Saturday, 31 December 2016

Will the Kangeroo Test supercede the 25 foot walk to measure outcomes?

Kirkland MC, Downer MB, Holloway BJ, Wallack EM, Lockyer EJ, Buckle NC, Abbott CL, Ploughman M. Bipedal Hopping Reveals Evidence of Advanced Neuromuscular Aging Among People With Mild Multiple Sclerosis. J Mot Behav. 2016:1-9.

Measures of walking such as the timed 25-ft walk test (T25FWT) may not be able to detect subtle impairment in lower limb function among people with multiple sclerosis (MS). We examined bipedal hopping to determine to what extent people with mild (Expanded Disease Severity Scale ≤ 3.5) MS (n = 13) would differ compared to age-, gender-, and education-matched controls (n = 9) and elderly participants (n = 13; ≥ 70 years old). We estimated lower limb power (e.g., hop length, velocity), consistency (e.g., variability of hop length, time), and symmetry (ratio of left to right foot). Participants completed the T25FWT and, after a rest, they then hopped using both feet 4 times along the walkway. We found that although all groups scored below the 6 -s cutoff for T25FWT, the elderly group had significantly shorter hop lengths, more variability, and more asymmetry than the controls. The results of the MS group were not significantly different from the elderly or controls in most measures and most of their values fell between the control and elderly groups. Hop length, but not measures of walking predicted Expanded Disease Severity Scale score (R2 = .38, p = .02). Bipedal hopping is a potentially useful measure of lower limb neuromuscular performance.


I wondered whether it was April 1 today and not the 31st of December. ProfG will be preparing his New yeaer blast for the 2016 past or the look forward to 2017 and will get lambasted in the process, no doubt:-(.  This study looks at comparing the hopping capability of pwMS and the eldery and concluded that hopping can pick up mobility issues. Will it get past the regulators as a new outcome?

#HappyNewYear: a better understanding of progressive MS

MS is #1-disease-not-2-or-3-diseases - #HappyNewYear

One of your wishes for 2017 is 'a better understanding of progressive MS. I would love an explanation of why MS morphs from RR to SP'.

I have tried many times to explain this in plain English. The following is an updated version of a previous post that I wrote more than a year ago in response to a statement by Steve Hauser that a proportion of his patients with relapsing MS who had been treated with rituximab have gone onto become secondary progressive; why?

People with MS and those of us who treat the disease want a cure. However, we may have a cure in hand and yet we don't reverse or prevent progressive disease. How can this be? I have tried to capture all the issues in this infographic; it is a work in progress so if you don't understand it please let me know and I will adapt it.


Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; so called delayed neurodegeneration. The mechanisms that result in delayed neurodegeneration of nerves are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, etc. Clearly anti-inflammatory drugs that prevent new lesions formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that has damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why we are doing the PROXIMUS trial; an add-on neuroprotective drug to try and modify the delayed die-off of neurons and axons.

What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I therefore suspect that those patients of Steve Hauser, who have been treated with rituximab and have now become secondary progressive, had a low reserve capacity and a large number of damage nerve fibres that had been primed to die off in the future. In other words they were treated with rituximab too late to prevent SPMS.

Please note that Steve Hauser's observations, and the above theoretical explanation, are not new and have been noted with with other high efficacy DMTs, i.e. mitoxantrone, HSCT, natalizumab and alemtuzumab. There are two conclusions to be drawn from the above observations and theory; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, or (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is one factor that underpins the component of the Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). If you have any New Year's resolutions please think about your general 'Brain Health'.


So unless you get treated with ocrelizumab, or another high efficacy DMT, early in the course of your disease it may not prevent you entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, anti-CD20 therapies and almost all of the other licensed DMTs don't kill long-live plasma cells that continue to make intrathecal (within the CNS) antibodies that my drive progressive MS. The exception may be natalizumab there are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a 'niche' or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard. However, the data on natalizumab and OCBs needs more work, a large German consortium of investigators' have not confirmed the earlier reports of the disappearing OCBs. To target the plasma cell, that are long-lived, we will need add-on therapies. The latter is something that is high on our list of priorities for 2017 and we have just been awarded a grant to test a myeloma (malignant plasma cells) drug in MS.

We have also made the argument that we should not be using the term progressive MS. The term is wrong. Progressive means progress, an improvement, however, in the context of MS it implies worsening. We prefer the term worsening MS. Instead of progressive MS we prefer the term advanced MS; which implies worsening disability. There is really very little scientific reason to split MS up into different sub-types, i.e. relapsing, vs. secondary and primary progressive disease. MS is one disease. As I have recently discovered defining MS two or three diseases was a ploy by Pharma to get MS recognised as an orphan disease, which allowed them to get interferon-beta licensed on the data from one trial and to charge a higher, than expected, price for the drug. MS is 1-disease-not-2-or-3-diseases.

Finally, those of you interested in animal models will find the study below of interest. This model has been developed by the Mouse Doctors over two decades models both the the early and late effects of inflammation in driving neurodegeneration. In other words there is animal data to support the delayed neurodegeneration theory presented above; our theory on what drives progressive MS is not a thumb suck.

Hampton et al. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun. 2013 Dec 23;1:84. doi: 10.1186/2051-5960-1-84.

BACKGOUND: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration.

OBJECTIVES: To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.

RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.

CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.

CoI: multiple

Friday, 30 December 2016

Fingol against Nataliziumab...and the Winner is....

A longitudinal real-life comparison study of natalizumab and fingolimod.Lanzillo R, Carotenuto A, Moccia M, Saccà F, Russo CV, Massarelli M, De Rosa A, Brescia Morra V.
Acta Neurol Scand. 2016 Dec 15. doi: 10.1111/ane.12718. [Epub ahead of print]

BACKGROUND:Different retrospective studies compared natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS), with conflicting results. We aimed to explore the prescriptive attitude and the clinical outcome of the two therapies.
METHODS:We retrospectively included all RRMS patients treated with natalizumab (n=101) or fingolimod (n=78) as their first second-line therapy with at least 24-month follow-up. Demographic and clinical features were recorded to calculate the propensity score (PS). Outcomes of interest were annualized relapse rate (ARR), risk of relapse, and change in the EDSS RESULTS: At baseline, natalizumab patients were younger and had a shorter disease duration, a higher number of relapse in 1 year (1yR) and 2 years (2yR) and overall (ARR-PT) pretherapy, compared to fingolimod patients. On therapy, the proportion of relapsing patients and the mean RR were similar in the two groups. However, the change in the ARR was higher in natalizumab than in fingolimod group (P<.002), but, using PS as a covariate, it was comparable (P=.960). Similarly, the change in EDSS was significantly different for the two groups (P<.004), but not after adjusting for the PS (P=.321).
CONCLUSION:We observed a comparable efficacy on ARR reduction and on EDSS progression with natalizumab and fingolimod correcting through PS, suggesting that the efficacy difference observed before correction might derive from the clinical attitude in prescribing natalizumab in more active MS patients in real life.



Tsivgoulis G, Katsanos AH, Mavridis D, Grigoriadis N, Dardiotis E, Heliopoulos I, Papathanasopoulos P, Karapanayiotides T, Kilidireas C, Hadjigeorgiou GM, Voumvourakis K; HELANI (Hellenic Academy of Neuroimmunology). The Efficacy of Natalizumab versus Fingolimod for Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review, Indirect Evidence from Randomized Placebo-Controlled Trials and Meta-Analysis of Observational Head-to-Head Trials. PLoS One. 2016; 11(9):e0163296

BACKGROUND:Although Fingolimod (FGD) and Natalizumab (NTZ) appear to be effective in relapsing-remitting multiple sclerosis (RRMS), they have never been directly compared in a randomized clinical trial (RCT).
METHODS AND FINDINGS: We evaluated the comparative efficacy of FGD vs. NTZ using a meta-analytical approach. Data from placebo-controlled RCTs was used for indirect comparisons and observational data was utilized for head-to-head comparisons. We identified 3 RCTs (2498 patients) and 5 observational studies (2576 patients). NTZ was associated with a greater reduction in the 2-year annualized relapse rate (ARR; SMDindirect = -0.24;95% CI: from -0.44 to -0.04; p = 0.005) and with the probability of no disease activity at 2 years (ORindirect:1.82, 95% CI: from 1.05 to 3.15) compared to FGD, while no differences between the two therapies were found in the proportion of patients who remained relapse-free (ORindirect = 1.20;95% CI: from 0.84 to 1.71) and those with disability progression (ORindirect = 0.76;95% CI: from 0.48 to 1.21) at 2 years. In the analysis of observational data, we found no significant differences between NTZ and FGD in the 2-year ARR (SMD = -0.05; 95% CI: from -0.26 to 0.16), and 2-year disability progression (OR:1.08;95% CI: from 0.77 to 1.52). However, NTZ-treated patients were more likely to remain relapse-free at 2-years compared to FGD (OR: 2.19;95% CI: from 1.15 to 4.18; p = z0.020).
CONCLUSIONS: Indirect analyses of RCT data and head-to-head comparisons of observational findings indicate that NTZ may be more effective than FGD in terms of disease activity reduction in patients with RRMS. However, head-to-head RCTs are required to independently confirm this preliminary observation.



You have been asking for comparisons of different drugs, but it cant be horses for courses because it is clear that efficacy is not top of the list otherwise we would not be going to the CRAB drugs. However, it is a balancee between efficacy, conveninece, safety etc etc etc. In this study they try and compare fingolimod and come to the conclusion that natalizumab is abit more efficacious. This is not a head to head, and companies are never going to do this exept when it is a no-brainer e.g. they put a new drug against beta interferon, like alemtuzumab and oceliziumab and it is obvious that the latter two are better than the CRAB drugs. However it can backfire, look at laquinimod verses beta interferon...oooops. Academics want to do these studies, but they cost too much  to do. The funders say is this a good use of our limited resource and the answer is usually no. Maybe the regulators should insist that drugs are compared to current best practise, but then we may get no new drugs as to show your new drug is better than a good drug is going to mean the studies are very large...and costly.

Thursday, 29 December 2016

Gut flora making susceptibility

Stanisavljević S, Lukić J, Soković S, Mihajlovic S, Mostarica Stojković M, Miljković D, Golić N.Correlation of Gut Microbiota Composition with Resistance to Experimental Autoimmune Encephalomyelitis in Rats. Front Microbiol. 2016;7:2005. doi: 10.3389/fmicb.2016.02005.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS). It is widely accepted that autoimmune response against the antigens of the CNS is the essential pathogenic force in the disease. It has recently become increasingly appreciated that activated encephalitogenic cells tend to migrate toward gut associated lymphoid tissues (GALTs) and that interrupted balance between regulatory and inflammatory immunity within the GALT might have decisive role in the initiation and propagation of the CNS autoimmunity. Gut microbiota composition and function has the major impact on the balance in the GALT. Thus, our aim was to perform analyses of gut microbiota in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Albino Oxford (AO) rats that are highly resistant to EAE induction and Dark Agouti (DA) rats that develop EAE after mild immunization were compared for gut microbiota composition in different phases after EAE induction. 


Microbial analyses of the genus Lactobacillus and related lactic acid bacteria showed higher diversity of Lactobacillus spp. in EAE-resistant AO rats, while some members of Firmicutes and Proteobacteria (Undibacterium oligocarboniphilum) were detected only in faeces of DA rats at the peak of the disease (between 13 and 16 days after induction). Interestingly, in contrast to our previous study where Turicibacter sp. was found exclusively in non-
DA rats that remained healthy 16 days after induction, as well as in four of 12 DA rats at the peak of the disease. Similar observation was obtained for the members of Lachnospiraceae. Further, production of a typical regulatory cytokine interleukin-10 was compared in GALT cells of AO and DA rats, and higher production was observed in DA rats. Our data contribute to the idea that gut microbiota and GALT considerably influence multiple sclerosis pathogenesis.

In this paper they look at the bactrial flora in the gut of different strains of rat and infere thtat they influence suceptibility. This is the mantra for the microbiomome story. There is also an implication that this is one of the reasons why a resistant strain does not develop disease. To make this claim they would need to change the microbiome and make the resitant susceptible and the susceptible resistant. I doubt this would really happen as genetics has already been shown to be a key player in this. Anyway as you rush for that feacal transplant to change your microbiome, I will still be wondering how much hype science is creating. 

I was having dinner with a non-scientitst, interested in science, the other night and they were reading loads of books on the gut and the microbiome, to the hype is being bought. Can it influence immunity? Probably, but is it a solution? I doubt it.

#ResearchSpeak: depression in MS is associated with focal brain damage

Would you be surprised if I told you that the black dog is associated with structural changes in the brains of pwMS? #ResearchSpeak #MSBlog

The smallish study below shows that depressive symptoms in pwMS is associated with gray matter loss in the left temporal lobe. The implication is that damage in the neuronal pathways that are linked to this particular area of the brain is associated with depression in MS. This is not surprising. Depression, like all symptoms, must have a neuroanatomical and/or neurophysiological correlate; in other words depression must be linked to malfunctioning of the brain. 

We know that the life-time prevalence of depression in pwMS is close to 50%; if this is causally linked to structural changes in the brain then preventing these changes should reduce the incidence and life-time prevalence of depression in MS. I wonder if this is occurring in pwMS who are being effectively treated with disease-modifying therapies?

Depression is part of a complex of hidden symptoms that are seldom discussed with pwMS who are early in the course of their disease. The others are anxiety, fatigue and cognitive impairment. If we made the point that depression, and these other symptoms, are linked to structural damage to the brain caused by MS would that affect decision-making around early-effective treatment? 

Depression has a major affect on quality of life and if we want to treat MS holistically we need to do everything possible to prevent this awful complication of MS and its consequences. Do you agree?    


Stuke et al. Cross-Sectional and Longitudinal Relationships between Depressive Symptoms and Brain Atrophy in MS Patients. Front Hum Neurosci. 2016 Dec 16;10:622.

Introduction: Depressive symptoms are a frequent and distressing phenomenon in Multiple Sclerosis (MS) patients. Cross-sectional research links these symptoms to reduced brain gray matter volumes in parts of the prefrontal and temporal lobe as well as subcortical structures like the hippocampus, nucleus caudatus and globus pallidus. Nevertheless, prospective relationships between regional gray matter volume and the course of depressive symptoms are poorly understood. 


Methods: Forty-four patients with relapsing-remitting or secondary progressive MS participated in a prospective study with two assessments of depressive symptoms and high-resolution MRI with an inter-test-interval of 17 months. Relationships between baseline gray matter volume and baseline depressive symptoms, as well as prospective associations between the development of atrophy and depression were assessed using voxel-based morphometry (VBM). 

Results: Cross-sectional analyses revealed an association between depressive symptoms and gray matter loss in the left temporal lobe. Prospective analysis showed that gray matter losses in the right middle cingulate and middle frontal gyrus at baseline predicted increasing depressive symptoms during follow-up. Increase in depressive symptoms was related to a concomitant increase in atrophy in the left thalamus and right globus pallidus. 

Discussion: Our results fit well into the concept of a disturbed cortico-striatal-pallido-thalamic loop in depression. In this framework, progressive gray matter loss in limbic basal ganglia structures including globus pallidus and thalamus may lead to depression-typical deficits in hedonic motivation, whereas atrophy of the prefrontal cortex may contribute to maladaptive coping strategies, promoting an unfavorable development of depressive symptoms.

Wednesday, 28 December 2016

#CaseStudy: off-label DMTs are not a panacea

How do we treat active PPMS whilst we wait for ocrelizumab? #CaseStudy #MSBlog #ClinicSpeak

This post is a follow-on from two preceding posts on a #CaseStudy of someone with active PPMS. You may want to read the prior posts and the relevant comments before proceeding with this post. 

#CaseStudy PPMS: post 1, 19 December 2016

#CaseStudy PPMS: post 2, 21 December 2016

I note that many of you were horrified that I would ask the community how to manage a patient of mine with active PPMS. I defined him as having active MS because his spinal fluid neurofilament levels are raised; in other words he has active neuroaxonal degeneration going on over and above what you would expect for his age. 

I note that some of you have asked about the sensitivty of MRI picking-up new lesions. You are correct in stating the MRI is not very sensitive and only detects lesions that are ~4mm in size or larger. We know this level of sensitivity is very poor as the majority of active lesions pathologically are microscopic and MRI also misses almost all of the gray matter lesions because of lack of contrast with the background. Therefore, his MRI that did not detect any new, or enlarging, T2 lesions or Gd-enhancing lesions, does not tell me that this patients disease in inactive. If you ask him he knows his disease is active; he is getting worse despite a 'stable MRI'.

In the past I would have motivated to treat this patient with off-label rituximab going the IFR (individual funding request) route. The latter has been stopped by NHS England. Similarly, other high-cost DMTs are out of the questions; our NHS Trust would not be prepared to pay for them and NHS England would say no, as none of our current guidelines allow using these agents in PPMS. 

Making him wait for ocrelizumab is difficult as we can't be sure it will get a license from the EMA for PPMS and then there is the issue of NICE; i.e. greenlighting it for use in the NHS. Waiting for Ocrelizumab could be a long and potentially a futile wait. Similarly, adding him to a waiting list for an upcoming trial is also problematic as there are no immediate trials on the horizon and there is also no gaurantee that he would be eligible for such a trial. This particular patient may not be prepared to be randomised to a placebo. I have not posed that question to him. 

Watchful waiting is an option. I note very few of you have opted for this option and I know that for this patient this position is a no-no. The reason he came for a second opinion is that he is not prepared to do nothing. He would rather go onto something than nothing. 

I have therefore offered him the option of either low-dose oral methotrexate or off-label subcutaneous cladribine. He will come back to me in the new year with a decision about which option he wants. I have explained to him that it us unlikely that either these agents will have a major impact on his lower limb function over the next 2-3 years. He needs to be prepared for his walking to continue to deteriorate. However, if we can suppress ongoing inflammation we may slow down progression after that. It is helpful that this particular patient understands therapeutic lag. The real reason he wants a treatment, however, is to try and preserve upper limb function. This patient is also prepared to undergo annual lumbar punctures so that we can montitor his spinal fluid neurofilament levels. We would expect to  reduce these levels overtime. 



I am sure the critics out there will say you have no evidence that cladribine works in PPMS. I would say yes, and no. We do have a study of cladribine in SPMS and PPMS that was too short, based on the study population, to show an affect on EDSS progression, but cladribine clearly had an impact on MRI activity. I am also of the opinion based on recent insights that all anti-inflammatories work in more advanced MS, however, we needed to look in the right window to see a treatment effect. 

The important principles in regard to treating this patient are:

1. Managing expectations about the treatment effect; i.e. there will be no dramatic effect.
2. Informed consent; this patient knows the risks of the treatment.
3. The therapeutic principles of offering an off-label treatment, including the concept of therapeutic lag.
4. Monitoring and treating-to-target; we are basing our treatment on  the principle that we are want to reduce spinal fluid neurofilament levels and to suppress the development of new and/or enlarging T2 lesions on MRI.

Please note that in an ideal world this patient would have received his first course of orcelizumab a month ago. However, we don't live in an ideal world, but a world of compromises. The decision to offer him low-dose methotrexate or off-label cladribine is a compromise. I don't think off-label drugs are a panacea for treating people with more advanced MS, in this case PPMS, but they offer some hope, albeit limited, over the certainty of getting worse whilst waiting for potential orcrelizumab treatment in several years time. 

Case Study:

Last week I saw a patient with PPMS (>55 years of age). He has had symptomatic disease ~15 years and is using a stick for outdoor mobility. He has a dropped left foot that gets worse when he is tired and as a result has had several falls. Fortunately, he has had no fractures. Other problems included sexual dysfunction, urinary hesitancy, urgency, urgency incontinence and nocturia, constipation, back pain, restless legs and nocturnal leg spasms, poor sleep, fatigue, low mood and the ubiquitous anxiety about the future. He has previously been part of the fingolimod in PPMS study, but doesn't feel fingolimod helped. His walking had continue to deteriorate. His latest MRI showed several spinal cord, cerebellar, pontine and brain lesions. There was gross spinal cord and cerebral atrophy. None of the lesions enhanced after the administration of gadolinium (contrast agent), indicating that none of the lesions were active. His recent cerebrospinal fluid analysis showed OCBs and a raised CSF neurofilament light chain level (1050 ng/ml; ~ double the upper limit of normal for his age). What should I do for this patient?

He has been following our blog for years and wanted something active done about his MS. He had read the literature and was keen to have something done about his disease progression. He was dissatisfied with his current neurologist's attitude who had said there is 'nothing to be done about your disease at present'. He has taken things into his own hands and had ordered high-dose biotin from a US-based compounding pharmacist, but has not noticed a response. After reading around he is keen to go onto low dose methotrexate; his was particularly concerned about losing arm and hand function and is convinced that our group are right about our length-dependent axonopathy hypothesis.

Should I listen to him and prescribe him off-label methotrexate or not? Should I say no and ask him to wait for ocrelizumab? Please note there is no guarantee that ocrelizumab will be licensed by the EMA for PPMS and not guarantee that it will be green-lighted by NICE. In addition, he is over 55, has an EDSS of 6.0 and no active lesions on MRI; this may be important as I suspect the EMA/NICE will want to define a subgroup of people with PPMS who are more likely to respond to ocrelizumab (for example, young (less than 50/55), less disabled (EDSS <=5.5), with active, or Gd-enhancing, lesions on MRI). Should I put him on a waiting list for upcoming clinical trials?


I have left the survey open for comment: 


Methotrexate was effective, compared to placebo, in delaying loss of upper limb function as assessed using the the 9-hole peg test and the box-and-block outcome measures. Methotrexate was not effective in slowing down loss of lower limb function as assessed using the EDSS and ambulation index over 2-years. 

Goodkin et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan;37(1):30-40.

Introduction and Methods: A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year.

Results: A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity.

Conclusions: We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.


Cladribine in advanced MS

Rice et al. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. CladribineMRI Study Group. Neurology. 2000 Mar 14;54(5):1145-55.

OBJECTIVE: To evaluate the safety and efficacy of two doses of cladribine in patients with progressive MS.

BACKGROUND: Treatment of progressive MS patients with cladribine in a previous single-center, placebo-controlled clinical trial was associated with disease stabilization.

METHODS: In the current study, 159 patients with a median baseline Kurtzke's Expanded Disability Status Scale (EDSS) score of 6.0 were randomly assigned to receive placebo or cladribine 0.07 mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7 mg/kg or 2.1 mg/kg, respectively), followed by placebo, for a total of eight cycles. Thirty percent had primary progressive MS (PPMS) and 70% had secondary progressive MS (SPMS). EDSS and Scripps Neurologic Rating Scale (SNRS) scores were assessed bi-monthly and MRI was performed every 6 months. The primary outcome measure was disability (mean change in EDSS).

RESULTS: Mean changes in disability did not differ among the groups at the end of the 12-month double-blind phase. Both cladribinet reatments were superior to placebo for the proportion of patients having gadolinium-enhanced T1 lesions and for the mean volume and number of such lesions (p < or = 0.003). Differences were statistically significant at the 6-month evaluation time, with < or =90% reduction in volume and number of enhanced T1 lesions, which was maintained through final evaluation. This effect segregated largely with the SPMS group. The T2 burden of disease showed a modest improvement in cladribine-treated patients and worsened in placebo-treated patients. Most adverse events were mild or moderate in severity and not treatment limiting.

CONCLUSION: No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS scores. Both doses of cladribine produced and sustained significant reductions in the presence, number, and volume of gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg reduced the accumulation of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally safe and well tolerated.

Filippi et al. The effect of cladribine on T(1) 'black hole' changes in progressive MS. J Neurol Sci. 2000 May 1;176(1):42-4.

We compared the changes of the volumes of T(1)-hypointense lesions seen on the magnetic resonance imaging scans of the brain from 159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T(1)-hypointense lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T(1)-hypointense lesion accumulation was found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS.
CoI: multiple

Dyeing to remember the good old stains

Sudan black: a fast, easy, and non-toxic method to assess myelin repair in demyelinating diseases.Ineichen BV, Weinmann O, Good N, Plattner P, Wicki C, Rushing EJ, Linnebank M, Schwab ME.
Neuropathol Appl Neurobiol. 2016. doi: 10.1111/nan.12373. [Epub ahead of print]AIMS:

The search for novel drugs that enhance myelin repair in entities such as multiple sclerosis has top priority in neurological research, not least because remyelination can hinder further neurodegeneration in neuro-inflammatory conditions. Recently, several new compounds with the potential to boost remyelination have been identified using high-throughput in vitro screening methods. However, assessing their potential to enhance remyelination in vivo using plastic embedded semi-thin sections or electron microscopy, even though being the gold standard for assessing remyelination, is toxic, extremely time-consuming, and expensive.


METHODS:We screened available myelin dyes for a staining candidate which offers a faster and easier alternative to visualize remyelination in cryo-sections.
RESULTS: We identified sudan black as a candidate with excellent myelin resolution and we show that our adapted sudan black staining can demonstrate myelin repair in rodent spinal cord cryosections as reliable as in semithin sections, but much faster, easier, less toxic and less expensive. Besides that, it can resolve the small myelinated axons in the corpus callosum. The staining can yet readily be combined with immunostainings which can be challenging in semithin sections. We validated the method in human spinal cord tissue as well as in experimental demyelination of the rat spinal cord by a lysolecithin time course experiment. As proof-of-principle, we demonstrate that sudan black is able to reliably detect the remyelination enhancing properties of benztropine.
CONCLUSION: Our adapted sudan black staining can be used to rapidly and non-toxically screen for remyelinating therapies in demyelinating diseases.
Sudan Blackdan dyes are synthetic organic compounds that are used as dyes for various plastics and are also used to stain sudanophilic biological samples, usually lipids. Sudan II, Sudan III, Sudan IV, Oil Red O, and Sudan Black B are important members of this class of compounds.Sudan dyes have high affinity to fats, therefore they unsurprising pick up myelin. Theses dyes have been around for ages. 

Funny how we reinvent the wheel

Anyway this may be of interest to people looking at remyelination

Tuesday, 27 December 2016

#ClinicSpeak & #ResearchSpeak: causes of death in MS

Tis the season to consider life and the end-of-life; have you thought about yours? #ClinicSpeak #ResearchSpeak #MSBlog
 
What awaits me at the end? The following Austrian study on the autopsies of 10 people with MS who were critically ill, i.e. who needed to be admitted to an ITU, and died and came to autopsy, tries to answer the question. All these individuals had longstanding MS and had developed respiratory problems, presumably pneumonia and needed ventilation. Importantly, one individual didn't have MS at autopsy, i.e. the had been misdiagnosed in life; a common problem. Another individual had a co-morbidity and had Lewy bodies in their brain at post-mortem. Lewy bodies are a marker of Parkinson's disease. Why shouldn't people with MS not get other neurodegenerative diseases? 


This study confirms what we already know about MS that the majority of people with MS die from MS-related complications; i.e. aspiration pneumonia, pulmonary emboli, urinary tract infections and septicaemia, suicide, etc. In the largest series of cause of death in MS that has been published, ~75% of deaths were attributable to MS-related complications. 


I would be interested to know if the pwMS. who had died in this post-mortem series, had signed an advanced directive before ending-up in ITU? An advanced directive needs to be done at a stage of your life when you are of sufficient mind to instruct your doctors and family how you want to be managed when critically ill. I know from a survey we did at Barts-MS several years ago that the majority of pwMS who were in the late, or terminal, stages of their disease and didn't want intensive therapy. If you haven't done so already I would urge you to discuss signing an advanced directive with your family and HCPs and then to complete one. There is good evidence that advanced directives are a very cost-effective tool in improving quality of life and saving you and society unnecessary and sometime futile healthcare expenses. Advanced directives also make things a lot easier for your family; they remove the stress of complex decision-making at the end-of-life. 

Karamyan et al. Causes of death in critically ill multiple sclerosis patients Acta Neurologica …, 2016

Background: Patients with multiple sclerosis (MS) experience higher mortality rates as compared to the general population. While the risk of intensive care unit (ICU) admission is also reported to be higher, little is known about causes of death CoD in critically ill MS patients.


Aim: To study the causes of death (CoD) in the series of critically ill patients with MS verified by autopsy.


Methods: We reviewed hospital electronic charts of MS patients treated at the neurological ICU of a tertiary care hospital between 2000 and 2015. We compared clinical and pathological CoD for those who were autopsied.

Results: Overall, 10 patients were identified (seven female; median age at death 65 years, range 27-80), and six of them were autopsied. The median MS duration prior to ICU admission was 27.5 years (range 1-50), and the median EDSS score at the time of ICU admission was 9 (range 5-9.5). The median length of ICU stay was 3 days (range 2-213). All the individuals in our series had experienced respiratory insufficiency during their ICU stay. The autopsy examination of brain tissue did not reveal evidences of MS lesions in one patient. In another patient, Lewy bodies were found on brain immunohistochemistry.


Conclusion: Mortality in critically ill MS patients is largely driven by respiratory complications. Sporadic disparities between clinical and pathological findings can be expected.

Lesions revisited

Kuhlmann T, Ludwin S, Prat A, Antel J, Brück W, Lassmann H.
Acta Neuropathol. 2016 Dec 17. [Epub ahead of print]

Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. 

In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. 

Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. 

Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas 

mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. 

Inactive lesions are almost completely lacking macrophages/microglia. 

Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). 

This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. 

For this classification of MS lesions, identification of myelin with histological stains [such as luxol fast blue-PAS] or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. 

We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination.

As it is christmas we have the three kings (pathologists) bringing wisdom. They say "no uniform classification exists".....This is because trying to get pathologiasts to agree to something is like herding cats  

However, when you have a few people providing guidelines the take up is not so great, as when it is a guideline created with consensus of the pathology community. 

Will they embrace the "mixed lesion" or will they continue to describe the lesions as "chronic active", "chronic inactive"?

The search for the MS autoantigen - fools gold or a reality?

Sci Rep. 2016 Dec 23;6:39430. doi: 10.1038/srep39430.

Antibodies from multiple sclerosis patients preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus influenzae.

Walvoort MT, Testa C, Eilam R, Aharoni R, Nuti F, Rossi G, Real-Fernandez F, Lanzillo R, Brescia Morra V, Lolli F, Rovero P, Imperiali B, Papini AM.

Abstract


In autoimmune diseases, there have been proposals that exogenous "molecular triggers", i.e., specific this should be 'non-self antigens' accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of the multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially-derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco-asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS.


Merry Christmas everyone! 🎄🎄🎄🎄🎄

Anyone on a tenure track will happily inform you that if you wanted an uneventful, yet guaranteed research career, stay away from the fools gold. These are the flamboyant areas of research that are everywhere, but literally worth nothing; sucking your combined research budget dry at the blink of an eye! In the field of MS, the never ending search for the MS autoantigen, that mimics host molecules initiating autoimmunity, is undoubtedly one of these ventures. But with technology, comes hope.

MOG (myelin oligodendrocyte glycoprotein) found on the surface of myelin sheaths is a potential antigen involved in the process of demyelination in MS.  Here, Walvoort et al. report on another potential candidate, the glycan (carbohydrate) gluco-asparagine (N-Glc) CSF 114 (N-glc)glycopeptide structure that decorate the cell-surface of bacteria. These are normally present to avoid immune detection as they are similar to motifs present in the host, but can unfortunately lead to the host antigen being recognized as foreign, leading to activation of the immune system against self. Previously, anti-CSF114(N-Glc) have been found in the blood of PwMS, and have been shown to correlate with disease activity and GAD+ brain lesions. Gluco-asparagine (N-Glc) modification are virtually absent in multicellular organisms but present in organisms that lack a nucleus, e.g. bacteria. Walvoort et al. report that the construction of gluco-asparagine (N-Glc) using the machinery present in H. influenza (bacteria that causes upper respiratory tract infection) is critical to isolating the anti-N-Glc antibodies from MS patients blood. Moreover, they demonstrate that antibodies isolated using these antigens react with myelin in the nervous system.

So gluco-asparagine (N-Glc) from H. influenza can trigger formation of autoantibodies in MS. The problem lies in that there may be as yet other unidentified mimics that may be recognized by anti-N-glc antibodies in MS. And so the story begins. It would appear in the case of Walvoort et al. it's only fools gold if you lack aspiration.

Monday, 26 December 2016

PML in Italy

Mouse Doctor is still away so I am adding a comment on this post for him. 

It is clear that the derisking of PML is working. When you pick-up PML in the asymptomatic phase PMLers do better. The real question is that with so many other options, and emerging treatment option, both on- and off-label, should we putting anyone at risk of developing PML unnecessarily? I would say no, but then I don't have rapidly evolving severe MS and I have not had my life transformed by natalizumab. 

Therefore wouldn't be nice if we could develop and anti-viral drug that could clear the JC virus from your body? A viral cure is not science fiction this has been done with other viruses, a good example are the new protease inhinitors for hepatitis C. I have recently become aware that teriflunomide (Aubagio) is a pretty potent antiviral with clinically effecitve activity against the BK virus, a cousin of JCV. Teriflunomide may be just the agent we are looking for. We have put forward a tentative proposal to test teriflunomide againts JCV. Let's hope 2017 bring forth a flurry of research activity to tackle the PML problem. PML is a biological problem and if we put our minds and efforts towards solving it we can solve it; most, if not all, biological problems in the long-term prove to be tractable.

With best wishes Prof G


Prosperini et al. Natalizumab-Related Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: Findings from an Italian Independent Registry. PLoS One. 2016 ;11(12):e0168376. doi: 10.1371/journal.pone.0168376.

BACKGROUND: The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV).


OBJECTIVE: To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions.


METHODS: An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated.


RESULTS: Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01).


CONCLUSION: Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients.


CoI: multiple

Sunday, 25 December 2016

Bad Breath

Nakhleh MK, Amal H, Jeries R, Broza YY, Aboud M, Gharra A, Ivgi H, Khatib S, Badarneh S, Har-Shai L, Glass-Marmor L, Lejbkowicz I, Miller A, Badarny S, Winer R, Finberg J, Cohen-Kaminsky S, Perros F, Montani D, Girerd B, Garcia G, Simonneau G, Nakhoul F, Baram S, Salim R, Hakim M, Gruber M, Ronen O, Marshak T, Doweck I, Nativ O, Bahouth Z, Shi DY, Zhang W, Hua QL, Pan YY, Tao L, Liu H, Karban A, Koifman E, Rainis T, Skapars R, Sivins A, Ancans G, Liepniece-Karele I, Kikuste I, Lasina I, Tolmanis I, Johnson D, Millstone SZ, Fulton J, Wells JW, Wilf LH, Humbert M, Leja M, Peled N, Haick H. Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules. ACS Nano. 2016. doi: 10.1021/acsnano.6b04930. [Epub ahead of print]

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.


This is blow in a bag diagnois. Maybe we will be getting rid of neuros:-). Happy Christmas

#BrainHealth & #ClinicSpeak: the beginning of my 2016 reflections

Our Brain Health campaign continues to grow; what will 2017 bring? #BrainHealth #MSBlog 

The end of the year is a time for quite reflection and recharging of batteries. Our Brain Health initiative continues to gain momentum; thank you. I sincerely hope you are looking after your brain this Christmas? 

Merry Christmas and a Happy New Year! 


Saturday, 24 December 2016

#ClinicSpeak: no wonder MSers have such a hard time in society

Subtle cognitive deficits in MS may underlie how MSers interact with society. #ClinicSpeak #ResearchSpeak #BartsMS

Definition: Empathy is the capacity to understand or feel what another person is experiencing from within the other being's frame of reference, i.e., the capacity to place oneself in another's position. Empathy is seeing with the eyes of another, listening with the ears of another and feelings with the heart of another. There are many definitions for empathy which encompass a broad range of emotional states. Types of empathy include cognitive empathy, emotional empathy, and somatic empathy. (Source Wikipedia)

It is said that to be a good doctor you have to have empathy; you have to have the ability to fee and understand what your patient's are experiencing. What about your patients? You may find the study below of interest, it showed that on average people with MS have lower levels of empathy than controls. Why? I suspect this is due to MS and is another example of a hidden MS symptom. 

Empathy is a complex emotion and involves the so called mirror neuron system.  The circuity starts in the premotor part of the frontal lobe and involves an extensive network including a behavioural and motor responses. I am not surprised this system is damage in MS. People who lack empathy have problems interacting with others and with society in general. Therefore this is another dimension to MS that needs to be considered when interpreting the high unemployment, high divorce rates, depression, anxiety and social exclusion in MS. If we treat MS early and effectively and protect your brain then the neurological circuitary responsible for empathy is likely to be preserved, and protected, and you won't suffer the consequences from it being damaged.

How sure are you that your MS is under control? Have you asked?  


Almeida et al. Patients with multiple sclerosis present low levels of empathy. Arq Neuropsiquiatr. 2016 Dec;74(12):982-985.

METHODS: This is a single center, cross-sectional study, of 34 patients with MS and 34 matched control subjects. A specific questionnaire (empathy quotient) was used.

RESULTS: Patients with MS showed significantly lower levels of empathy. This finding was not correlated with disease duration, degree of disability, drugs for treating MS or lesion load on resonance magnetic imaging.

CONCLUSION: Decreased empathy is a frequent condition in patients with MS and should be addressed in order to diminish the psychosocial burden of this neurological disease.

Advent Calendar 24



Friday, 23 December 2016

#ThinkSpeak: Do you have any wishes for 2017?

Any MS ideas and suggestions for 2017? #ThinkSpeak #BartsMS #MSBlog

My 'holidays' started last night. We had dinner with a very good friend from my clinical firm in medical school. Her son has just graduated from Wits medical school in Johannesburg. This is 29 years after we graduated; where has the time gone? We all agreed that 2016 was an annus horribilis; I have never felt so unsettled about global, national and local events. It is clear that the status quo is not an option; change happens. Despite this I am grateful for what I have; my health, my family, a dog who loves me, I am still running, I have a vocation that continues to stimulate me and it makes me think and I think we are making a difference. I am determined to make the next 2 weeks count; I want to return to work rested, full or vigour and ready for the year ahead. 

Barts-MS has set it self many challenges for 2017; some are ongoing projects that need closure. However, there will be a few new ones and some that we have yet to think of. I would therefore like you to think about what you want us to do? Do you have any Christmas wishes, any ideas, any challenges for us and the wider MS community? Don't be shy this blog is forum for open and honest discussion. 




Merry Christmas and a Happy New Year or Happy Holidays!

What is a neutralizing response?

Bachelet D, Hässler S, Mbogning C, Link J, Ryner M, Ramanujam R, Auer M, Hyldgaard Jensen PE, Koch-Henriksen N, Warnke C, Ingenhoven K, Buck D, Grummel V, Lawton A, Donnellan N, Hincelin-Mery A, Sikkema D, Pallardy M, Kieseier B, Hemmer B, Hartung HP, Soelberg Sorensen P, Deisenhammer F, Dönnes P, Davidson J, Fogdell-Hahn A, Broët P; ABIRISK Consortium.. Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis. PLoS One. 2016;11(11):e0162752. doi: 10.1371/journal.pone.0162752.

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial aetiology. Here we study associations between   A subset of 5638 interferon-beta (IFNβ)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. 

IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). 


IFN 1 beta is made in bacteria rather than mammalian cells for 1a and we know that subcutaneous 1a was also causing neutralizing antibodies and this was reduced by the new formulation that had fewer aggregates. Likewise it is well know that intra muscular causes less neutralizing antibody events but this advantage may be offset by being less active than the others. Importnatly as I have said many many times the subcutaneous route is a sensitizing route and in this case the subcutaneous agents caused 6-8 times more cases of neutralising responses.

There currently are trials using myelin peptides subcutaneously.

Patients older than 50 years at start of IFNβ therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). 

Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). 

Interestingly we observed that in Sweden and Germany, patients who started IFNβ in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). 

Is this the month of treatment effect and it is all to do with vitamin D or does this show if you do enough comparisons one or two will show a difference.

This result is not confirmed in the other cohorts and warrants further investigations..... Does it Really?:-)

Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). 

So says the same as the beta interferon results so more reason to start therapy in your youth.

We confirmed previously reported differences in immunogenicity of the different types of IFNβ. 

Yeah

Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

So neutralizing antibodies are a problem for drugs and if they occur the drugs can stop working.

The occurrence of neutralising antibodies varies from agent to agent for the interferons it may be about 30% for natalizumab its about  6%....what happens with alemtuzumab where it occurs in 80% of people?.....Yes about 80% of people

Advent Calendar 23