Journal of Neurology

, Volume 261, Issue 6, pp 1170–1177

Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients

  • Per Soelberg Sorensen
  • Nils Koch-Henriksen
  • Thor Petersen
  • Mads Ravnborg
  • Annette Oturai
  • Finn Sellebjerg
Original Communication

Abstract

A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3–12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval [CI] 0.88–1.00), 0.47 (95 % CI 0.43–0.52) during natalizumab therapy, 0.63 (95 % CI 0.51–0.76) 1–6 months after natalizumab and 0.55 (95 % CI 0.42–0.70) 7–12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.

Keywords

Natalizumab treatment discontinuation Relapse rebound Multiple sclerosis 

References

  1. 1.
    O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C et al (2011) Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76(22):1858–1865CrossRefPubMedGoogle Scholar
  2. 2.
    Stuve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von Geldern G et al (2009) Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 72(5):396–401PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    West TW, Cree BA (2010) Natalizumab dosage suspension: are we helping or hurting? Ann Neurol 68(3):395–399CrossRefPubMedGoogle Scholar
  4. 4.
    Kerbrat A, Le PE, Leray E, Anani T, Coustans M, Desormeaux C et al (2011) Natalizumab and drug holiday in clinical practice: an observational study in very active relapsing remitting multiple sclerosis patients. J Neurol Sci 308(1–2):98–102CrossRefPubMedGoogle Scholar
  5. 5.
    Rigau V, Mania A, Befort P, Carlander B, Jonquet O, Lassmann H et al (2012) Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology 79(22):2214–2216CrossRefPubMedGoogle Scholar
  6. 6.
    Rinaldi F, Seppi D, Calabrese M, Perini P, Gallo P (2012) Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler 18(11):1640–1643CrossRefPubMedGoogle Scholar
  7. 7.
    Miravalle A, Jensen R, Kinkel RP (2011) Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 68(2):186–191CrossRefPubMedGoogle Scholar
  8. 8.
    Killestein J, Vennegoor A, Strijbis EM, Seewann A, van Oosten BW, Uitdehaag BM et al (2010) Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol 68(3):392–395CrossRefPubMedGoogle Scholar
  9. 9.
    Papeix C, Depaz R, Tourbah A, Stankoff B, Lubetzki C (2011) Dramatic worsening following plasma exchange in severe post-natalizumab withdrawal multiple sclerosis relapse. Mult Scler 17(12):1520–1522CrossRefPubMedGoogle Scholar
  10. 10.
    de Seze J, Ongagna JC, Collongues N, Zaenker C, Courtois S, Fleury M et al (2013) Reduction of the washout time between natalizumab and fingolimod. Mult Scler 19(9):1248CrossRefPubMedGoogle Scholar
  11. 11.
    Laroni A, Brogi D, Milesi V, Abate L, Uccelli A, Mancardi G (2013) Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab interruption. Mult Scler 19(9):1236–1237CrossRefPubMedGoogle Scholar
  12. 12.
    Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA et al (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348(1):15–23CrossRefPubMedGoogle Scholar
  13. 13.
    Fox RJ, Cree BAC, De Sèze J, Gold R, Hartung H-P, Jeffery D, Kappos L, Kaufman M, Montalbán X, Weinstock-Guttman B, Anderson B, Natarajan A, Ticho B, Duda P. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study, in pressGoogle Scholar
  14. 14.
    Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354(9):899–910CrossRefPubMedGoogle Scholar
  15. 15.
    Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW et al (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354(9):911–923CrossRefPubMedGoogle Scholar
  16. 16.
    Goodman AD, Rossman H, Bar-Or A, Miller A, Miller DH, Schmierer K et al (2009) GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology 72(9):806–812PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Hellwig K, Haghikia A, Gold R (2011) Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 17(8):958–963CrossRefPubMedGoogle Scholar
  18. 18.
    Rossi S, Motta C, Studer V, Monteleone F, De Chiara V, Buttari F et al (2013) A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation. Mult Scler 19(1):59–68CrossRefPubMedGoogle Scholar
  19. 19.
    Hakiki B, Portaccio E, Giannini M, Razzolini L, Pasto L, Amato MP (2012) Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases. Mult Scler 18(11):1636–1639CrossRefPubMedGoogle Scholar
  20. 20.
    Havla JB, Pellkofer HL, Meinl I, Gerdes LA, Hohlfeld R, Kumpfel T (2012) Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol 69(2):262–264CrossRefPubMedGoogle Scholar
  21. 21.
    Borriello G, Prosperini L, Marinelli F, Fubelli F, Pozzilli C (2011) Observations during an elective interruption of natalizumab treatment: a post-marketing study. Mult Scler 17(3):372–375CrossRefPubMedGoogle Scholar
  22. 22.
    Magraner MJ, Coret F, Navarre A, Bosca I, Simo M, Escutia M et al (2011) Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of natalizumab therapy: a prospective, 6-month observational study. J Neurol 258(10):1805–1811CrossRefPubMedGoogle Scholar
  23. 23.
    Rossi S, Motta C, Studer V, De Chiara V, Barbieri F, Monteleone F et al (2013) Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab. Eur J Neurol 20(1):87–94CrossRefPubMedGoogle Scholar
  24. 24.
    Sempere AP, Martin-Medina P, Berenguer-Ruiz L, Perez-Carmona N, Sanchez-Perez R, Polache-Vengud J et al (2013) Switching from natalizumab to fingolimod: an observational study. Acta Neurol Scand 128(2):e6–e10CrossRefPubMedGoogle Scholar
  25. 25.
    Havla J, Tackenberg B, Hellwig K, Meinl I, Krumbholz M, Seitz F et al (2013) Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis. J Neurol 260(5):1382–1387CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Per Soelberg Sorensen
    • 1
  • Nils Koch-Henriksen
    • 2
    • 3
    • 6
  • Thor Petersen
    • 4
  • Mads Ravnborg
    • 5
  • Annette Oturai
    • 1
  • Finn Sellebjerg
    • 1
  1. 1.Danish Multiple Sclerosis Center, Department of NeurologyRigshospitalet and University of CopenhagenCopenhagenDenmark
  2. 2.Department of Clinical Epidemiology, Clinical InstituteUniversity of AarhusÅrhusDenmark
  3. 3.The Danish Multiple Sclerosis Registry, Neuroscience CentreRigshospitalet, University of CopenhagenCopenhagenDenmark
  4. 4.Department of NeurologyAarhus University HospitalÅrhusDenmark
  5. 5.Department of NeurologyUniversity Hospital of OdenseOdenseDenmark
  6. 6.The Multiple Sclerosis RegistryRigshospitaletCopenhagenDenmark

Personalised recommendations