“Earlier this week I saw an unfortunate young woman with a spinal cord relapse post-natalizumab. She had rapidly-evolving severe MS and had done very well on natalizumab (NEDA) for ~2 years. Despite being JCV seronegative her neurologist switched her to DMF (Tecfidera) on the grounds that he was worried about her being on natalizumab long-term. This young lady was very anxious and concerned about whether or not she would make a full recovery from the relapse. I suspect she will make a good recovery as she is young and was fully functional prior to the relapse; i.e. she has good functional reserve. As the relapse was impacting on her mobility and she had bothersome sensory symptoms I treated her with high-dose oral steroids (500 mg methylprednisolone x 5 days). This is another relapse that could have been prevented.”
“I have recently been taken to task on whether or not rebound of MS disease activity post-natalizumab is a real phenomenon, or simply a ‘statistical artefact’. One commentator used the oft-quoted paper below (O’Connor et al.) and refers to the conclusion as evidence that rebound does not occur: ‘a rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted’. The problem with this statement is that it assumes, and defines, rebound as disease activity beyond placebo-treated levels. I personally disagree with this statement and prefer to define rebound according to the English definition of the word.”
Source: Google Dictionary
“In the context of natalizumab withdrawal rebound is simple the occurrence of disease activity when the mode of action of the drug wears off. Whether or not this is more, or less, than some arbitrary figure is irrelevant. One lesion in a strategic location is potentially enough to cause a devastating relapse and can even cause death. This is why we go to a lot of trouble to prevent rebound when stopping natalizumab. In the study below comparing the level of activity to that which occurred in the placebo treated group is fraught with difficulties. Firstly, the placebo treated figures are from an earlier epoch. We know that disease activity regresses to the mean; i.e. goes down with time making this comparison difficult.”
“Any analysis that looks at rebound should not include the initial 3 months post-natalizumab when the drug is still on board and working. As you can see from the slide show that there is very little rebound activity in months 1, 2 and 3. However, in month 4, 5 and 6 and beyond there is a clear signal of rebound disease activity. Rebound coincides with desaturation of the VLA-4 antigen on the surface of lymphocytes and their retrafficking into the brain and spinal cord. You would anticipate a similar thing with fingolimod; fingolimod traps disease causing lymphocytes in lymph nodes. When fingolimod is stopped and washed out of the system these lymphocytes migrate from the lymph nodes and retraffick to the brain and spinal cord and trigger focal inflammatory events. The difference between fingolimod and natalizumab is the timing; on stopping treatment fingolimod levels drop earlier than natalizumab and hence you would expect rebound to occur earlier, which has been the observation to date. The observation that most DMTs, with the exception of fingolimod, are not effective in preventing post-natalizumab rebound is interesting. I suspect this is due to fingolimod’s mode of action; trapping lymphocytes in lymph nodes prevents reconstitution of immune surveillance to the central nervous system and prevents rebound. However, for fingolimod to prevent rebound it needs to be started before natalizumab has time be cleared from the system. This is why we start it within 4 weeks of the last natalizumab infusion.”
“I hope I have convinced you; rebound is not a statistical artifact but a real phenomenon with consequences. If you don’t believe me read the literature or come and meet some of my patients who have suffered the consequences of rebound.”
O’Connor et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011 May 31;76(22):1858-65.
BACKGROUND: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies.
OBJECTIVES: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS.
METHODS: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumabdosing that occurred in February 2005.
RESULTS: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted.
CONCLUSIONS: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.
Kappos et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. Neurology. 2015 Jul 7;85(1):29-39.
OBJECTIVE: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod.
METHODS: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.
RESULTS: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6-2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred.
CONCLUSIONS: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.