Thursday, 23 March 2017

Natural Killer cells and MS

Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia.Caruana P, Lemmert K, Ribbons K, Lea R, Lechner-Scott J. Mult Scler. 2016:1352458516679267. doi: 10.1177/1352458516679267

To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity.

METHODS: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to 'No Evidence of Disease Activity' (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression.

RESULTS: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment ( p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects ( p < 0.05).

CONCLUSION: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

So a suggestion that NKbright cells that are expanded by daclizumab in this study they suggest high levels are associated with stable disease...Is this a sign that its not B cells?

#PoliticalSpeak & #OffLabel: it is okay to use off-label DMTs

Off-label prescribing; how do we get it adopted? #PoliticalSpeak #MSBlog #OffLabel
My number one book from my homeland, South Africa. 

'Who knows for what we live, and struggle, and die? Wise men write many books, in words too hard to understand. But this, the purpose of our lives, the end of all our struggle, is beyond all human wisdom.'

'You ask yourself not if this or that is expedient, but if it is right.'

'There is only one way in which one can endure man's inhumanity to man and that is to try, in one's own life, to exemplify man's humanity to man.'

'I envision someday a great, peaceful South Africa in which the world will take pride, a nation in which each of many different groups will be making its own creative contribution.'

'To give up the task of reforming society is to give up one's responsibility as a free man.'

'Cry, the beloved country, for the unborn child that is the inheritor of our fear. Let him not love the earth too deeply... For fear will rob him of all if he gives too much.'

Alan Paton

One of the most important issues we have tried to address on this blog in access to effective DMTs for pwMS in resource-poor settings. I had a Skype call with a young neurologist from South Africa yesterday and she informs me that she has not been able to get permission to start any of her patients on a licensed DMT in the last 18 months. In addition, she is unable to offer these patients off-label subcutaneous generic cladribine or leflunomide as these drugs are not licensed in South Africa for MS. This is a true Catch-22! 

These and other experiences of what it is like to be a pwMS living in a resource-poor country remains our primary motivator for this policy initiative. We will continue to promote the use of off-label, cheaper, alternative DMTs to treat MS. What we need is some action. I wish politicians would read this blog and meet pwMS face-to-face. May be it should be them who say you can't have drug x, or drug y, and explain to them why.

The following is our essential off-label DMT list (click on each drug for more information):

Comments from the survey (updated 20h15, 23-Mar-3017):

I suspect I would be in a very dark place today without ldn being prescribed (since 2004), for my PPMS.

I have had SPMS since optic neuritis in 1985 at age 27. No relapses since that episode. Have slowly, steadily progressed since then. MRI shows spinal cord but not brain atrophy, with few lesions. I am now taking simvastatin, since nothing approved and progression has been constant. Drug is cheap, downside of use is low and we are monitoring liver health.

Trials and expensive drugs are a much trickier problem. Govt. needed to fund these things. Clinical research is so expensive.

I live in a different country each year for work. In a disease like MS which is so variable, off label uses of existing drugs offers some flexibility to deal with symptoms and syndromes that affect some msers but not others. And as for off label use in tx attempts (eg LDN), if the safety profile of the drug is known, and their are no contraindications, I see no harm in trying. In fact, it would be borderline negligent not to try everything possible to ease the symptoms at least. Providing the pt accepts responsibility for their decision to take the drugs.

If the drug is considered safe and not likely to react badly with concurrent medication, exacerbate symptoms or reduce quality of life with intense side effects, it's a sound way to find out if the drug has any disease-altering or symptom-modifying capability in MS. Funding RCTs to find out the results is expensive and time-consuming, so retrospective analysis of case studies - properly documented and analysed, seems a good use of resources, as long as organizations such as NICE don't block on the grounds of medication costs.

Full process for getting commercialization approval takes 12 years, Phase IIa should be enough for open label prescription, for a neurodegenerative illness like MS.

My son had his first dose of Campath 2 years ago. Since then no relapses and  no new MRI activity. If he hadn't had a neurologist willing to prescribe off licence, he'd be in a dire state by now, as it is likely it will be another 2 years before it may be licensed, and he would have missed his window of therapeutic opportunity.

I would like to comment, although I think I mostly agree with what Prof G has laid out on the blog, As an MSer, I would like to think that a mechanism can be made to do this more effectively, and also give a return to the drugs companies, everyone is happy then.

Surely some consent for off labelling between practitioner and patient with a really good explanation of the risks would stop law suits (from potentially being proved!)

I'm just not well enough informed to comment properly I feel, but understand the basics of the market and legal sphere.

I support off label prescribing so long as the drugs do not contain poisons such as antifreeze, etc. 

I'm currently taking Modafinil for fatigue issues. My insurance won't cover the cost ($564 USD), so I wait until my max out of pocket expenses are exhausted, and only then does my co-pay drop to 10 bucks. Modafinil has been a Godsend for me, and without it, I'm not sure I could continue to work. It may be off-label, but so essential to PwMS!

I support it as long as the patient is fully informed of the status of the drug.

I am taking LDN and it is helping me like nothing else has, I fully support it being prescribed.

Yes as long as it works the same as the name brand stuff.

I'm currently taking 40 mg simvastatin bid. SPMS since 1985 -not taking dmds.

For me I've had Provigil prescribed off-label. It's a very helpful drug for me for energy but I am concerned that it is not tested in people with MS. Maybe it worsens the disease or allows neurons to incur damage that wouldn't be done if the patient was respecting their fatigue. It should be tested so we know it's safe. But I don't want it taken away either. Dilemma. That's why I answered 'Maybe.'

In general, it's a bit difficult to comment intelligently on this, clearly if there are drugs that look like they might work in MS for relapses and/or morre importantly progression, we need to find this out. This clearly needs a different mechanism so that we get our drugs and pharma get their coin....
Its the only way I could get Rituxan (Copaxone, Avonex, Betaseron, and Tysabri all failed to stop progression on my MRI).

I have secondary ms and would have no options without off label treatment.

In the experience and opinion of the commentator, it would seem as if off-label prescribing is an exception, not the rule. This is understandable and expected from the perspective of the use of established standards for initial, mid and long-term therapies for "non-orphan" types of disease. Unfortunately, if low (clinical, measurable, qualitative) efficacy of these standards is an issue for the patient, physicians appear particularly sensitive to the potential legal liability of other forms of treatment, even following discussions with the patient releasing the physician from such liability. Again understandable if secondary therapies exist. However, in the absence of such, or at the request of the patient for other reasons, (low efficacy, side effects) this sensitivity, ultimately, may deprive the patient of avenues of treatment that might otherwise provide relief both clinically and from the standpoint of an improved quality of life. Further, this commentator has concluded that the importance of quality of (the patient's) life has, over time, been de-emphasized in the medical community as part of, and as a result of the above and would suggest that views similar to those offered here will be dismissed by this same community.

Great initiative!

There´s a large amount of people here on Rituximab, let´s see what happens when Ocrelizumab gets to the market...

As a physician as well as MS patient I would pursue these DMTs and repurposed drugs like statins if required ; but I am fortunate to have gone straight to Gilenya 3 yrs ago, NEDA since.

Why has Mitoxantrone to be prescribed off-label in the UK?

It is important to make many resources available in countries that do not have access.

The cost of MS drugs is prohibitive. Prescribing off labels drugs will surely force Pharma to reduce their price to the consumer.

My doctor does significant off-label prescribing and it works. Every second infusion I get to sit across from someone that looks like my mother - it's very hard. This lady has been receiving off-label treatment since '89 - my mother died after a long untreated illness in 2003.

The path I am currently going down... Tysabri ,Gilenya now rituxan.

I have no chance to get Rituximab instead of Alemtuzumab

If the drug a exists and can help in the treatment of MS I find it highly unethical to not let those suffering have access to it. people in powerful positions seem to have forgotten they exist to help the patients. how does the old expression go? 'one day a rain will come and wash the streets clean'
I think you're right in your quest. As long there is data showing good results, then off-label should definitely be considered, in both resource-rich and poorer countries. Thank you for this effort. Have a Happy New Year!

I think you're right in your quest. As long there is data showing good results, then off-label should definitely be considered, in both resource-rich and poorer countries. Thank you for this effort. Have a Happy New Year!

Whatever it takes to keep us with MS on our feet and in the best shape as possible.

Please God, let this happen.

Prescribing limited by NICE, off-label may be necessary to obtain best drug for patient.

Great initiative.

It is important to try a possible treatment, having weighed the pros and cons. We all react to treatments differently.

I support all use of medication to try to find a cure.

As an MS sufferer diagnosed with a mild form of RRMS in 2011 with symptoms progressing now I have had little or no support from my neuro because I don't meet criteria for drug intervention. The options are too limited. Aged 38 I now face an uncertain future.


We're lucky in Australia most of the prescribed MS drugs are on our PBS (free and available) but with our right wing government who knows what the future holds...

Dear All, in Kosovo are 1200 people with MS and only 80 get free treatment. It would be great if any Neurologist will visit Kosovo and explain to our MD s for other alternatives of the treatment in cheaper way.

To benefit those without access to on-label drugs.

Off label in no way means untried / unknown / ineffective / risky. Let physician and informed patient decide if appropriate - especially where alternative is inadequate or even nonexistent treatment.

My son got alemtuzumab earlier than he would have in the UK- time is brain- due to the bravery and conviction based on evidence of a UK neurologist.

If it helps people why not.

We should have the right to use all tools at our disposal.

My yes is for resource poor countries. I think I have understood from the blog that pharma companies need to make money in rich countries or disaster strikes.

People will look back and wonder why?

I don't actually trust Barts' opinions on this issue - too many conflicts of interests, far too much bias.

I am concerned about the lack of affordable treatments in developing countries, and the lack of any treatments anywhere, so far, for people with PPMS.

I support early treatment, and this among many other initiatives you have tried to overcome inertia and complacency among medics. I also support any attempt to mitigate the iniquitous lottery of health care provision both within UK and globally.

It's legal here as long as you can afford cost of the meds.

I work in the pharmaceutical industry and see first hand the aversion to off-label prescribing! On the flip side if there is an opportunity to obtain an additional indication on a license and extend a drugs patent they will provide all the necessary resource!

Access to medications and/or other generic treatments are as important in MS as any other condition.

Pharma and tort laws here won't let it happen. Sad.

When an off-label drug costs less, gives a better overall quality of life, and saves hospitalization from relapse costs, it should no longer be off-label.

Off label Rituxan and Imuran (in combo with interferon in 2004) has been useful to me.

Providing access to resources allowing a better quality of life for people diagnosed with MS seems logical & compassionate. This issue should not be about putting obstacles in the way of providing assistance to people in need or maximizing profits but helping people who need the help.

If effective treatments exist, PwMS should always have access to them. Political and commercial obstacles should be pushed aside.

I think Big Pharma only wants to earn money. They do not care about the MS patients.
Generic copy of rituximab is expected to come on the market here summer '17, or is it still too expensive for SA?

Since 2004 I have taken ldn to treat PPMS and suspect I would be in a very dark place today without it.

If there are no licenced alternatives available (or alternatives are too expensive / contraindicated) then it is morally right to prescribe off-label. 

Eg resource poor countries (all forms MS) or people categorised as ppms / spms in US, UK etc.

My understanding of 'off-label is that the drug has been tested with positive results but not yet authorized for prescription. Equally important the drug is significantly cheaper than many other drugs that are available. In this world where there is a shortage of money for treatment it strikes me that not allowing a less expensive but effective medical solution is inexcusable. Even in the UK there are excellent drugs available to help people with MS that have not been authorized by NICE.

I am so confused by DMTs and the differing messages. Certainly in countries where the newer and more expensive drugs are not allowed or are far too expensive then the use of these off label drugs should be allowed. They are widely used for other illnesses and at least their side effects and interactions are understood. But how effective are they? Or is anything that is moderately safe better than nothing at all. What a poor choice for so many people in this world.

I think it essential that there is off-label prescribing because the cost of new drugs is not affordable in much of the world.

No brainer.

Obtaining an off-label prescription is very difficult. You have to be very persuasive, and your local neurologist is more likely to refer you to a London teaching hospital than prescribe the drug himself. 

Entirely agree that the politicians and civil servants responsible for decisions to deny license or allocation should not be allowed to remain faceless and nameless, and should publicly take responsibility for their decisions.

CoI: multiple

Wednesday, 22 March 2017

ClinicSpeak; gardening post-alemtuzumab

Another opportunistic infection associated with alemtuzumab use in a person with MS. #MSBlog #ClinicSpeak

Question: "I am day 12 day after last alemtuzumab dose and probably have lymphopenia/leukopenia at the moment. Should I avoid the garden this spring :-(?"

Answer: Yes, you are putting yourself at risk of Nocardial infection. Nocardia species live in the soil. There have been cases described post alemtuzumab (see below). 

The first case below presented with a 3-week history of cough, shortness of breath, and a high fever 8 weeks after the first cycle of alemtuzumab treatment. Nocardia are aerobic gram-positive bacteria found in soil and water.  Nocardia is an opportunistic infection and needs to be taken very seriously. At the moment nocardial infections are rare and I am not sure what the risk is post-alemtuzumab. However, whilst you are neutropaenic and lymphopaenic I would advise avoiding soil exposure. 

Nocardia in the brain at autopsy; image from Wikipedia

Sheikh-Taha & Corman. Pulmonary Nocardia beijingensis infection associated with the use of alemtuzumab in a patient with multiple sclerosis. Mult Scler. 2017 Feb 1:1352458517694431.

Nocardia is a Gram-positive aerobic pathogen that usually affects immunocompromised patients. We report a case of pulmonary infection caused by a rare Nocardia species, Nocardia beijingensis, in a 50-year-old woman who had received alemtuzumab for the treatment of her multiple sclerosis. The invasive pulmonary infection was successfully treated with meropenem.

Penkert et al. Fulminant Central Nervous System Nocardiosis in a Patient Treated With Alemtuzumab for Relapsing-Remitting Multiple Sclerosis. JAMA Neurol. 2016 Jun 1;73(6):757-9.

#ClinicSpeak & #Neurospeak: low platelets with alemtuzumab

Not all low platelet counts post-alemtuzumab are due to ITP. #ClinicSpeak #NeuroSpeak #MSBlog

I received a query from a colleague a few months ago about a low platelet count in one their patients treated with alemtuzumab. The low platelet count was in the first week, it was transient and was not due to ITP. We became aware of this a few years ago and dropped Professor Coles an email about the observation. He sent us this picture from his thesis (below) and reassured us that the low platelet count will be transient and it was. The explanation he provided is that platelets stick to blood vessels due to adhesion molecule expression secondary to the cytokine release that occurs with alemtuzumab. In his experience, and our experience, this is nothing to worry about. I hope this helps. 

Background: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). Although Immune thrombocytopenia (ITP) has been reported as a secondary autoimmune phenomenon following alemtuzumab infusion, immediate thrombocytopenia during the infusion has not been reported.

Objective: We report transient, reversible, self-limiting acute-onset thrombocytopenia during the first course with alemtuzumab.

Results and conclusion: In total, 3 of 22 paitents developed mild self-limited bruising associated with a drop in platelet count from their baseline during the intial 5-day course of alemtuzumab. Upon chart review, all 22 patients who received alemtuzumab developed an immediate mostly asymptomatic drop in platelet count which returned to normal within 2 months post-infusion.

CoI: multiple

Imaging hot microglia.

Datta G, Colasanti A, Kalk N, Owen DR, Scott G, Rabiner EI, Gunn R, Lingford-Hughes A, Malik O, Ciccarelli O, Nicholas R, Nie L, Battaglini M, De Stefano N, Matthews P.
[11C]PBR28 or [18F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis.J Nucl Med. 2017. pii: jnumed.116.187161. doi: 10.2967/jnumed.116.187161. [Epub ahead of print]
Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). 
Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands (11C-PBR28 or 18F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). 
Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. 
Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. 

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain.

TSPO has been proposed to interact with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria. It has been suggested to be a marker of microglial activation. 

In this study they reported more activity in MS and found lesions in relapsing and SPMS and the lesions were more active in relapsing rather than SPMS, but still there are active lesions. So as we have been saying, RRMS and SPMS are not distinct. 

However, it gives an indication of the presence of hot microglia, it  seems increasingly evident that there is a broader activity than just microglia so we have to interpret the data more cautiously