Advertisement

Therapeutic lag in reducing disability progression in relapsing-remitting multiple sclerosis: 8-year follow-up of two randomized add-on trials with atorvastatin

  • Roberta Lanzillo
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy
    Search for articles by this author
  • Marcello Moccia
    Correspondence
    Corresponding author at: Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Federico II University, Via Sergio Pansini, 5 - Building 17, Ground floor, Naples, Italy.
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy

    Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, UK
    Search for articles by this author
  • Cinzia Valeria Russo
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy
    Search for articles by this author
  • Antonio Carotenuto
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy
    Search for articles by this author
  • Agostino Nozzolillo
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy
    Search for articles by this author
  • Martina Petruzzo
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy
    Search for articles by this author
  • Raffaele Palladino
    Affiliations
    Department of Primary Care and Public Health, Imperial College, London, UK

    Department of Public Health, Federico II University, Naples, Italy
    Search for articles by this author
  • Jeremy Chataway
    Affiliations
    Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, UK
    Search for articles by this author
  • Vincenzo Brescia Morra
    Affiliations
    Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy
    Search for articles by this author
Published:January 02, 2019DOI:https://doi.org/10.1016/j.msard.2018.12.042

      Highlights

      • Exposure to atorvastatin was associated with milder disease progression after 8 years.
      • There is a therapeutic lag in the effect of statins on disability progression.
      • Clinical trials should be extended in the long-term to evaluate any delayed or latent effect of the intervention.

      Abstract

      Background

      Current treatments for relapsing remitting multiple sclerosis (RRMS) reduce inflammation, but have a partial or modest effect on disability. This effect may require a much longer follow-up than standard trial design, in particular in RRMS with relatively-preserved functional reserve. We aimed to assess the long-term clinical evolution of RRMS patients exposed to atorvastatin in two trials (ACTIVE and ARIANNA).

      Methods

      We retrospectively looked at 69 participants randomized with atorvastatin or placebo as add-on therapy to interferon-beta for 24 months at a single MS centre. We recorded relapses, 1-point EDSS progression and progression to EDSS 4.0. Cox regression was performed for these three questions. A Poisson regression model was used to evaluate the association between atorvastatin treatment and annualized relapse rate (ARR).

      Results

      After 8.4 ± 2.3 (3.7–11.9) years from trial, the use of atorvastatin was associated with reduced risk of 1-point EDSS progression (HR = 0.440; 95%CI = 0.225–0.861; p = 0.017), and of EDSS 4.0 (HR = 0.310; 95%CI = 0.123–0.784; p = 0.013). We found no significant association between atorvastatin and relapses.

      Discussion

      These data suggest that a delayed treatment effect may be seen with atorvastatin added to interferon-beta, eight years after entering the clinical trials. Long-term follow-up of trial cohorts should be mandated.

      Keywords

      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:

      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

      References

        • De Angelis F.
        • John N.
        • Brownlee W.
        Disease-modifying therapies for multiple sclerosis.
        BMJ. 2018; 363
        • Youssef S.
        • Stüve O.
        • Patarroyo J.O.
        • et al.
        The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.
        Nature. 2002; 420: 78-84
        • Blume C.
        • Sabuda-Widemann D.
        • Pfeilschifter J.
        • et al.
        Cerivastatin inhibits proliferation of interleukin-1 beta-induced rat mesangial cells by enhanced formation of nitric oxide.
        Eur. J. Pharmacol. 2004; 485: 1-10
        • Guzik T.J.
        • Korbut R.
        • Adamek-Guzik T.
        Nitric oxide and superoxide in inflammation and immune regulation.
        J. Physiol. Pharmacol. 2003; 54: 469-487
        • Tsakiri G.P.A.
        Statin treatment in multiple sclerosis: a systematic review and meta-analysis.
        CNS Drugs. 2015; 29: 277-291
        • Sorensen P.S.
        • Lycke J.
        • Erälinna J.P.
        • et al.
        Simvastatin as add-on therapy to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial.
        Lancet Neurol. 2011; 10: 691-701
        • Chataway J.
        • Schuerer N.
        • Alsanousi A.
        • et al.
        Eff ect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): A randomised, placebo-controlled, phase 2 trial.
        Lancet. 2014; 383: 2213-2221
        • Giovannoni G.
        • Cutter G.
        • Pia-Sormani M.
        • et al.
        Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.
        Mult. Scler. Relat. Disord. 2017; 12: 70-78
        • Lanzillo R.
        • Orefice G.
        • Quarantelli M.
        • et al.
        Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy.
        Mult. Scler. 2010; 16: 450-454
        • Lanzillo R.
        • Quarantelli M.
        • Pozzilli C.
        • et al.
        No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing – remitting multiple sclerosis (the ARIANNA study).
        Mult. Scler. 2016; 22: 1163-1173
        • Signori A.
        • Gallo F.
        • Bovis F.
        • Di Tullio N.
        • Maietta I.
        • Sormani M.P.
        Long-term impact of interferon or Glatiramer acetate in multiple sclerosis: a systematic review and meta-analysis.
        Mult. Scler. Relat. Disord. 2016; 6: 57-63
        • Tur C.
        • Montalban X.
        • Tintoré M.
        • et al.
        Interferon beta-1b for the treatment of primary progressive multiple sclerosis: Five-year clinical trial follow-up.
        Arch. Neurol. 2011; 68: 1421-1427
        • Kappos L.
        • Kuhle J.
        • Multanen J.
        • et al.
        Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.
        J. Neurol. Neurosurg. Psychiatry. 2015; 86: 1202-1207