Wednesday, 30 September 2015

Calling all Neurologists...Please Read.

A BBC report says
A brain specialist who advises the National Institute of Health and Care Excellence (NICE) says although disease-modifying drugs have a role in established relapsing, remitting disease, there is still debate about their use early on in the condition.

Please Read

Is the MS Community Prepared to Promote Brain Health?

With comments like the have your work cut out ProfG & DrK.

The ABN (Association of Britsh Neurologists) must be such an amazing  place for knowledge transfer:-(

ResearchSpeak: B cells in the spotlight

How long will the B cell remain top of the pops? I am a plasma cell fan. #MSBlog #MSResearch #ResearchSpeak

"The B cell is now firmly in the MS spotlight and will be even more so after we get to hear the ocrelizumab results at ECTRIMS. When proposing a cause of MS we have to be able to explain the effect of all the DMTs on the causal pathway. When I did this exercise using cell types the B cell was the only common cell to all the highly effective DMTs with exception of daclizumab (anti-CD25). It appears that B cell function in MSers treated with daclizumab is relatively normal although B cell numbers in the spinal fluid do drop. The lack of a direct impact of daclizumab on B cell function is one of the reasons why I find the drug so interesting."

"Back to the B cell; why is it so important? I would like to think it has to do with EBV, but until we have a treatment that targets the EB virus and leaves B cells intact we won't be able to address this issue. This is why we launched the Charcot Project and why we still want to do the ARTEMIS study. However, is it simply good enough to deplete B cells, or block their trafficking into the central nervous system? There is evidence that B-cell follicle like structures in the brain of MSers is responsible for progressive MS. The problem with simply targeting B cells with anti-CD20 therapies is that you leave the plasma cells intact. Plasma cells are long-lived specialised factory cells that produce antibodies in large quantities. This is why we need to test treatments that cull the plasma cell pool within the brains of MSers."

"We know already that the OCBs (oligoclonal IgG bands) in the spinal fluid don't disappear with rituximab treatment and are unlikely to disappear with ocrelizumab treatment as well. Nor do they disappear with alemtuzumab treatment and HSCT or BMT. However, there is an emerging literature that in MSers on long-term natalizumab treatment OCBs may disappear. Unfortunately, most of the studies looking at this have been relatively small and one study was negative. Therefore a larger more systematic study is needed. The question is how does natalizumab get rid of OCBs? I nearly fell off my chair at the EAN meeting earlier this year when I heard that the plasma cells need VCAM-1-VLA interactions to remain in their niche. As natalizumab blocks the VCAM-1-VLA interaction it may be responsible for displacing plasma cells and results in the death of long-lived plasma cells within the CNS. If this is true it may change the treatment paradigm of MS. What is clear is that plasma cell biology within the CNS in MSers needs much more careful study; particularly in MSers on highly effective DMTs."

"Since learning about the plasma cell niche I am much more upbeat about natalizumab's chances in progressive MS. We won't have to wait too long; Biogen are due to announce the results of the ASCEND trial (natalizumab in SPMS) in the next few weeks. Let's hope it is good news. I am still concerned that the ASCEND trial may have be too short (24 months) to give a positive read-out. However, Biogen enriched the study for rapid progressors and it is one of the most effective DMTs we have so it has more than a fighting chance of clearing the efficacy hurdle."

"When you look at B-cell and plasma cell biology it is clear that that there are therapeutic targets other than CD20 and VLA-4. Anti-CD19 is expressed on plasmablasts and plasma cells so it has the potential to be more effect that anti-CD20 treatments. Similarly, the recent trial of anti-CD38 in myeloma (a malignancy of plasma cells) was very encouraging. Maybe we can target anti-CD38 to the CNS as a potential MS treatment? Similarly, thalidomide and thalidomide-derivatives are drugs that are used to treat myeloma; could they be used to treat MS? I suspect the side effect profile makes them too risky. The good news is there is still much to learn about MS and many therapeutic strategies to test."

The peripheral plasma cell niche is likely to be similar to the CNS niche in MS!

Mancuso et al. Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: a longitudinal study. Mult Scler. 2014 Dec;20(14):1900-3.

Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years ofnatalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy. Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed thatnatalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.

von Glehn et al. Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients. Mult Scler. 2012 Jul;18(7):1038-41.

Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MS patients. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.

Warnke et al. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler. 2015 Jul;21(8):1036-44.

BACKGROUND: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).

OBJECTIVE: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37).

METHODS: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.

RESULTS: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.

CONCLUSIONS: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.

Lokhorst et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19.

BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.

METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics.

RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.

CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; number, NCT00574288.).

CoI: multiple

Sex hormones and glucose

Triantafyllou N, Thoda P, Armeni E, Rizos D, Kaparos G, Augoulea A, Alexandrou A, Creatsa M, Tsivgoulis G, Artemiades A, Panoulis C, Lambrinoudaki I.Association of sex hormones and glucose metabolism with the severity of multiple sclerosis. Int J Neurosci. 2015:1-8. [Epub ahead of print]

Purpose/Aim of the study: We evaluated possible associations between the severity of multiple sclerosis (MS) and levels of sex hormones as well as biochemical parameters in a sample of ambulatory patients.
MATERIAL AND METHODS:This cross-sectional study recruited 133 adults (52 men, 66 premenopausal and 15 postmenopausal women), with relapsing-remitting MS. Fasting venous blood samples were drawn for biochemical and hormonal evaluation. These parameters were tested for possible associations with MS severity, assessed using the Expanded Disability Status Scale (EDSS)-scores.
RESULTS:Follicle-stimulating hormone correlated with mean EDSS scores (r = -0.369, p = 0.038) in the premenopausal subgroup. However, this association became non-significant in the age-adjusted multivariate analysis (p = 0.141; power = 67%, type α error 0.10). Free androgen exhibited a borderline negative effect on EDSS-scores in the subgroup of men (r = -0.367, p = 0.093), which was lost after adjusting for age and duration of disease (p = 0.192; statistical power = 93%, type α error 0.05). Levels of oestradiol tended to affect disability status of postmenopausal women (normal-mild vs. severe impairment: 23.33 ± 11.73pg/mL vs. 14.74 ± 6.30pg/mL, p = 0.095). Levels of sex hormones or indices of glycemic metabolism did not differ between patients presenting with EDSS scores higher or lower than the median value.
CONCLUSION:Sex hormones and indices of glucose metabolism exhibited only a middle effect on EDSS scoring, which was not independent from the presence of confounders like age and duration of MS. The present study highlights the need for additional research, in order to elucidate the role of sex hormones and insulin resistance in the course of MS.
This study looks at the influence of hormones on MS and again we have the dreaded r=-0.4 as being interesting. 

Some of you buy this,  I don't.  A correlation of r=0.4 or r=-0.4 tells us very little about the individual and so here the FSH hormone levels showed essentially nothing , The levels of osestrodiaol showed essentially nothing and the levels of testosterone showed essentially  nothing.  

P=0.05 gives a probability of one in twenty chance that the result obtained is a fluke. In science-land P>0.05 means there is no effect, do it again with a bigger group size or find something more interesting,  but in clinical-science-land it means almost interesting. Look at the graph above for what an r=0.4 looks like, can you see an interesting correlation?

Potassium Channel Opener bombs in MS

Villoslada P, Rovira A, Montalban X, Arroyo R, Paul F, Meca-Lallana V, Ramo C, Fernandez O, Saiz A, Garcia-Merino A, Ramió-Torrentà L, Casanova B, Oreja-Guevara C, Muñoz D, Martinez-Rodriguez JE, Lensch E, Prieto JM, Meuth SG, Nuñez X, Campás C, Pugliese M; NeuroAdvan study. Effects of diazoxide in multiple sclerosis: A randomized, double-blind phase 2 clinical trial. Neurol Neuroimmunol Neuroinflamm. 2015 Sep 10;2(5):e147.

OBJECTIVE: The aim of this study was to test the safety of diazoxide and to search for signs of efficacy in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: In this multicenter, randomized, placebo-controlled, double-blind trial (treatment allocation was concealed), 102 patients with RRMS were randomized to receive a daily oral dose of diazoxide (0.3 and 4 mg/d) or placebo for 24 weeks (NCT01428726). The primary endpoint was the cumulative number of new T1 gadolinium-enhancing lesions per patient, recorded every 4 weeks from week 4 to week 24. Secondary endpoints included brain MRI variables such as the number of new/enlarging T2 lesions and the percentage brain volume change (PBVC); clinical variables such as the percentage of relapse-free patients, relapse rate, and change in the Expanded Disability Status Scale score; and safety and tolerability.
RESULTS: Diazoxide was well-tolerated and it produced no serious adverse events other than 1 case of Hashimoto disease. At the 2 doses tested, diazoxide did not improve the primary endpoint or the MRI and clinical variables related to the presence of new lesions or relapses. Patients treated with diazoxide showed reduced PBVC compared with the placebo group, although such changes could be confounded by the higher disease activity of the treated group and the vascular effects of diazoxide.
CONCLUSION: At the doses tested, oral diazoxide did not decrease the appearance of new lesions evident by MRI. The effects in slowing the progression of brain atrophy require further validation.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RRMS, diazoxide (0.3 and 4 mg/d) does not significantly change the number of new MRI T1 gadolinium-enhancing lesions.

Diazoxide (INN; brand name Proglycem) is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions. This switches off voltage-gated calcium ion channels, preventing calcium flux across the sarcolemma and activation of the contractile apparatus. Diazoxide is used as a vasodilator in the treatment of acute hypertension. In this study they find no effect on inhibiting relapsing MS.

There is a thought that targeting potassium channels can block lymphocyte function.

I wonder why they would expect this...the answer is clear ......the dreaded EAE.

However, if you look at the EAE data (above), diazoxide is not really stopping the immune response, as animals are getting EAE. 

So why would you want to target relapsing MS? 
People should get MS attacks if the animal data is correct and this is what happened.

However ,the drug may influence neurodegeneration and be neuroprotective. Enhance potassium levels and it blocks too much nerve signalling..which can cause excitoxicity (nerves fire themselves to damage). The
 brain volume loss may have been protected in MS. 

So in my opinion a different trial design may have found a difference. 

Virgili N, Mancera P, Wappenhans B, Sorrosal G, Biber K, Pugliese M, Espinosa-Parrilla JF. K(ATP) channel opener diazoxide prevents neurodegeneration: a new mechanism of action via antioxidative pathway activation. PLoS One. 2013 ;8(9):e75189. 

However, this study is unlikely to be repeated as it is seen as a failure...a failure of EAE? or a failure to see what EAE can show?...

However, as we (the EAEers not TeamG) are doing EAE experiments that make it hard to dissociate immunosuppression from neuroprotection. Until people wake up and change how they do and interpret EAE experiments, this confusion and resultant failure will continue. 

Should I shut this does not send out a good message I am sure you will appreciate. I may suffer the consequences....However, firstly, it is an opinion and may be wrong. 

Secondly if nothing is said, nothing will change and it is more ammunition for the EAE bashers. 

People can argue otherwise if they like and say everything is great, but the truth is we have not delivered drugs to PPMSers/SPMSers. 

People can argue their case and I may be full of mushroom food, but I will say the graph above is there for everyone to see. what's your interpretation.

P.S. Note the top graph starts a 1 not 0 this is to make the small differences look bigger.

P.P.S. Yes I'm Mr. Grumpy today

#PoliticalSpeak: time is brain

Does time matter? #BrainHealth #PolticalSpeak #MSBlog #MSResearch

Tuesday, 29 September 2015

ClinicSpeak: managing expectations

What are you expecting ocrelizumab to do for your PPMS? #ClinicSpeak #MSBlog #MSResearch

"In the past I have always warned that we should not expect too much from the first effective DMTs in progressive MS. They are unlikely to be miracle drugs. I therefore would like to prepare you for the ocrelizumab results when they are presented. In other words I want to set realistic expectations."

"I agree with all the comments from yesterday that the announcement of the positive ocrelizumab in PPMS trial results was great news; probably the best news we have had in a decade or more. However, I would like to remind you of a survey we did on this blog a few years ago (see slideshow below). About 40% of progressive MSers are expecting an effective DMT to improve their functioning or to result in a full recovery; this is unlikely to happen. At best ocrelizumab will stabilise your disease or more likely slow down the rate of disability progression. What this means is that progressive MSers on an effective treatment may not notice much. Getting worse more slowly may be difficult to notice on a background of progression. However, ocrelizumab is a start and will allow us to begin to target different processes in MS with the hope of developing add-on neurorestorative therapies. Innovation tends to be incremental; having an effective anti-inflammatory therapy for progressive MS provides the base of the pyramid; we now need to add the neuroprotective, remyelinative and neurorestorative tiers."

CoI: Multiple. Please note I do not at this stage know the results of the PPMS ocrelizumab trial.

The History of B cell depletion in PPMS

Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, Hauser S, Waubant E, Vollmer T, Panitch H, Zhang J, Chin P,Smith CH; OLYMPUS trial group.Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial.Ann Neurol. 2009;66(4):460-71.

OBJECTIVE: Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS(PPMS) through 96 weeks and safety through 122 weeks.
METHODS: Using 2:1 randomization, 439 PPMS patients received two 1,000 mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans.
RESULTS: Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. 

Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. 

Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses.
INTERPRETATION: Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions.
Current Ocrelizumab trial

Ages Eligible for Study: 18-55 Years 
(responder population)
Expanded Disability Status Scale (EDSS) 3 to 6.5 points
(Early MS so capable of responding and in the time frame when progression is most rapid i.e. between EDSS 4-6) so change in the placebo arm can be seen. How many other trials have started past this point when it is change is slow.
Disease duration from onset of MS symptoms < 15 years if EDSS > 5.0, < 10 years if EDSS >/= 5.0 (Shortish duration)

Exclusion Criteria:
History of progressive relapsing multiple sclerosis at screening.

The inclusion criteria are not that different from the failed fingolimod primary progressive trial.

We only have to wait a couple of weeks to find out if every one benefitted of if it was the gadolinium-enhancing subgroup that will be enriched in people in this trial.

It's all the RAGE measuring progression

Sternberg Z, Chiotti A, Tario J, Chichelli T, Patel N, Chadha K, Yu J, Karmon Y.

Reduced expression of membrane-bound (m)RAGE is a biomarker of multiple sclerosis disease progression. 

Immunobiology. 2015. pii: S0171-2985(15)30060-7.


This study is one in series measuring RAGE axis (receptor for advanced glycation end products, its isoforms, and ligands) as a biomarker in multiple sclerosis (MS). We identified and quantified membrane-bound RAGE (mRAGE) expression levels on freshly isolated PBMCs and its subpopulation (monocytes and T cells), and determined the relationship between mRAGE expression levels and MS disease severity.


mRAGE expression was determined for 28 MS patients and 16HCs, by flow cytometry, using fluorochrome unconjugated primary RAGE monoclonal antibody and a polyclonal secondary antibody conjugated to R-Phycoerythrin (PE).


After adjusting for multiple comparisons and correcting for group differences in age and gender, MS patients showed higher percentages of mRAGE-positive on PBMCs (12.4±2.1 vs. 4.08±0.8, P=0.02), monocytes (37.4±5.8 vs. 20.1±5.0, P=0.08) and T cells (4.1±1.2 vs. 2.1±0.3, P=0.05). SPMS patients' showed lower percentages of RAGE-positive monocytes (13.7±5.5 vs. 49.5±6.6, P=0.0006) and RAGE-positive T cells (4.1±1.8 vs. 6.6±1.5, P=0.04) than RRMS patients. We observed a negative relationship between the percentages of mRAGE-positive PBMCs and MS severity scale (MSSS) (r=-0.39, P=0.04), monocytes and EDSS (r=-0.48, P=0.01), monocytes and MSSS (r=-0.58, P=0.001), and T cells and MSSS (r=-0.40, P=0.04). Monocytes expression of mRAGE showed 0.811 area under the curve (95% CI: 0.64-0.98) sensitivity/specificity for MSSS.


The reduced mRAGE expression on PBMCs in general, and on monocytes in particular, can be used as biomarker of MS disease severity and progression.

Figure: The different RAGE receptors and its soluble versions (sRAGE)

The receptor for advanced glycation endproducts (RAGE) is predominantly expressed in the lungs, but is also found on immune cells (PBMCs), and has a number of roles; but commonly directs response to cell stress. As far as inflammation is concerned, one of the molecules which binds RAGE, HMGB1 leads to migration of inflammatory cells into a region, thereby sustaining the inflammatory response, but the binding of HMGB1 can also initiate immune response to stem off invading micro-organisms and at the same time direct the regeneration of damaged tissue. Therefore, one mechanism can serve several purposes. Moreover, RAGE has also been directly linked to cancer progression, diabetes, heart disease and Alzheimer's disease.

What interests me about RAGE, aside from RAGE on PBMCs, is soluble RAGE. RAGE in its unbound form has the potential to bind proinflammatory molecules in the blood taking them out of circulation. Low levels of RAGE are insufficient to bind circulating proinflammatory molecules and therefore cannot protect against chronic inflammation. Previously, those on DMTs (disease-modifying therapies) have been noted to have greater circulating RAGE levels than DMT naive individuals. And not surprisingly low RAGE levels are also associated with greater levels of disability, with SPMS individuals demonstrating lower levels than RRMS individuals (see figure below).

Figure: Cell surface RAGE expression in RRMS and SPMS. Greater levels of RAGE are found in monocytes than T cells and may have a greater role to play in inflammation driven by the innate immune system.

RAGE therefore may be a promising biomarker in MS for predicting progression, however, creating therapies which modulate the RAGE pathway will be unpredictable as it signals via many binding partners with very different end-results.

Monday, 28 September 2015

Ocrelizumab Results

You said

Dear B cells,

I want to end our relationship.

It's not you its me, I feel that you participate in an attack against me for no good reason. We've had a long time together but I think that you need to leave.


NewsSpeak: finally some good news for PPMSers

Finally a positive trial for PPMS. #NewsSpeak #MSBlog #MSResearch

"As far as news, and good news, goes this ECTRIMS is going to be the best ever. As you can see from the Roche press release below the phase 3 study of ocrelizumab (anti-CD20) in PPMS is positive. Yes, ocrelizumab slows the acquisition of disability in PPMSers."

"What more can I say? Except, I would like to thank all the PPMSers who participated in this study; without your commitment this study would never have happened."

"I have been saying for years on this blog that the B cell is where all the action is in MS. These results prove that! Why? I have an hypothesis, many of you know it, but more on that later. I need to take a moment to reflect on this result, and to savour the moment, before saying anymore."

CoI: multiple, Prof G sits on the steering committee of this trial, Dr K was the PI of this study at Barts Health. 

Cannabinoids control symptoms and may limit nerve loss

#MSresearch Fantastic review of cannabis in MS

Pryce G, Baker D. Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Handb Exp Pharmacol. 2015;231:213-231

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

A fantastic review on the effects on the cannabinoid system as symptom control agents and their neuroprotective potential. However yes CoI it is our work.

Our work on symptom control in beasties was realised by being able to control symptoms in MS.Will the neuroprotective potential that we found every be realised?  

Sadly I doubt it, because of the clinical trial failure with tetrahydrocannabinol has probably sunk this avenue from ever being realised or properly researched. No one is going to fund this. 

However, symptom control use , will be neuroprotective in our humble opinion so with medical marijuana there may be added benefit. Will pot smoking be monitored to address this issue. I doubt it too. However, we can do the same with pharmacological agents that avoid cannabis and the issues of recreational use/abuse.

We continue to maintain that cannabinoids are of essentially no use in controlling the T cell-mediated immune response and relapsing MS, despite the sea of papers showing that cannabinoid inhibit immune responses. However the animals are so whacked-out by the doses use, the data in animals is in our opinion utterly useless.

If cannabis was so immunosuppressive, why wouldn't we have seen this in trials and in general use given that it is the third largest drug of abuse.

Why would people with AIDS be smoking an immunosuppressive agent (it stimulates appetite)...simple answer is they wouldn't do it.

Why comment on this as a review...Almetrics;-)

PoliticalSpeak: Brain Health

If you are going to ECTRIMS have you signed up for the Brain Health launch? #MSBlog #MSResearch #PoliticalSpeak

"Version one of our brain health policy document, to try and change the way we view and manage multiple sclerosis, has gone to press. We will be updating the endorsement page once we have had responses from all the organisations we have asked to endorse the document. However, the main document has now been approved by all members of the writing committee."

"If I can say so myself, I think it is an excellent document and I want to thank all my colleagues, stakeholder organisations and the staff of the Oxford Policy Forum for making it happen."

"In short the document simply promotes the holistic management of MS, the need to empower MSers, to involve them in shared-decision making and to adopt the slogan 'time matters' as a call to action. The document is simply stating that we should be aiming to maximise the lifelong brain health of MSers (diagnose early, treat early, treat effectively, monitor & document, treat-2-target)."

"We will be making the document available via the web after its launch on the 6th of October. If you want to attend the launch meeting please RSVP online at; places are limited."

CoI: Please note that the launch symposium is being funded by generous grants from AbbVie and Genzyme and by educational grants from Biogen, Hoffmann La-Roche and Novartis, all of whom had no influence on the content of the programme or document.

Sunday, 27 September 2015

Docs blowing the whistle on Pharma. Oiling the pharma cogs, greasing the neuros pockets

#MS Research Oiling the pharma cogs, greasing the neuros pockets

Doctors have been taking a self-inflicted bashing at the end of last week, so you may be interested to read this article whilst sticking the boot in.

You may have noticed that ProfG has not been posting as often as he used to. Is it because he is adjusting his life-style or has he been knobbled by Pharma to stop posting negative things:-)

Scientists are surprised by the assistance given to Neuros in many things, so we have "ghost writers "who write the trial manuscripts for the neuros, we have pharma making the posters for many people attending ECTRIMS...Don't believe me, then look out for the corporate branding on the posters and ask how many neuros come and go with poster tubes...(Not many because the companies print and bring them).

British cardiologist Peter Wilmshurst described in 2012 by the British Medical Journal as a "successful and cheerful whistleblower" began his crusade against dishonesty in medical research in 1986. In the course of the 66-year-old's career, he conducted studies for pharmaceutical and medical devices companies, and unlike many of his colleagues, never hesitated to publish negative results. He's been the subject of multiple cases of legal action and risked bankruptcy and his reputation to expose misconduct in the pharmaceutical industry. Today he advises and supports other whistleblowers with the organization "Patients First."

Read an interview

In your early years as a researcher, a pharmaceutical company offered you a bribe equivalent to two years of your salary: They wanted to prevent you from publishing negative study results. 

"I was just a bit surprised to be offered any money, really. I was a very junior researcher and doctor, only 33 years old, so I didn't know that sort of thing happened. I didn't know that you could be offered money to conceal data".
"Initially we were talking about the results that I'd obtained: That the drug that I had been testing for them did not work and had dangerous side effects". 
"Then the company representatives asked me to leave some of the patients out of the data analysis. Without these patients, the study result would have been positive.When I said I couldn't do that, they asked me not to publish the data. And to compensate me for the work I had done in vain, they said, they would offer me this amount of money".
"They terminated the trial prematurely, and to prevent us from doing more research with the drug, a representative from the pharmaceutical company came to the hospital pharmacy and asked for the stocks. The pharmacist noticed that something was wrong and tried to call me. While he was on the phone the drug rep picked up the box with the drug in it and left."

We know know if trials are going ahead because they are registered on places like clinical  

However there is a publication bias for positive  results and there is no urgency placed on publishing negative results. We are still waiting to see the negative fingolimod data in PPMS. It will appear in som small journal years down the line.

Scientists are guilty of not rushing to publish negative data either. You can sometimes drop in the negative stuff with the positive stuff and am doing this as I write. Likewise last week I put some data into a manuscript that we did in 1990s. Now was the right time to publish this. I am writing a manuscript which is solely will have a hard time.

You don't want to spend resource on a dead avenue, however sometimes finding out why things don't work is the positive.

However in the clinical case above it is not about burying data about something that didnt work it is about hiding something that was dangerous.

Is research fraud like this widespread?
"I can't tell you exactly what percentage of the trials are flawed. But I think the problem is far bigger than you imagine. And it is getting worse. Because research is getting more important for a doctor's career, and it is so easy to manipulate data, conceal it or fabricate it. Or make unimportant research look like a huge success."

Flaws in trials is one thing but fraud is another and far more serious accusation. There is a move for pharma to deposit the whole trial data set into the public domain for re-analysis. This is being resisted by some pharma, but it is possible to get your hands on trial data..we have done this via a freedom of information request. However pharma could have re-dacted the information. Likewise, the suggestion that it is easy to fabricate, I doubt due to trial monitoring, multi-national nature of trials and the blinded nature of the studies. However things are spotted. I was once at a talk when we were accused of having too varied an EDSS scoring, which made something not statistically significant.

Are studies about drugs with dangerous side effects also systematically hushed up?

"Yes, absolutely." 

Graphic: The Trillion Dollar Pharmaceuticals Industry

Graphic: The Trillion Dollar Pharmaceuticals Industry

As a hypothetical, it was asked how pharma can excerpt influence 

"Well, I think the way you should do it is to get eminent doctors on your side by paying them a lot of money. Officially they are still independent consultants or university professors, but the truth is, they lose their independence the moment they are on your payroll. What these opinion-leaders say has a lot of weight among other doctors."

What wiil ProfG say to this?...I would add it is none of our business, if you provide a service it is correct that pharma should pay for it.

However, whilst we are stirring it....Have you noticed that the same neurologists appear as leaders of trials, over and over again. Have you noticed that the same speakers present at ECTRIMS over and over again.

Pharma will get opinion leaders to do talks on their products, because they are trusted. Pharma spend money doing surveys to find out who is an opinion leader.

I once got a survey of this nature and they offered to pay £150 by paypal Yes I declared it and paid tax on it!). It was for neurologists... but the way the questions were asked, I could answer without lying..i.e. how many people with MS have you seen this year I said 3,000 because I had just got back from MS life in Manchester.
How many times did I seek a second opinion?. Never.
Which speaker would you listen to Nationally, In Europe and Internationally...ProfG of course.

Thanks for the lolly:-)

However it does back fire, because these opinion leaders can role up to present slides made for them and have not thought about the problem. e.g. If daclizumab is inhibiting CD25 interleukin two receptor it will block Treg function and as daclizumab inhibits MS, it argues that T regs are not that important. The person could not give an answer and looked a real fool in front of one or two thousand neuros.  Anyway  

"I think for many of them enough money is all they need, really. I mean, most people have a price. But of course you have to be very friendly with them, you have to go and talk to them, have lunch with them, discuss the research. They have to forget that it is your aim to make the maximum amount of money".

Some people will do it for the money, but some people see it as a way to make a difference and the money is incidental. (I would bet that this is the majority of cases) My company has offered ProfG some consultancy money and I don't think he has ever requested any. 

I once was offered some consultancy to attend a company meeting. It was interesting that some neuros arrived a few min before coffee and left as coffee (15min break) finished...probably cash in hand. I gave 4-5 hours of my time.

What if the professor produces results in a trial that we don't like?
You have made the principal investigator sign a confidentiality agreement beforehand, so that you have control over the data. And you may put into the contract arrangements for a bonus in case of a positive result. (grins) This may help the researcher interpret the data in a more favorable way for you.

News to me, sounds like footballers bonus, but as contracts for trials in UK is with the universities/hospitals they get any money and not the neuros. In other countries this may not be the case. 

But there's one obstinate researcher who keeps insisting on publishing negative results. And he doesn't accept the bribe that we offer him. What now?

Well, you can try and discredit him, you can try to ruin his reputation and cast doubts on his results. That's what was done with me. And then in the end you can sue him. The threat is often enough to keep him quiet.

In a phase III the data is not going to be in the hands of a single neuro as the company will get a statistician to analyse the data and even in a phase II investigator-led study it will be the statistician who analyses the data. If you don't agree with the conclusion then you remove your name from the paper

Most young people start medical school with very high ideals ...
"yes, at the beginning they all want to work for Doctors without Borders......I think it starts in a very innocent way. You go to a lecture and the pharmaceutical industry provides sandwiches for lunch. You don't think of a sandwich as a bribe, do you? And then you see other people taking more -- money for lectures, tickets to conferences. Gradually you accept bigger and bigger bribes"

The days of company sponsored jollies are being reduced year on year but there will be VIP lounges at ECTRIMS and companies will be bringing Neuros to ECTRIMS. But if I eat an apple with a companies name on what..give people abit of credit.

So many senior doctors are not very good role models?

"Unfortunately not. As a junior doctor what you see is that money is very, very important. Many doctors judge their value to society by how much they earn. Like bankers. If they haven't got enough to drive a Porsche, then they're not a very good doctor"

What do you recon NDG and ProfG. Is cash the driver....I suspect not

"Colleagues and superiors don't trust whistleblowers, because they think it could be their turn to be reported next. Also, the reputation of the medical institution they work for is at risk if a whistleblower reports fraud, so loyalty to your employer is valued higher than the truth. But I think as a doctor your loyalty should be primarily to your patients. And as a scientist it should be to the truth of your research. But I think some people have forgotten what it means to be a doctor and a scientist"

Mushroom food me thinks

What in your view are the most important changes that should be made to prevent fraud?

"Research should be independently checked".

"Since it's the money of the pharmaceutical companies that controls the researchers, it would be important to put a barrier between the company and the scientific investigators. The company could pay the money that is needed to do a study to an independent body, e.g. the Department of Health. The Department of Health then suggests which researcher could do the study, and when the company agrees, pays out the money. So there is no direct contact between the company and the researcher".

So the department of Health picks the very same researchers that Pharma would pick and you have a middle man, taking their slice. The consultancy money will still need to be paid

Who pays for the MHRA, NICE, yes the pharma industry

Stem cells promoting repair

Glenn JD, Smith MD, Kirby LA, Baxi EG, Whartenby KA. Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination. PLoS One. 2015 Sep 25;10(9):e0139008.

Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG35-55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1) and IL-17A-producing (TH17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.

So you wanted stem cells and you are getting trials in stem cells, but should we be running before we can walk. The answer is its too late the studies are happening . But this study underscores the problem. The results were hyped and were either marginally effective or as shown here they were ineffective and so now we wait for the results in MS. Lets hope they are fantastic but I fear not. This study argues that mesenchymal stem cells are pretty rubbish in EAE and so pretty rubbish as an immune modulator.
I have argued numerous times however that current DMT can do more than these stem cells. 

What we want to see is repair because this is why you want stem cell studies. In this study there is a suggestion that the stem cells can promote repair here, but in other studies this effect has been weak.

What will the human trials show?

Saturday, 26 September 2015

Factors affecting long term outcomes

Kappos L, Kuhle J, Multanen J, Kremenchutzky M, Verdun di Cantogno E, Cornelisse P, Lehr L, Casset-Semanaz F, Issard D, Uitdehaag BM. Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15. J Neurol Neurosurg Psychiatry. 2015 Sep. pii: jnnp-2014-310024.

An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) β-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS).
METHODS:Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN β-1a dose groups, and according to total time receiving sc IFN β-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed.
RESULTS:Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥4 or ≥6, ≤5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years.
CONCLUSIONS:These findings suggest that higher cumulative exposure to sc IFN β-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.

The yin Yang of Beta interferon, one paper saying it doesn't lead to long term benefit, the next saying yeah. 

Hopefully the situation will be very much clearer in the era of highly effective DMT. One would hope it makes a difference in the long-term. 

Has natalizumab changed the result its been around for more than a decade. However, people getting natalizumab have more active disease and so the long term data will be skewed as the CRAB drugs are still the norm. 

Unless we start with moderestly to highly active treatment it may be difficult to see. 

Primary Progressive MS, who should be in trials?

Following on from yesterdays post by PostG

Ziemssen T, Rauer S, Stadelmann C, Henze T, Koehler J, Penner IK, Lang M, Poehlau D, Baier-Ebert M, Schieb H, Meuth S. Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review. PLoS One. 2015 Sep 22;10(9):e0138243.
BACKGROUND:So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population.
OBJECTIVE:The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator.
METHODS:A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared.
RESULTS:Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately.
CONCLUSION: Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

So for "meta analysis of the week" we have this paper which looks at trials in PPMS. As it is open access you can all have a read. So out of the 50 fifty or so trials only 4 were put under scrutiny. There was the suggestion that there may be problems in the trials and that yet again the old faithfull EDSS may not be the best endpoint to have.

One does not have to be a rocket scientist to come to the conclusion that there needs to be better outcomes than EDSS.

Why do the regulators and neuros persist with these measures to be the gold standards on what trial success is based. It is clear that the EDSS is not a scale that is linear and if you load up your trials with people with a certain EDSS, then this may change so slowly that your trials have to be years longer than anyone is going to want to wait to know if the drug such the patent life will be long gone and there will be no interest in going the study in the first place. 

We need to find functional systems that progress at a reasonable rate to measure within a trial and we need to start a study when there is still enough neural circuitry left so that a change can be seen. Is the 9 hole peg test and walking outcomes the answer?

We know that imaging such as atrophy measures is missing a lot of nerve loss and is subject to all sorts of artifacts too.

I have not done a meta-analysis but based on my reading it would seem to me that if we persist in T cell immunotherapies in PPMS or SPMS for that matter then they are unlikely to succeed properly.
However, I think people with gadolinium lesion active, relapsing PPMS will respond to these treatments, but progression will not.

As recruitment has finished, I will make a prediction that the ASCEND trial (in SPMS) with Natalizumab will fail and the PPMS trial with anti-CD20 will fail also, except for benefit in the subset above. I could extend this to a few more drugs too. 

I don't know the answer and ProfG may have a different view/ knowledge, as he must have done to allow some of his patients to enter the trials. He is an optimist and if you are not willing to fail, you can never succeed and you can do nothing or try what is available.

I hope I am proved wrong, as some of the mutterings I have heard from the pharma grapevine,and maybe the rate of progression will slow because I am sure that new lesions are forming in all MSers.

However, if I am not, then we need to wake up and smell the roses and try different approaches and stop this endless procession of demoralizing failures. 

Some companies are trying their drugs in PPMS/SPMS because of the unmet need and because they can still do placebo-control trials rather than do a non-inferiority trial against a current drug. This is because they would have to purchase the comparator drug to do a head to head trial. Easy for a company with a low hanging fruit comparator but you would have to shell out about an extra $50,000,000-$100,000 to buy the drug for say 500 people if you don't already have a drug in the market place.  However, think of the millions some companies are flushing down the toilet by doing a trial that has no/little hope of success. In my opinion it is happening as I write.

We will soon know the answers.