Monday, 25 January 2016

ResearchSpeak & OffLabel: how good are steroids in preventing natalizumab rebound?

Will NHS England ever endorse off-label prescribing in MS? #ResearchSpeak #OffLabel #MSBlog #MSResearch

"The relatively small study below shows that when PwMS who are stable on natalizumab stop treatment that pulsed monthly steroids can prevent rebound activity compared to pwMS not receiving this treatment. This observation has not been seen by others. In the RESTORE study (study 2 below); in this study methylprednisolone was not effective at preventing rebound. The following slide set makes the case for using either fingolimod or rituximab post- natalizumab. Unfortunately, in the NHS we are not allowed to use rituximab to treat MS. We have however made a case to NHS England's Neuroscience CRG (Clinical Reference Group) to consider the case for us using rituximab in this situation. We have provided them with the Swedish data. However, preliminary feedback from NHS England is that we are unlikely to get the greenlight as rituximab is  not a licensed MS therapy. In other words NHS England are not in a position to condone off-label prescribing. Interesting; I wonder if we can challenge them on this position?"

Study 1: Evangelopoulos et al. Pulsed corticosteroid treatment in MS patients stabilizes disease activity following natalizumab withdrawal prior to switching to fingolimod.Int J Neurosci. 2016:1-6.

PURPOSE: Interruption of natalizumab (NTM) treatment in multiple sclerosis (MS) patients may be followed by disease reactivation. On the other hand, patients with positive John Cunningham virus (JCV) antibodies treated with NTM over 24 months demonstrate a higher risk for developing progressive multifocal encephalopathy (PML). No established therapeutic approach is available for treating these patients to prevent disease reactivation.

MATERIALS AND METHODS: Of the MS patients treated with NTM at the authors' institution, 30 were found positive for JCV abs. NTM was interrupted followed by a washout period of 6 months. During this period, 20/30 patients received monthly intravenous (i.v.) methylprednisolone (MPD) 1000 mg infusion and regular clinical assessment. On months 3 and 6, brain MRI was performed and 1000 mg MPD was administered for 5 days.

RESULTS: All patients were clinically and radiologically stable at the time of NTM break. No clinical relapse was observed during the six-month washout period for the MS patients under monthly MPD treatment, while one patient had a relapse and active lesions in the MRI on month 6. Of the other patients not receiving i.v. MPD regularly after NTM withdrawal, one showed several active lesions in brain MRI and the other had a severe relapse.

CONCLUSIONS: Despite the limited size of this patients' cohort, the results of this study support that monthly MPD treatment for 6 months may result in a clinically stable disease status, thus ensuring safe transition to another second-line therapy such as fingolimod, following NTM withdrawal.

Study 2: Fox et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology. 2014 Apr 29;82(17):1491-8. 

OBJECTIVE: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.

METHODS: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.

RESULTS: Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.

CONCLUSIONS: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.

CoI: multiple


  1. What about IVIG? Can it prevent a relapse post tysabri?

    1. RE: "What about IVIG? Can it prevent a relapse post tysabri?"

      I have no idea!

  2. Can you prescribe rituximab under the NHS if I pay for it myself?

    1. Re: "Can you prescribe rituximab under the NHS if I pay for it myself?"

      Yes, we have done this twice before and there is a mechanism under new NHS regulations to do this. However, I don't like doing it and do it under duress. The NHS is founded on the principles of equity and health care that is free at point of access. Private prescribing undermines these founding principles; private prescribing means health care is not equitable and it is not free at point of access. In one fowl swoop the last coalition government changed things forever. What is more I have inside information that this change had cross party support. Apparently Andy Burnham who was then the shadow minister of health was gagged. We tried to set-up a question time webinar to discuss this policy change and we couldn't get one single MP to discuss it from all the major parties. This single policy change on private prescribing has changed the NHS in my books forever. I resisted for awhile, but realised as a clinician I have to do what I think is best for my patients, which is why I/we have relented. If somebody has any solutions to this quandary we find ourselves in please let me know what to do. I have even sought the help of our policy unit to investigate this.

      Please note that both the patients that were treated off-label with rituximab were young people with active PPMS; the population that responded to rituximab in the original rituximab PPMS trial.

  3. The same practiced by the NHS here in the UK is very similar to the NHS in Brazil, called SUS in Portuguese ...

    The big question is where the line between what is the better treatment to be offered to the patient and what is "legally permitted" by the NHS...

    Which and where is the Ethics in all this?


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