Wednesday, 16 April 2014

Clinic Speak: what happens when you stop taking natalizumab

NHS England green-lights switch from natalizumab to fingolimod in MSers at high-risk of PML #MSBlog #MSResearch #ClinicSpeak

Interferon-beta, GA or steroids not good enough to prevent rebound activity #MSBlog #MSResearch #ClinicSpeak

"The study below confirms what we already know; stopping natalizumab leads to rebound in MS disease activity. Switching to a DMT on a lower-tier of efficacy, i.e. interferon-beta or glatiramer acetate, or taking steroids does not prevent this rebound. In comparison, a higher-efficacy drug such as fingolimod appears to prevent this rebound provided it is started within 4 weeks after the last natalizumab infusion."

"Most MSers stopping natalizumab are doing it because they are at high-risk of developing PML. The major safety concern we have is so called carry-over PML; i.e. PML that presents in the first few months after starting fingolimod. I am aware of two cases of carry-over PML on fingolimod. Carry-over PML is a problem in that we rely on the immune response to clear you of PML; it takes about 6-8 weeks for fingolimod to wash-out of your system and during this time PML can cause devastating damage. Our practice, to prevent carry-over PML and rebound disease activity, is to do a MRI and lumbar puncture shortly after the last natalizumab infusion. If the spinal fluid analysis shows no JC virus DNA and the MRI shows no evidence of asymptomatic PML we start fingolimod within 4 weeks of the last natalizumab infusion. So far this practice seems to be  working; touch wood we have had no cases of carry-over PML."

"In clinic last week someone asked me about switching from natalizumab to alemtuzumab? Alemtuzumab is an induction agent and hence you can't reverse its action. If you developed carry-over PML after switching from natalizumab to alemtuzumab the chances are you will die from the PML as your immune system will not be able to respond quickly enough to clear the virus. Post alemtuzumab it takes over 3 months for your immune system to recover. For this reason I am telling my patients that it will be much safer for them to switch to a maintenance agent, for example fingolimod, for several months or years, before switching to alemtuzumab post-natalizumab. The latter advice is not evidence-based and is unlikely to become evidence-based in the future; this advice is based in scientific principles on how the different DMTs affect your immune system."

"For UK MSers who read this blog we have finally been given the green-light by NHS England to switch MSers at high-risk of PML on natalizumab to fingolimod, who have never been treated with interferon-beta or GA in the past. We applied for this policy change in June last year; therefore, it has taken 10 months to get this change in policy. I sincerely hope none of the MSers who have been caught in this bureaucratic quagmire  have developed, or will develop, PML as a result of this delay. We really need a more responsive system than the current one; 10 months is a long time in the life of an MSer not to mention my own anxieties, and the anxieties of my colleagues, over this issue."

Rebound MRI activity post-natalizumab. Arch Neurol. 2011;68(2):186-191. doi:10.1001/archneurol.2010.257.

Epub: Fox et al. MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study. Neurology. 2014 Mar.

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 MSers were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. MSers 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, MSers underwent clinical and MRI assessments every 4 weeks.

RESULTS: MSers (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 MSers 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-treated MSers and in 15%-29% of MSers 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 MSers (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 MSers 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

Survey results: MS Society CTN

Survey results MS Society Clinical Trials Network relaunch. #MSBlog #MSResearch

"The following are the results of the short survey I did in relation to the MS Society's relaunch of their clinical trials network (CTN). The CTN is an initiative to stimulate and help researchers in the UK to do investigator-led clinical studies in MS. For those of you who missed the post I have left the programme up for you to read it."






Natalizumab PML Update March 2014

March 2014 natalizumab PML update. #MSBlog #MSResearch

"The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; I continue to be told by Biogen-Idec that if you are not a health professional you should not be reading this presentation. If you are a MSer you should be reading my previous post that has been designed for you."


Headline information

"As of the 6th March 2014 there have been 448 cases of natalizumab-associated PML. This represents an increase of 9 cases from last month; the number of cases each month is going down. The mortality associated with PML in this setting is currently 24%, i.e. 108 MSers have died as result of PML. Please note that the majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of well over 123,000 MSers been treated with natalizumab worldwide with over 320,000 years of natalizumab exposure."


"It is now clear that the numbers of MSers developing PML are falling due to the successful risk mitigation strategy that has been implemented Biogen-Idec with JC virus serological testing. This is a success story and it should be reassuring for MSers on natalizumab."


"Good news for UK MSers at high-risk of PML who have been waiting for permission from NHS England to switch to fingolimod; we have just been given a provisional green-light to go ahead with switching. This is a big relief for me; once we have cleared our list of patients I will sleep more easily at night."

"The following is the most important headline data slide for MSers regarding risks based on the three identified PML risk factors:

  1. JCV serostatus
  2. Duration of treatment
  3. Previous exposure to immunosuppression

In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and this needs to be incorporated into future risk models."


"We have developed a simple infographic to help you intergrate all this information. You can download and print this infographic for your own information."



Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.








"The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch. In those MSers who are high risk and have elected to stay on natalizumab we have started doing 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 above."

CoI: multiple

Compensating for brain problems

Loitfelder M, Fazekas F, Koschutnig K, Fuchs S, Petrovic K, Ropele S, Pichler A, Jehna M, Langkammer C, Schmidt R, Neuper C, Enzinger C. Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study. PLoS One. 2014; 9(4):e93715

BACKGROUND: Extrapolations from previous cross-sectional fMRI studies suggest cerebral functional changes with progression of Multiple Sclerosis (MS), but longitudinal studies are scarce. We assessed brain activation changes over time in MS patients using a cognitive fMRI paradigm and examined correlations with clinical and cognitive status and brain morphology.
METHODS: 13 MS patients and 15 healthy controls (HC) underwent MRI including fMRI (go/no-go task), neurological and neuropsychological exams at baseline (BL) and follow-up (FU; minimum 12, median 20 months). We assessed estimates of and changes in fMRI activation, total brain and subcortical grey matter volumes, cortical thickness, and T2-lesion load. Bland-Altman (BA) plots served to assess fMRI signal variability.
RESULTS: Cognitive and disability levels remained largely stable in the patients. With the fMRI task, both at BL and FU, patients compared to HC showed increased activation in the insular cortex, precuneus, cerebellum, posterior cingulate cortex, and occipital cortex. At BL, patients vs. HC also had lower caudate nucleus, thalamus and putamen volumes. Over time, patients (but not HC) demonstrated fMRI activity increments in the left inferior parietal lobule. These correlated with worse single-digit-modality test (SDMT) performance. BA-plots attested to reproducibility of the fMRI task. In the patients, the right caudate nucleus decreased in volume which again correlated with worsening SDMT performance.
CONCLUSIONS: Given preserved cognitive performance, the increased activation at BL in the patients may be viewed as largely adaptive. In contrast, the negative correlation with SDMT performance suggests increasing parietal activation over time to be maladaptive. Several areas with purported relevance for cognition showed decreased volumes at BL and right caudate nucleus volume decline correlated with decreasing SDMT performance. This highlights the dynamics of functional changes and the strategic importance of specific brain areas for cognitive processes in MS.

When you do any action your brain uses more oxygen in areas that are active and this can be seen with a combination of a MRI and an oxygen dye this is called functional MRI. What happened to the cognitive abilities of MSers in this paper was nothing but when you look at MSers verses non-MSers the MSers were using more brain bits, because they were compensating for probable damage due to MS. This is called "plasticity" and whilst it can give compensatory capacity for awhile so you don't notice much, this is the "iceberg effect" and things are going on