This document discusses rebound/reactivation in multiple sclerosis patients switching between disease-modifying therapies. It defines rebound as evidently higher disease activity after starting a new drug. Principal causes include cells driving disease gaining access to their targets when previously suppressed. Drugs particularly associated with rebound are natalizumab and fingolimod upon withdrawal. The document recommends patients be aware of rebound risk and not stop therapies abruptly. Transitioning to dimethyl fumarate or immune reconstitution therapies can help avoid reactivation by not leaving cells unchecked.

1. Klaus Schmierer, MB BS PhD FRCP
Reader in Clinical Neurology & Consultant Neurologist
Reactivation/rebound
@KlausSchmierer
26 Jan 2018

2. Disclosures (~acknowledgements)
PI of trials sponsored by Novartis, Roche, Teva, Medday.
Involved in trials sponsored by Biogen, Genzyme, BIAL, Cytokinetics,
Canbex.
Speaking honoraria from, and/or served in an advisory role for, Biogen,
Merck, Merck Inc., Novartis, Roche, Teva
Supported for attendance of meetings by Genzyme, Merck, Novartis, and
Roche.
Research grant support from Biogen, Lipomed, Novartis, MS Society of
Great Britain & Northern Ireland, National MS Society (US), Royal College of
Radiologists, and Barts Charity.

3. The Royal London Hospital
St Bartholomew's Hospital
Mile End Hospital
The London Chest Hospital
Newham University Hospital
Whipps Cross University Hospital

4. Rebound/reactivation
• What is it?
• Why does it happen?
• Which drugs are affected?
• How can it be avoided?
• NICE ideas (and nonsense)

5. Rebound/reactivation
Definition:
Disease activity that is evidently higher than the
activity prior to starting the drug concerned.
Can be a little tricky to define when several
treatments have already been tried.

6. Rebound/reactivation
Principal cause:
Cell population(s) driving disease activity, and
previously held “in check”, gain access to their
target.

7. Immunotherapies for relapsing MS
https://www.mstrust.org.uk/understanding-ms/ms-symptoms-and-treatments/ms-decisions/decision-aid

8. Natalizumab

9. The complex immunology of EAE/MS
Baker D, et al. EBioMed 2017;16:41-50.

10. Switching off adaptive immune-response inhibits MS
Baker D, et al. EBioMed 2017;16:41-50.Miller, et al N Engl J Med 2003;348:15-23.

11. Switching off adaptive immune-response inhibits MS
PML
Herpes encephalitis
Rebound on withdrawal
1. Selective adhesion molecule blocker
2. Infusion reactions
a. Anaphylactoid
b. Associated with anti-drug antibodies
3. Blocks CNS immune surveillance
a. PML
b. CNS infections
c. Possible link with CNS lymphomas
4. Rebound activity post-washoutwww.clinicspeak.org
Khatri et al. Neurology 2009;72:402–409.

13. Brain Behaviour 2017;7:e00671

14. Gonzalez-Suarez, et al. Brain Behaviour 2017;7:e00671

15. Neurology 1999;52:1072–4.
Khatri, et al. Neurology2009;72:402–9.
Pharmacodynamics of natalizumab

18. Rasenack M & Derfuss T. Exp Rev NeuroRx 2016;16:587-94.

19. Mult Scler Int 2015:809252.

20. Honce, et al. Mult Scler Int 2015:809252.

21. Avoiding rebound

22. Uphaus, et al. J Neurol 2017;264:2491-4

23. Calabrese, et al. J Neurol Neurosurg Psychiatry 2017;88:1073-8.

24. Pract Neurol 2016;16:389-93.

25. Pract Neurol 2016;16:389-93.
/cladribine
/cladribine
/cladribine

26. Fingolimod

27. • 38 years old woman of Afro-Caribbean
extraction
• Diagnosed with primary progressive MS in 2009
• Enrolled in trial of fingolimod (INFORMS) in 2011
• Examination at baseline: brain stem signs
(bilateral INO), hemiparesis on right, walking
range 100-200m. EDSS= 5.5.
A slightly unusual, yet typical case…
Alvarez-Gonzalez C, et al. Ann Clin Trans Neurol 2017;4:506-11.

28. Lancet 2016;387:1075-84.

29. May 2011 Dec 2014
EQ-5D
May 2011 Dec 2014
EDSS
May 2011 Dec 2014
9-HPT
Dec 2014
Alvarez-Gonzalez C, et al. Ann Clin Trans Neurol 2017;4:506-11.
A slightly unusual, yet typical case…

30. A slightly unusual, yet typical case…
Alvarez-Gonzalez C, et al. Ann Clin Trans Neurol 2017;4:506-11.

31. Czlonkowska, et al. Neurol Neurochir Poland 2017;51:156-61.

32. Czlonkowska, et al. Neurol Neurochir Poland 2017;51:156-61.

33. Ther Adv Neurol Disord 2015;8:233-8.

34. Faissner, et al. Ther Adv Neurol Disord 2015;8:233-8.

35. Chun & Hartung. Clin Neuropharmacol 2010;33:91–101.
Fingolimod MoA

37. Litwin, et al. Neurol Neurochir Poland 2018;52:98-101.

38. Avoiding rebound

39. Before it’s too late…
Alvarez-Gonzalez C, et al. Ann Clin Trans Neurol 2017;4:506-11.

40. Teriflunomide

41. Yamout, et al. J Neurol Sci 2017:380:79-81

42. Conclusions
• Rebound disease significant challenge for management of pwMS
• Main culprits: Natalizumab & Fingolimod
• Patients need to be made aware of the problem
• Cold turkey is not an option
• Decent results with Dimethyl-Fumarate to cover potential
reactivation, however discrepancy between license and use here
• Immune-reconstitution therapies useful to avoid rebound as no
“cells waiting in the wings”

44. @KlausSchmierer
www.ms-res.org David Baker
Bryan Ceronie
Cristo Albor
Cesar Alvarez-Gonzalez
Daniele Carassiti
Dayo Afolabi
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