Safety liver profile of teriflunomide versus interferon β in multiple sclerosis: Systematic review and indirect comparison meta-analysis

Published:September 22, 2018DOI:


      • As both teriflunomide and IFN β are similar in terms of effectiveness in the treatment of patients with RRMS, evaluation of safety profile can help the clinician to choose the most appropriate therapy.
      • All MS medications target the immune system and therefore have the theoretical potential to predispose patients to infection, to reduce surveillance of neoplasms, or to induce autoimmune disease, among other potential adverse effects.
      • Liver toxicity might be a reason for discontinuation of any drug prescribed, as it could potentially be a life-threating complication.
      • Elevated ALT is an indication of liver impairment particularly in acute cases, as drug-related liver failure, and is preferred over AST, as the former is more liver-specific while the latter is also produced by other tissues and can be increased in extrahepatic diseases.



      To compare the liver safety profile of interferon β (IFN β) and teriflunomide in patients with multiple sclerosis.


      A network meta-analysis was carried out following the Cochrane Collaboration methodology. All trials comparing all types of IFN β with teriflunomide, or disease-modifying drugs, or placebo in RRMS were included. An indirect comparison network meta-analysis within a Bayesian framework with STATA (version 13.0) was done for this study.


      The database searches yielded 284 titles, with 15 records as duplicates. One study was identified by manually searching. Thirteen articles were included in the systematic review. Twelve studies compared IFN β (4203 patients) vs another DMT. Four studies evaluated the effectiveness and safety of teriflunomide (906 patients) vs another DMT. Six studies reported drug-induced liver injury as per the Hy's Law. However, only one study had a direct comparison and reported no cases of liver toxicity in either group, so it was not possible to estimate the OR. The indirect comparisons metanalysis shows that there was no statistically-significant difference between teriflunomide and IFN β (OR 1.09, 95% CI 0.02–2.16).


      There were no significant difference when comparing IFN β and teriflunomide in terms of liver failure or elevation of transaminases.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. 1
        • Krieger SC
        New approaches to the diagnosis, clinical course, and goals of therapy in multiple sclerosis and related disorders.
        Continuum (Minneap Minn). 2016; 22: 723-729
      2. 2
        • Torkildsen Ø
        • Myhr K-M
        • Bø L
        Disease-modifying treatments for multiple sclerosis - a review of approved medications.
        Eur. J. Neurol. 2016; 23: 18-27
      3. 3
        • Farber RS
        • Sand IK
        Optimizing the initial choice and timing of therapy in relapsing-remitting multiple sclerosis.
        Ther. Adv. Neurol. Disord. 2015; 8: 212-232
      4. 4
        • Wingerchuk DM
        • Weinshenker BG
        Disease modifying therapies for relapsing multiple sclerosis.
        BMJ. 2016; 354: i3518
      5. 5
        • Dörr J
        • Paul F
        The transition from first-line to second-line therapy in multiple sclerosis.
        Curr. Treat. Options Neurol. 2015; 17: 354
      6. 6
        • Interferon beta
        1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.
        Neurology. 1993; 43: 655-661
      7. 7
        • Interferon beta
        1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB multiple sclerosis study group and the University of British Columbia MS/MRI analysis group.
        Neurology. 1995; 45: 1277-1285
      8. 8
        • PRISMS
        (Prevention of relapses and disability by interferon beta-1a suncutaneously in multiple sclerosis) study group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis.
        Lancet. 1998; 352: 1498-1504
      9. 9
        • Durelli L
        • Verdun E
        • Barbero P
        • et al.
        Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).
        Lancet (London, England). 2002; 359: 1453-1460
      10. 10
        • Calabresi PA
        • Kieseier BC
        • Arnold DL
        • et al.
        Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study.
        Lancet Neurol. 2014; 13: 657-665
      11. 11
        • Tremlett HL
        • Yoshida EM
        • Oger J
        Liver injury associated with the beta-interferons for MS: a comparison between the three products.
        Neurology. 2004; 62: 628-631
      12. 12
        • Francis GS
        • Grumser Y
        • Alteri E
        • et al.
        Hepatic reactions during treatment of multiple sclerosis with interferon-beta-1a: incidence and clinical significance.
        Drug Saf. 2003; 26: 815-827
      13. 13
        • O ’Connor P
        • Wolinsky JS
        • Confavreux C
        • et al.
        Randomized trial of oral teriflunomide for relapsing multiple sclerosis. Chill maz (HB, PT) — both fr stock (TPO).
        Sanofi-Aventis N. Engl. J. Med. 2011; 14365: 1293-1303
      14. 14
        • Confavreux C
        • O'Connor P
        • Comi G
        • et al.
        Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Neurol. 2014; 13: 247-256
      15. 15
        • Morris C.
        Annex I - Teriflunomide summary of product characteristics.
        Eur. Med. Agency. 2009; ([Accessed July 14, 2017]): 1-16
      16. 16
        • Hutton B
        • Salanti G
        • Caldwell DM
        • et al.
        The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
        Ann. Intern. Med. 2015; 162: 777-784
      17. 17
        • Cohen JA
        • Barkhof F
        • Comi G
        • et al.
        Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
        N. Engl. J. Med. 2010; 362: 402-415
      18. 18
        • Cohen JA
        • Coles AJ
        • Arnold DL
        • et al.
        Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
        Lancet. 2012; 380: 1819-1828
      19. 19
        • AJ Coles
        • Compston DAS
        • et al.
        • CAMMS223 Trial Investigators
        Alemtuzumab vs. interferon beta-1a in early multiple sclerosis.
        N Engl J Med. 2008; 359: 1786-1801
      20. 20
        • Coles AJ
        • Twyman CL
        • Arnold DL
        • et al.
        Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.
        Lancet. 2012; 380: 1829-1839
      21. 21
        • De Stefano N
        • Sormani MP
        • Stubinski B
        • et al.
        Efficacy and safety of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study.
        J. Neurol. Sci. 2012; 312: 97-101
      22. 22
        • Kappos L
        • Wiendl H
        • Selmaj K
        • et al.
        Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis.
        N Engl J Med. 2015; 373: 1418-1428
      23. 23
        • Mikol DD
        • Barkhof F
        • Chang P
        • et al.
        Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the rebif vs glatiramer acetate in relapsing ms disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.
        Lancet Neurol. 2008; 7: 903-914
      24. 24
        • O'Connor P
        • Filippi M
        • Arnason B
        • et al.
        250 ??G or 500 ??G interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study.
        Lancet Neurol. 2009; 8: 889-897
      25. 25
        • Vermersch P
        • Czlonkowska A
        • Grimaldi LM
        • et al.
        Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial.
        Mult. Scler. J. 2014; 20: 705-716
      26. 26
        • Confavreux C
        • Li DK
        • Freedman MS
        • et al.
        Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years.
        Mult. Scler. J. 2012; 18: 1278-1289
      27. 27
        • Hurwitz BJ
        • Jeffery D
        • Arnason B
        • et al.
        Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 μg QOD in patients with relapsing-remitting multiple sclerosis: A multicenter, randomized, double-blind, parallel-group pilot study.
        Clin. Ther. 2008; 30: 1102-1112
      28. 28
        • Singer B
        • Bandari D
        • Cascione M
        • et al.
        Comparative injection-site pain and tolerability of subcutaneous serum-free formulation of interferonβ-1a versus subcutaneous interferonβ-1b: results of the randomized, multicenter, Phase IIIb REFORMS study.
        BMC Neurol. 2012; 12: 154
      29. 29
        • The IFNB Multiple Sclerosis Study Group
        Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial.
        Neurology. 1993; 43: 655-661
      30. 30
        • Woreta TA
        • Alqahtani SA
        Evaluation of abnormal liver tests.
        Med. Clin. North Am. 2014; 98: 1-16