events of multiple sclerosis disease-modifying drugs.

Therapy	Adverse events of particular concern	Other adverse events
Interferon-β	Depression Thrombotic microangiopathy ITP*	ISRs Flu-like LFT elevation Leucopoenia
Glatiramer acetate		ISRs Benign systemic reaction
Mitoxantrone	Cardiac toxicity Leukaemia	Nausea
Natalizumab	Infusion reactions PML	Infusion-related fatigue
Fingolimod	Bradyarrhythmia Macular oedema Herpes virus infection	LFT elevation Lymphopenia Mild hypertension
Teriflunomide	Hepatotoxicity	Peripheral neuropathy Alopecia Nausea/diarrhoea
Dimethyl fumarate		Flushing Gastrointestinal
Alemtuzumab	Infusion reactions ITP Goodpasture syndrome	Autoimmune thyroid disease Infections

*ITP has been reported with interferon-β although less frequently than with alemtuzumab.

ISRs: Injection-site reactions; ITP: Idiopathic thrombocytopenic purpura; LFT: Liver function test; PML: Progressive multifocal leukoencephalopathy.

Teriflunomide requires more frequent liver function tests (LFT) monitoring based on the concern for serious hepatotoxicity [3]. Alopecia (hair thinning) is a cosmetic side effect of teriflunomide that is especially worrisome for many people. DMF has a satisfactory safety profile, although gastrointestinal side effects and flushing may affect the adherence to treatment. Four European cases of progressive multifocal leuckoencephalopathy (PML) were reported in association with the use of fumaric acid esters for the treatment of psoriasis, although there were confounding factors such as immunosuppression and prolonged leucopoenia [4-6]. No case of PML has been reported with DMF. Cardiac events are the main concern with fingolimod [7]. EMA and FDA guidelines require an electrocardiogram (ECG) prior to dosing and at 6 h after the first dose. In addition, continuous ECG monitoring during the 6 h observation period is recommended in the European Union. A recent study that enrolled 2417 patients confirmed that cardiac effects of fingolimod were transient and mostly asymptomatic; no patient developed a Mobitz type II second-degree or complete atrioventricular block [8].

Although the overall risk of infection does not appear to be significantly increased, appropriate pretreatment screening and monitoring for infectious complications (especially herpesvirus and varicella) during fingolimod treatment are prudent [2]. One study showed that the antiviral immune response under fingolimod treatment may be compromised [9]. Patients with negative varicella antibody serology should be vaccinated, at least 1 month prior to initiation of fingolimod. Live attenuated virus vaccinations should be avoided during treatment with fingolimod.

Teratogenicity is an important issue in a disease that mainly affects women of childbearing age where unplanned pregnancies are not uncommon [10]. The new oral medications for relapsing MS (fingolimod, teriflunomide and dimethyl fumarate) are all small molecules that readily diffuse across the placenta. A recent study of 66 pregnancies exposed to fingolimod revealed a congenital malformation rate of 14.6%, which exceeds the expected rate in the general population [10,11]. Teratogenicity is an important safety consideration with teriflunomide (pregnancy category X), and it is recommended that women stop teriflunomide 2 years prior to conception due to its prolonged half-life unless they use an inconvenient elimination procedure with cholestyramine or activated powdered charcoal [3].

Neurologists will need to have a detailed and structured discussion with patients before the selection of a DMD. This selection should be a shared decision that considers prognostic factors, concomitant medical illnesses and medications, lifestyle factors, potential risks, patient preferences and cost.

Declaration of interest

A Sempere has received fees for speaking or participation in advisory boards from Biogen Idec, Bayer, Schering Pharma, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.