Monday, 20 October 2014

Dublin Talks: thank you

Slides from my Dublin talks last Friday. #MSBlog #MSResearch

"As promised the following are my slides from my visit to Dublin last Friday. The first was a talk on the viral hypothesis of MS at the grand round at the Beaumont Hospital on Friday morning and the second set from my debate against Professor David Bates in the evening on switching to oral therapies. It depends on how you view the results on who won the debate; more people voted for me, but Prof Bates had a larger swing his way. The good thing about the debate is that it allowed a lot of discussion on the topic. As always Dublin was a pleasure to visit, including the new terminal at the airport."




Brain Damage is occurring even before diagnosis

Rojas JI, Patrucco L, Míguez J, Besada C, Cristiano E.Brain Atrophy in Radiologically Isolated Syndromes. J Neuroimaging. 2014. doi: 10.1111/jon.12182. [Epub ahead of print]

INTRODUCTION:The aim of this study was to compare brain atrophy in radiologically isolated syndrome (RIS), in clinically isolated syndrome (CIS), and in individuals with subjective complaints (ISC).


METHODS: Patients with RIS were included prospectively during June 2009 to June 2012. CIS patients and ISC were used to compare the RIS sample. An automated analysis tool, SIENAX, was used to obtain normalized total brain volume (NTBV), normalized cortical volume (NCV), and normalized white matter volume (NWMV).


RESULTS: A total of 10 RIS patients, 43 CIS patients, and 29 ISC were included. 
The NTBV in RIS was 1.56 mm3 × 10-6 , 1.52 × 10-6 in CIS, and 1.64 × 10-6 in ISC (P = .003);  The NCV in RIS was 0.59 × 10-6 , 0.55 × 10-6 in CIS, and 0.71 × 10-6 in ISC (P = .002), and NWMV in RIS was 1.1 × 10-6 , 1 × 10-6 in CIS and 1.12 × 10-6 in ISC. 

CONCLUSIONS: NTBV and NCV were significantly lower in RIS compared with ISC while no differences were observed in NWMV.


As ProfG has suggested before that it looks like damage to brain notably the grey matter (cortex) is occurring early and even before diagnosis. The Volume of the white matter does not appear to change but this is a balance between volume loss and swelling due to the disease. However, again it suggests that we should be getting on top of MS as soon as possible.  

Risks of heart problems after mitoxantrone

Low-risk of cardiotoxicity from mitoxantrone in MSers. #MSBlog #MSResearch

"This study on cardiac dysfunction comes hot on the heels on my post on mitoxantrone being one of the DMTs on the essential MS DMT list for healthcare settings in which high-cost licensed DMTs are not available. This article is interesting in relation to two issue; firstly, how much mitoxantrone was used in Germany and secondly how infrequent gross cardiac toxicity occurs in MSers treated with mitoxantrone. The figure of no cases of congestive cardiac failure out of 639 treated patient and only 26 or 4.1% with mild cardiac involvement is compatible with other publications on this topic. I suspect the incidence of cardiotoxicity in MS is low as MSers are relatively young and infrequently have other co-morbid cardiac pathologies. In addition, it is rare for MSers to have received other cardiotoxic drugs prior to receiving mitoxantrone; this is not the same in other settings in which mitoxantrone is used, particularly in the field of oncology. Please note that cardiotoxicity is dose related and hence nobody with MS should receive more than 140mg/m-squared and they should all have their cardiac function monitored during the period of treatment so the drug can be stopped to prevent irreversible cardiac damage."



BACKGROUND AND PURPOSE: The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment.

METHODS: Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. 

RESULTS: None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. 

CONCLUSIONS: The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically). 

ClinicSpeak: natalizumab PML update - September 2014

September 2014 natalizumab PML update: underestimating the PML risk? #ClinicSpeak #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; if you are not a health professional Biogen-Idec don't want you to see this presentation. If you are a MSer you should be reading my previous post that has been designed for MSers."


Headline information


"As of the 2nd September 2014 there have been 495 cases of natalizumab-associated PML. This represents an increase of 20 cases over the last 2 months. Over 129,100 MSers have been exposed to natalizumab. The following graph demonstrates the number of new PML cases per month seems to be relatively stable, despite a gradual and linear increase in number of exposed MSers. Clearly the ratio is decreasing which indicates that the PML de-risking programme is working; in other words less MSers at risk of PML are staying on the natalizumab. Herein lies the problem; this means that the proportion of JCV-ve MSers on natalizumab is increasing. However the total number of MSers on treatment is used in the denominator to calculate the risk of getting PML. If this denominator is changing by including an increasing proportion of MSers who are not at risk of getting PML it will give a falsely low risk of PML. What we need are monthly updates of the PML risk, by excluding all JCV-ve MSers from the analysis. Unfortunately, Biogen-Idec are unable to access this information, despite them providing the JCV antibody assay free. Why? They don't have consent from the MSers who are being tested for JCV to use their data in this way."




"The following ratios are my attempt to explain why I think we are under-estimating the PML risk. At present Biogen-Idec is calculating the PML risk using the top equation. What I would like to see are PML risks calculated using the lower equation."


"The mortality associated with PML was 22% in September; in other words 109 MSers have died as result of PML; this has not increased since July. 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 129,100 MSers been treated with natalizumab worldwide with over 362,000 years of natalizumab exposure."


"Since NHS England gave us permission to switch high-risk natalizumab patients to fingolimod, we are continuing to de-risk our natalizumab-treated population. We are hoping by doing this to prevent anyone at our centre from getting PML. Despite this some MSers are not prepared to stop natalizumab, simply because they are doing so well on the drug."


"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 integrate 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