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):



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