Background: Disease-modifying therapies (DMTs) for multiple sclerosis aim to specifically reduce inflammation in relapsing multiple sclerosis and promote neuroprotection and neurorepair in progressive multiple sclerosis (MS). Most of the currently available disease-modifying drugs (DMDs) require regular and frequent parenteral administration, which imposes a burden on patients and leads to reduced adherence. Not all MS patients respond adequately to current DMDs and, therefore, alternative MS treatments with less invasive routes of administration and new modes of action are required to expand the current treatment repertoire, increase adherence, and thereby improve efficacy. As one of the oral DMDs, teriflunomide is a potentially promising new oral agent in the treatment of relapsing MS. It inhibits dihydro-orotate dehydrogenase (DHODH) and the synthesis of pyrimidine and has selective immunosuppressive and immunomodulatory properties.

Objectives: To explore the potential benefits of teriflunomide and so expand the available DMT options, the effectiveness and safety of teriflunomide, as monotherapy or combination therapy, were assessed versus placebo or approved DMDs (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS.

Search methods: The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 June 2012). We checked references in identified trials and manually searched the reports (2004 to June 2012) from neurological associations and MS societies. We also communicated with researchers participating in trials on teriflunomide and contacted Sanofi-Aventis.

Selection criteria: All randomised, double-blind, controlled, parallel clinical trials (RCTs) with a length of follow-up of at least one year evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other treatments (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for patients with MS. Titles and abstracts of the citations retrieved by the literature search were screened independently for inclusion or exclusion by two review authors. Any disagreement regarding inclusion was resolved by discussion or by referral to a third assessor if necessary.

Data collection and analysis: Two review authors independently extracted data and assessed trial quality. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation of information.

Main results: Two studies involving 1204 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFN-β, versus placebo for adult patients with relapsing forms of MS (relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)) and an entry Expanded Disability Status Scale (EDSS) score of ≤ 5.5. Both studies had high attrition bias (26.8% and 36.4% attrition respectively). Teriflunomide 7 or 14 mg alone had potential benefits on reducing relapse rates, and alone or with add-on IFN-β was safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Four ongoing trials were identified.

Authors' conclusions: We found low-level evidence for the use of teriflunomide as a disease-modifying therapy for MS, due to the limited quality of the available RCTs. We did not conduct meta-analysis because of the clinical and methodological diversity of the included studies. Short-term teriflunomide, 7 or 14 mg alone or with add-on IFN-β, was safe for patients with relapsing MS. Both teriflunomide 7 and 14 mg alone had potential benefits for patients with relapsing forms of MS. We are waiting for the publication of ongoing trials. RCTs with high methodological quality and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life.