Relapses During High-Dose Biotin Treatment in Progressive Multiple Sclerosis: a Case-Crossover and Propensity Score-Adjusted Prospective Cohort

Abstract

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Some reports have suggested that HDB treatment may be associated with an increased risk of relapse. We evaluate the relationship between exposure to HDB for treating PMS and the risk of relapse. We screened for PMS patients prospectively registered in a French regional cohort being part of the OFSEP national registry. In a case-crossover design among patients who received HDB, we first compared number of relapses before and after initiation of HDB. Second, time to the first clinical relapse was compared between patients who received HDB (biotin group) and a control group using a Cox survival analysis after a propensity score (PS) matching (1:1) and inverse probability of treatment weighting (IPTW) method. In the 42 PMS patients who received HDB, the number of relapses was statistically and clinically significant higher after biotin initiation than before biotin initiation (incident rate ratio [IRR] 7.4, 95% confidence interval [CI] 3.5–15.9, p < 0.0001). With the PS matching method, the risk of relapse was significantly higher in the biotin group compared to the control group (hazard ratio [HR] 4.3, 95% CI 1.4–13.3, p = 0.01). The IPTW method with 440 control patients revealed consistent results (HR 5.1, 95% CI 2.3–11.3, p < 0.0001). In our non-randomized study, HDB treatment for PMS was associated with an increased risk of relapse. The follow-up of PMS patients initiating HDB should include careful assessment of clinical and radiological activity to monitor the potential pro-inflammatory effect of biotin.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

HDB:

High-dose biotin

MS:

Multiple sclerosis

PMS:

Progressive multiple sclerosis

ARR:

Annualized relapse rate

PS:

Propensity score

IPWT:

Inverse probability of treatment weighting

References

  1. 1.

    Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278–286.

    Article  Google Scholar 

  2. 2.

    Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209–220.

    CAS  Article  Google Scholar 

  3. 3.

    Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mult Scler 2016;22:1719–1731.

    CAS  Article  Google Scholar 

  4. 4.

    Granella F, Tsantes E, Siena E, et al. Breakthrough disease under high-dose biotin treatment in progressive multiple sclerosis. Mult Scler 2017;23:85–426 (P750).

  5. 5.

    Lebrun C, Cohen M, Mondot L, et al. A case report of solitary sclerosis: this is really multiple sclerosis. Neurol Ther 2017;6:259–263.

    Article  Google Scholar 

  6. 6.

    Branger P, Derache N, Kassis N, et al. Relapses during high doses of biotin in progressive multiple sclerosis: a case series (P5.348). Neurology 2018;90(S15).

  7. 7.

    Vukusic S, Casey R, Rollot F, et al. Observatoire Français de la Sclérose en Plaques (OFSEP): a unique multimodal nationwide MS registry in France. Mult Scler 2020;26(1):118-122.

    Article  Google Scholar 

  8. 8.

    Paz Soldán MM, Novotna M, Abou Zeid N, et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology 2015;84:81–88.

    Article  Google Scholar 

  9. 9.

    Tourbah A, Gout O, Vighetto A, et al. MD1003 (high-dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, placebo-controlled study. CNS Drugs 2018;32:661–672.

    CAS  Article  Google Scholar 

  10. 10.

    Sedel F, Bernard D, Mock DM, et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology 2016;110:644–653.

    CAS  Article  Google Scholar 

  11. 11.

    Peyro Saint Paul L, Debruyne D, Bernard D, et al. Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis. Expert Opin Drug Metab Toxicol 2016;12:327–344.

    CAS  Article  Google Scholar 

  12. 12.

    Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord 2015;4:159–169.

    Article  Google Scholar 

  13. 13.

    Lee AJ, Beno DWA, Zhang X, et al. A (14)C-leucine absorption, distribution, metabolism and excretion (ADME) study in adult Sprague-Dawley rat reveals β-hydroxy-β-methylbutyrate as a metabolite. Amino Acids 2015;47:917–924.

    CAS  Article  Google Scholar 

  14. 14.

    Mathais S, Moisset X, Taithe F, et al. Incidence of Relapses in Patients with Biotin-Treated Progressive Multiple Sclerosis (IPBio-SeP Study): intermediate analysis of a French, multicenter study (P3.2-038). Neurology 2019;92(S15).

Download references

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Pierre Branger.

Ethics declarations

Disclosures

The authors declare that there is no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(PDF 188 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Branger, P., Parienti, J., Derache, N. et al. Relapses During High-Dose Biotin Treatment in Progressive Multiple Sclerosis: a Case-Crossover and Propensity Score-Adjusted Prospective Cohort. Neurotherapeutics (2020). https://doi.org/10.1007/s13311-020-00880-z

Download citation

Key Words

  • Multiple sclerosis
  • relapses
  • biotin
  • progressive
  • propensity score