Saturday, 31 May 2014

Alemtuzumab approved in the UK...Let the European Experiment begin

A news report has been issued the National Institute for Health and Care Excellence (NICE) has issued final guidance recommending that Lemtrada should be reimbursed on the NHS, as an option for treating adults with active RRMS, within its marketing authorisation.

So the "game" changes as more choice arises and a new first line appears.

The FDA has expressed concerns about Alemtuzumab, but will re assess the licencing package.

Perhaps they are waiting to see what happens with the European Guinea Pigs. They will look to see how safety issues play out as the drug is used post-licencing. Look at Tysabri the plug was pulled pretty soon, once the risk of PML appeared.

Already we know of some risks from Alemtuzumab, what new ones will appear?

At least people are being monitored monthly for 4 years after their last dose, so hopefully things will be picked-up and any problems will be treatable.

Whilst this regular follow-up may be a reminder that you have/had? MS, to some it will be re-assuring and means that you will get better care, with a regular check up rather than seeing someone once a decade.

The trial data suggested 20% autoimmunities but the long-term follow up was closer to 50%. This all adds to the cost to the NHS and all cost of monitoring and dealing with these autoimmunities will add at least an extra third as much as the drug costs. So when the anti-CD20's (that is if they use it as an induction therapy...which I doubt although the data probably supports this belief) come to try knock anti-CD52 off its perch. Will they add an extra 30% to the cost?

Modelling PPMS for Trials

Harding KE, Wardle M, Moore P, Tomassini V, Pickersgill T, Ben-Shlomo Y, Robertson NP. Modelling the natural history of primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014 May. pii: jnnp-2014-307791. doi: 10.1136/jnnp-2014-307791. [Epub ahead of print]

BACKGROUND:A minority of patients with multiple sclerosis (MS) have primary progressive disease (PPMS). Treatment options are currently limited, but as prospects for interventional studies become more realistic, understanding contemporary outcome data will be key to successful trial design.
METHODS:234 PPMS patients were identified from a population-based cohort of 2131 (11.0%) and mean follow-up of 13.1 years. Time to established disability endpoints was compared with patients with relapsing-onset MS (ROMS)  Results were used to create predictive power models for clinical trials in PPMS.
RESULTS:Time to fixed disability milestones was shorter than in ROMS 
EDSS) 4.0: 8.1 vs 17.1 years, p<0.001; 
EDSS 6.0: 9.6 vs 22.1 years, p<0.001; 
EDSS 8.0: 20.7 vs 39.7 years, p<0.001), 
but there were no differences in age-related disability. 
Age and cerebellar symptoms at onset affected rate of progression. 

Modelling of these data indicated that trials employing EDSS change of 1.0 as the primary outcome measure would be powered to detect a 20% difference in progression using 600 patients with initial EDSS of 4.0 per trial arm, or 400 patients with initial EDSS of 5.0 per arm. However, trials including patients with fixed EDSS of ≥6.0 will be underpowered even with large numbers or prolonged duration.
CONCLUSIONS:Disability progression in PPMS is variable and influenced by age at onset. Although progression is more rapid, age-related disability milestones are identical to relapsing-onset disease. These data offer a contemporary paradigm for clinical trial design in progressive MS.

This study indicates that for the purposes of trials we need to start with people who have less disability if we want to see changes using a reasonable number of people, because if we look at people with more advanced MS, it may mean the trials will fail because there simply are not enough people in them and they will cost a fortune. 

The most recent PPMS trial of fingolimod recruited at EDSS 3.5-6, I wonder what is the result we will find out soon, but these is an extension study o the original trial. 


It seems that when we post on this subject, it brings out the worse of some of the readers. So when your blood is boiling over some comment we have made and you have that urge to post something insulting, take a deep breath and stop.

We performed a monocentric observational prospective study to evaluate coagulation activation and endothelial dysfunction parameters in patients with multiple sclerosis undergoing endovascular treatment for cerebro-spinal-venous insufficiency. Between February 2011 and July 2012, 144 endovascular procedures in 110 patients with multiple sclerosis and chronical cerebro-spinal venous insufficiency were performed and they were prospectively analyzed. Each patient was included in the study according to previously published criteria, assessed by the investigators before enrollment. Endothelial dysfunction and coagulation activation parameters were determined before the procedure and during follow-up at 1, 3, 6, 9, 12, 15 and 18 months after treatment, respectively. After the endovascular procedure, patients were treated with standard therapies, with the addition of mesoglycan. Fifty-five percent patients experienced a favorable outcome of multiple sclerosis within 1 month after treatment, 25% regressed in the following 3 months, 24.9% did not experience any benefit. In only 0.1% patients, acute recurrence was observed and it was treated with high-dose immunosuppressive therapy. No major complications were observed. Coagulation activation and endothelial dysfunction parameters were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. Endovascular procedures performed by a qualified staff are well tolerated; they can be associated with other currently adopted treatments. Correlations between inflammation, coagulation activation and neurodegenerative disorders are here supported by the observed variations in plasma levels of markers of coagulation activation and endothelial dysfunction.

Epub: Lubelski D, Alvin MD, Silverstein M, Senol N, Abdullah KG, Benzel EC, Mroz TE. Quality of life outcomes following surgery for patients with coexistent cervical stenosis and multiple sclerosis.Eur Spine J. 2014 May.

PURPOSE: To investigate the quality of life outcomes following surgical treatment of patients with coexisting multiple sclerosis (MS) and cervical stenosis with associated myelopathy (CS).

METHODS: A retrospective review of the medical records and of prospectively acquired quality of life (QOL) data was performed for all patients with symptoms of myelopathy and coexisting diagnoses of MS and CS that underwent cervical decompression surgery between 2008 and 2011. The study population was matched (1:4) to a control cohort of patients that did not have MS but presented with similar myelopathic symptoms due to cervical stenosis, were of the same age and gender, and underwent the same cervical decompression procedure within the same year.

RESULTS: Sixty-five patients were reviewed, including 13 in the MS group and 52 in the control group that were followed for an average of 22 and 18 months, respectively. Whereas patients in the MS cohort remained at a Quality-Adjusted Life-Year (QALY) gain of 0.51 both pre- and post-operatively (p = 0.96), patients in the matched control cohort improved from a preoperative QALY of 0.50 to a postoperative QALY of 0.64 (p < 0.0001). The latter represents an improvement that exceeds the minimum clinically important difference. Overall, 70 % of patients in the control group experienced an improvement in QALY, compared to only 54 % in the MS group (p = 0.4).

CONCLUSION: Patients in the control cohort had clinically and statistically significant improvements in QALY outcomes. Those in the MS cohort averaged no change in QALY. However, only a minority of MS/CS patients had worsening QALY following surgery, and as such surgery may still be considered for these patients. It is imperative that there are preoperative discussions with the MS/CS patient regarding the likelihood that surgery will only provide limited, if any, improvements in QOL.

Google Trends

Friday, 30 May 2014

Alemtuzumab: Will the FDA be moved?

Will the FDA licence Alemtuzumab? #MSBlog #MSResearch

"Some news regarding alemtuzumab. The FDA has accepted Genzyme’s resubmission of Alemtuzumab for the treatment of relapsing forms of MS. A 6-month review period has been assigned and Genzyme expects an FDA decision before the end of the year. Please note that the resubmission is based on data from the same clinical studies included in the original submission, but provides supplemental analyses and additional information to specifically address issues previously noted by the FDA in its response to the alemtuzumab submission."

"I an quietly confident that the FDA will now license Alemtuzumab, which will save US MSers from having to travel abroad for treatment."

"The full press release can be read below."

CoI: multiple

Do different interferons preparations affect cognition differently?

What will the impact of long-acting pegylated interferon-beta have on brain atrophy? #MSblog #MSResearch

"Could there really be a difference between the interferon preparations and cognition? The study below suggests interferon-beta-1a has a positive impact on cognition, but not interferon-beta-1b. This is a very small study and will need to be reproduced. However, there seems to be a difference between low frequency interferon (Avonex) and the high frequency interferon preparations (Rebif and Betaferon/Betaseron) when it comes to an impact on brain atrophy. Avonex seems to have a small but consistent impact on slowing brain atrophy compared to the other innovator compounds. Why? It may be that intermittent stimulation of the type 1 interferon receptor is neuroprotective, whilst continuous stimulation of the receptor is not. Continuous stimulation with high frequency interferon internalises receptors and may change the biology of certain cell types within the central nervous system. It is surprising that Biogen-Idec, who have known about the differential impact of the different interferon preparation on brain atrophy went ahead and developed a long-acting pegylated interferon. I would be interested to see what effect pegylated-interferon, which will all most certainly stimulates the receptor continuously and reduce expression on the cell surface, will have on brain atrophy. I would not be surprised if it behaves in the same way as Rebif and Betaferon/Betaseron."

Epub: Mokhber N et al. Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical trial.J Neurol Sci. 2014 Feb 4. pii: S0022-510X(14)00062-8. doi: 10.1016/j.jns.2014.01.038. [Epub ahead of print]

BACKGROUND: MS is a chronic autoimmune disease that can deteriorate cognitive function in at least 50% of MSers even in the early stages.

OBJECTIVE: We conducted a three-arm parallel study with balanced randomization to evaluate the effect of various disease-modifying therapies (DMTs) on cognitive function in MS.

METHODS: Ninety newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran, were enrolled into this study between 2006 and 2009. They were randomly categorized into three DMT groups; Avonex, Rebif and Betaferon. Cognition status was assessed in MSers at baseline and 12 months after treatment with DMTs using the 5 tests of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N).

RESULTS: The Symbol Digit Modalities Test scores improved in all groups at 12 month vs. baseline (Avonex: 34.50 vs. 38.95, p=0.011; Rebif: 35.30 vs. 40.13, p=0.001; Betaferon: 26.18 vs. 29.32, p=0.029). The Selective Reminding Test (SRT)-Total, the 10/36-Delay, and the Paced Auditory Serial Addition Test-Easy were improved in Avonex and Rebif but not in Betaferon group. The SRT-Delay and Word List Generation were improved only in the Avonex group. There was no significant difference in other components of the BRB-N among these three treatment groups.

CONCLUSIONS: Different types of DMTs may improve some aspects of cognitive function in patients with MS. Treatment with Avonex and Rebif (Interferon beta-1a preparations) were more helpful in resolving the cognitive impairments in MSers compared to Betaferon (Interferon beta-1b) as investigated in this study.

CoI: multiple

Who Chooses?

Here is a recent comment I picked off the web about treatment

"Whether your Neuro will put you forward for it (a drug) is another question......."
This is a common theme. 

Is it right that your Neuro plays God?...

For many I suspect this is the view...and if they get it right you  will sing their praise. 

Your Neuro has trained for years so that they should understand what is on offer.  

However, it is clear that many MSers are not up to speed with their options (Based on conversations at MS life 2014) and so rely on their Neuros for guidance and information. 

But you may miss out if your neuro makes the wrong choice. It is your body! It is you risk!

So the more you know, the more you are empowered to discuss with your neuro the best options that you have.

If you don't like what you hear, you can always get a second opinion

Recovering from Optic Neuritis

Malik MT, Healy BC, Benson LA, Kivisakk P, Musallam A, Weiner HL, Chitnis T. Factors associated with recovery from acute optic neuritis in patients with multiple sclerosis.Neurology. 2014 May. pii: 10.1212/WNL.0000000000000524. [Epub ahead of print]

OBJECTIVE: To identify clinical and demographic features associated with the severity and recovery from acute optic neuritis (AON) episodes in patients with multiple sclerosis (MS).
METHODS: Adult (n = 253) and paediatric (n = 38) patients whose first symptom was AON were identified from our MS database. Severity measured by loss of visual acuity (mild attack ≤20/40, moderate attack 20/50-20/190, and severe attack ≥20/200) and recovery in visual acuity at 1 year after the attack (complete recovery ≤20/20, fair recovery 20/40, and poor recovery ≥20/50) were recorded. Demographic and clinical features associated with attack severity and recovery were identified using proportional odds logistic regression. For another group of patients, blood samples were available within 6 months of an AON attack. In this group, the impact of vitamin D level on the severity/recovery was also assessed.
RESULTS: Men (adjusted odds ratio [OR] = 2.28, p = 0.03) and subjects with severe attacks (adjusted OR = 5.24, p < 0.001) had worse recovery. AON severity was similar between the pediatric and adult subjects, but recovery was significantly better in pediatric subjects in the unadjusted analysis (p = 0.041) and the analysis adjusted for sex (p = 0.029). Season-adjusted vitamin D level was significantly associated with attack severity (OR for 10-U increase in vitamin D level = 0.47; 95% confidence interval: 0.32, 0.68; p < 0.001). Vitamin D level was not associated with recovery from the attack (p = 0.98) in univariate analysis or after accounting for attack severity (p = 0.10).
CONCLUSION: Vitamin D levels affect AON severity, whereas younger age, attack severity, and male sex affect AON recovery. Underlying mechanisms and potential therapeutic targets may identify new measures to mitigate disability accrual in MS.
Normal visual acuity is commonly referred to as 20/20 vision, the metric equivalent of which is 6/6 vision. At 20 feet or 6 meters, a human eye with nominal performance is able to separate contours that are approximately 1.75mm apart. A vision of 20/40 corresponds to lower than nominal performance, a vision of 20/10 to better performance.

In the expression 20/x vision, the numerator (20) is the distance in feet between the subject and the chart, and the denominator (x) is the distance at which a person with 20/20 acuity would just discern the same optotype. Thus, 20/20 means "normal" vision and 20/40 means that a person with 20/20 vision would discern the same optotype from 40 feet away. This is equivalent to saying that with 20/40 vision, the person possesses half the resolution and needs twice the size to discern the optotype.
Acuity is a measure of visual performance and is unrelated to the eyeglass prescription required to correct vision. Instead, an eye exam seeks to find the prescription that will provide the best corrected visual performance achievable. The resulting acuity may be greater or less than 20/20 = 1.0. Indeed, a subject diagnosed as having 20/20 vision will often actually have higher visual acuity because, once this standard is attained, the subject is considered to have normal (in the sense of undisturbed) vision and smaller optotypes are not tested.

This study looks at factors which may predict better outcomes after optic neuritis and is a guide only, but having your vitamin D levels up may protected you before not after the event, so remeber to keep them topped up.

Thursday, 29 May 2014

World MS Day: Coming out at Work-Circle of Truth

A new video from Shift.MS on the challenges of disclosure in the workplace.

Re Engineering Beta Interferon

Song K, Yoon IS, Kim NA, Kim DH, Lee J, Lee HJ, Lee S, Choi S, Choi MK, Kim HH, Jeong SH, Son WS, Kim DD, Shin YK. Glycoengineering of Interferon-β 1a Improves Its Biophysical and Pharmacokinetic Properties. PLoS One. 2014;9(5):e96967. doi: 10.1371/journal.pone.0096967. eCollection 2014.

The purpose of this study was to develop a biobetter version of recombinant human interferon-β 1a (rhIFN-β 1a) to improve its biophysical properties, such as aggregation, production and stability, and pharmacokinetic properties without jeopardizing its activity. To achieve this, we introduced additional glycosylation into rhIFN-β 1a via site-directed mutagenesis. Glycoengineering of rhIFN-β 1a resulted in a new molecular entity, termed R27T, which was defined as a rhIFN-β mutein with two N-glycosylation sites at 80th (original site) and at an additional 25th amino acid due to a mutation of Thr for Arg at position 27th of rhIFN-β 1a. Glycoengineering had no effect on rhIFN-β ligand-receptor binding, as no loss of specific activity was observed. R27T showed improved stability and had a reduced propensity for aggregation and an increased half-life. Therefore, hyperglycosylated rhIFN-β could be a biobetter version of rhIFN-β 1a with a potential for use as a drug against multiple sclerosis.

You can engineer to alter the way it hangs round in the body..however it needs to be engineered to work better:-)

Simply monitoring brain function

Van Schependom J, D'hooghe MB, Cleynhens K, D'hooge M, Haelewyck MC, De Keyser J, Nagels G. The Symbol Digit Modalities Test as sentinel test for cognitive impairment in multiple sclerosis.Eur J Neurol. 2014 May. doi: 10.1111/ene.12463. [Epub ahead of print]

BACKGROUND AND PURPOSE:Cognitive impairment (CI) is found in about half of the multiple sclerosis (MS) population and is an important contributor to employment status and social functioning. CI is encountered in all disease stages and correlates only moderately with disease duration or Expanded Disability Status Scale scores. Most present neuropsychological test batteries are time-demanding and expensive. The Symbol Digit Modalities Test (SDMT) has been suggested as a screening tool for CI in MS. In this paper, we aim to assess the performance of the SDMT in predicting the outcome of an extensive battery.
METHODS: Neuropsychological test results from 359 patients were assessed in a multidisciplinary MS center (National MS Center Melsbroek, Belgium). Using receiver operating characteristic curves, the performance of the SDMT in predicting the general cognitive outcome of the extensive Neuropsychological Screening Battery for MS (NSBMS) could be assessed. The performance of the SDMT was assessed for different levels of CI and compared with other cognitive tests. Finally, useful covariates were included in a logistic regression model.
RESULTS: At a specificity of 0.60 a high sensitivity (0.91) was obtained indicating the potential of the SDMT as a sentinel test for CI in MS. The SDMT outperformed the individual tests included in the NSBMS, used as benchmark. As the logistic regression model did not result in a relevant improvement, it is concluded that most clinical variables influence both the SDMT and the NSBMS in a similar way. Excluding patients with possible practice effects, an optimal cutoff of 40 was found for the SDMT.
CONCLUSION: As the SDMT is an easy, low-cost and fast test, this result may help to detect CI in everyday clinical practice.
The Symbol Digit Modalities Test (SDMT) detects cognitive impairment in less than five minutes. This  can detect changes in cognitive functioning over time and in response to treatment. It is an economical way to screen apparently normal children and adults (ages 8-78 years) for possible motor, visual, learning, or other cerebral dysfunction.

The SDMT involves a simple substitution task. Using a reference key (See above), the examinee has 90 seconds to pair specific numbers with given geometric figures. Because examinees can give either written or spoken responses, the test is well suited for use with individuals who have motor disabilities or speech disorders. Because it involves only geometric figures and numbers, the SDMT is relatively culture free as well and can be administered to individuals who do not speak English. 

Wednesday, 28 May 2014

MS genes three quarters left to find

Sawcer S, Franklin RJ, Ban M Multiple sclerosis genetics.Lancet Neurol. 2014. pii: S1474-4422(14)70041-9. doi: 10.1016/S1474-4422(14)70041-9. [Epub ahead of print]

Genome-wide association studies have revolutionised the genetic analysis of multiple sclerosis. Through international collaborative efforts involving tens of thousands of cases and controls, more than 100 associated common variants have now been identified. These variants consistently implicate genes associated with immunological processes, overwhelmingly lie in regulatory rather than coding regions, and are frequently associated with other autoimmune diseases. The functional implications of these associated variants are mostly unknown; however, early work has shown that several variants have effects on splicing that result in meaningful changes in the balance between different isoforms in relevant tissues. Including the well established risk attributable to variants in genes encoding human leucocyte antigens, only about a quarter of reported heritability can now be accounted for, suggesting that a substantial potential for further discovery remains.
Three forths of the genetic cause are still yet to be found, I sense we need to genome sequence everyone with MS, will that be enough?

Red Hot Debates

Today is World MS Day

Neuros love a good debate and contrary to what you may think there is not always a uniformity of ideas.

They have been having debates for years and sometimes these occur in print. 

Here is a list of examples that have occurred in the Multiple Sclerosis Journal over the past couple of years, with someone presenting the Yes over someone presenting the case for No.

  • Epstein-Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis: 
  • Is MRI monitoring useful in clinical practice in patients with multiple sclerosis? 
  • Preventing brain atrophy should be the gold standard of effective therapy in MS 
  • Funding CCSVI research is/was a waste of valuable time, money and intellectual energy
  • We should abandon interferons and glatiramer acetate as first-line therapy for MS
  • Industrial pharmaceutical drug research has done more for the health of people with MS than academic neurologists
  • There is no such thing as a mild MS relapse. The mild relapse is an Anglo-Saxon delusion 
  • Epidemiology in multiple sclerosis has had its day: there are no more unanswered questions
  • Truly benign multiple sclerosis is rare: let's stop fooling ourselves
  • Relapses do not matter in relation to long-term disability
  • The major cause of multiple sclerosis is environmental: genetics has a minor role

If you were to listen to heavy weight Neurologists having a live debate, What would be important for you to hear?

Please make some suggestions.......for subjects to debate

Are placebo controlled trials for RRMS ethical?

How about Are placebo-controlled trials for RRMS ethical?

Surely an academic PI on a pharma trial or a pharma bod should be able to defend this position or maybe the people on the ethical review panels could make a case.
Pharma hunts in packs and once one company gets a hit, others will follow. 

First we had Gilenya (fingolimod) and then Siponimod (BAF312) for a different slice of the pie, but lurking in the wings we have ceraimod ONO-4641), Ponesimd (ACT-12880) and the other MODs called RPC1063 and GSK2018682, etc, etc.

They all have a similar mechanism of action and so target-related side effects may be similar. Probably they will be more or less the same price, as there seldom seems to be price competition. Some may be better than others, so give it an edge, others will be better marketed. They should be about 50% effective at blocking the annualised relapse rate. Some may get a first line licence in contrast to the current second line in Europe for Gilenya. Now that Alemtuzumab is there it will be hard to make the case that an S1P modulator is less safe than alemtuzumab

Probably all will go through a placebo controlled trial. 

Should I "Get real and wakeup and smell the roses" and accept that this is morally fine or should the regulators extract a cost for the use of "have not" volunteers and make these new kids on the block use an active comparator.

If you were a "have" why would you accept nothing but the placebo effect,when you could get something that works to some extent.

It would cost more to do active comparator but the regulators do not care about cost, 

You could do a superiority trial against less effective agent it may boost numbers required  because the comparator drug will have an affect but more "have nots" get access to a drug designed to sell to the "haves". It may bethat the increase in numbers make thestudy non viable any statistician out there care to put figure on this

Or should they be made to do a non-inferiority trial against say fingolimod (You accept fingolimod works and then power the study so show that it is no worse than fingolimod). This could be marketing suicide if it was worse, but if it looks worse people would not want it anyway. However, this type of study takes a better moral high ground in an era when there are many active drugs

However, how long is it until the (Gilenya) patents die and the first chemical generic becomes available, will the price tumble, as its cost is peanuts. I suspect the generic biologicals will not be that much cheaper. 

Will there then there be "have nots" to do placebo on ..probably or will pharma have moved on to pastures new by then and no new MS drugs.

WORLD MS DAY: New EMSP Code of Practice

MS in the EU: new code of practice. #MSBlog #MSResearch

"Today is world MS day and its the official launch of European MS Platform's new code of practice. The aim of this document is lobby EU Governments to do something about the way we tackle and manage MS in Europe. The disparity between the haves and have nots of Europe is shocking; the UK is close to the bottom of the league table when it comes to the barometer. If you get time I would appreciate your feedback on this document."

EMSP MS Code of Practice 2008

EMSP New MS Code of Practice 2014

Tuesday, 27 May 2014

Guest post: Imaging Hot Microglia

Guest post: imaging hot microglia.#MSBlog #MSResearch

"In response to interest generated by an earlier post on hot microglia as a therapeutic target, we have invited Professor Laura Airas, who presented her much talked about work on this topic at the recent AAN, to do a guest post. She has agreed to answer questions on the topic so please feel free to ask. This innovation in imaging has particular implications for progressive MS trials."

Laura Airas, MD, PhD. Positron emission tomography (PET) holds promise for better treatment of progressive MS. Turku University Hospital, Turku, Finland

While there is increasing number of efficient therapies available for relapsing-remitting MS (RRMS), secondary and primary progressive MS (SPMS and PPMS) still remain the under-treated and under-investigated forms of the disease, and treatment of the progressive patients represent today the greatest unmet need in the field of MS. Consequently, many sufferers of progressive MS end up wheelchair-bound or bed-ridden, which not only causes huge impact on the quality of life, but also leads to enormous societal costs due to inability to work and dependence on carers.

We have been working with positron emission tomography (PET) imaging to see whether PET could provide more information about the underlying neuropathology in patients with secondary progressive MS than conventional MRI imaging can do. With PET imaging we can use radioligands that bind to activated microglial cells. This is an inflammatory cell type within the CNS, which gets activated in association with chronic degenerative diseases. Our latest work which was just recently presented at the American Academy of Neurology meeting in Philadelphia, USA, demonstrates that PET imaging allows us to visualize microglial cell activation in and around the MS lesions, and in areas of normal-appearing white matter, i.e. in areas that look normal in MRI. In other words, PET can give us more detailed information of the ongoing disease process in progressive MS, than MRI.

A patient in a PET scanner

Our work indicates that PET holds promise as a research tool in understanding the central nervous system pathology of secondary progressive MS, and will also aid in recognizing new therapeutic targets. We have recently demonstrated using an animal model of progressive MS, that fingolimod-treatment led to reduced microglial activation, and this could be measured in vivo using PET. We believe that PET imaging could potentially be used as a biomarker in the development of novel treatments targeting progressive MS, and our findings will thus hopefully ultimately lead to better treatments for progressive MS.

Biography: Adjunct professor Laura Airas presently works as a neurology consultant at the Department of Neurology at Turku University Hospital, Turku, Finland. She graduated from Turku University medical school in 1991 and continued her studies in form of a basic immunology PhD in the field of adhesion molecules and lymphocyte-endothelial cell interactions. She did part of her thesis work at the Glaxo Institute for Molecular Biology in Geneva, Switzerland. From 1996-2001, she obtained her specialization in neurology, and after this has practiced as a general neurologist, MS-specialist, researcher and a teacher of medical students in Turku, Finland.

Special interests of Dr. Airas include multiple sclerosis and pregnancy-related issues, mechanisms controlling lymphocyte homing into the CNS, development of novel drugs for MS, and advanced imaging techniques such as positron emission tomography (PET). She has been coordinating a Finnish nation-wide study looking at pregnancy-related alterations in MS immunopathology, and has numerous international collaborations in immunology and imaging fields. Dr. Airas also actively participates in clinical studies investigating new drugs to treat multiple sclerosis.

In addition to her scientific activities, she is responsible for neuroimmunological patients in the outpatient clinic of Turku University Hospital, and takes an active part in giving neuroimmunology-related education to fellow neurologists, other health care professionals, medical students and patients.

Squeaking out that somethings wrong

Sheridan GK, Dev KK. Targeting S1P receptors in experimental autoimmune encephalomyelitis in mice improves early deficits in locomotor activity and increases ultrasonic vocalisations. Sci Rep. 2014;4:5051. doi: 10.1038/srep05051.

Fingolimod (FTY720) is an oral therapy for relapsing remitting multiple sclerosis (MS) and targets sphingosine 1-phosphate receptors (S1PRs). FTY720 also rescues animals from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effects of FTY720 in EAE are primarily scored manually by examining weight loss and limb paralysis that begins around 10-12 days after immunisation. To our knowledge, pre-clinical effects of FTY720 on animal behaviour early in EAE have not been explored. Here, we developed an automated behaviour monitoring system to examine the early effects of FTY720 on subtle pre-symptomatic behaviour of mice induced with EAE. Our automated home-cage monitoring system (AHC-MS) enabled non-contact detection of movement and ultrasonic vocalisations (USVs) of mice induced with EAE, thus allowing detection of subtle changes in mouse behaviour before paralysis occurs. Mice receiving FTY720 emit longer USVs and display higher levels of motor activity than vehicle-treated EAE mice before clinical signs become apparent. Importantly, this study promotes the 3Rs ethics (replacement, reduction and refinement) in the EAE animal model and may also improve pre-screening of potentially novel MS therapies. In addition, this is the first report showing the early effects of FTY720 in EAE which underscores its protective effects.

The use of EAE is increasingly coming into the spotlight and is considered a substantial (compared to mild and moderate) procedure. 

There is an ethical case to be made that you may not really need to allow animals to become paralysed, as a read out for experiments. For example studies on immune function using knockouts where you use paralysis as a readout for gene activity.  You could simply do your test tube experiments and say record time to onset of pre-clinical weight loss, development of the first sign, etc....rather than letting paralysis occur. In this current study you could use vocalisations. However, do this and you run the risk of the referee pool from regions who are not so bothered about the 3Rs (not reading riting and rithmatic...but refinement, reduction and replacement) of animal use, who may bin your work.

However, just because in the past it was done, does not mean that it should be done. The 3Rs is now the corner stone of Animal experimentation in Europe. Times are changing.

It is becoming increasingly difficult to do such experiments in the UK. 

In this study they designed a monitor to see what the mices were doing and in the first few days after induction with an adjuvant (stimulates the immune system) and whooping cough toxin, there was perhaps a sickness behaviour where they did not move as much and they were off their water. The toxin makes the number of white blood cells grow ten times to make them get EAE, we don't use it. This no doubt is associated with immune growth factors which may you under the weather.

They used a drug FTY720 which is the ingredient drug in Gilenya/fingolimod to stop EAE and they found that these animals gave longer squeaks. We can't hear it because it is ultrasonic.

The mice destined to get EAE did not squeak as much..

ProfG has had loads of whacky ideas about how to monitor movement of mices, but this system was all automatic and so unbiased and provides constant monitoring. The camera and Bat sound detector went onto a standard cage, which is what you want. There are systems that can monitor movement that can be implanted like a microchip for dogs and cats that can detect movement and temperature 24/7 (when a mouse gets EAE it moves around less and gets colder) but the system only worked for one mouse per cage and required a special cage and was very expensive, the manufacturers at the time were not interested for developing a system that would track multiple animals in a cage as mice are social animals and prefer to live in groups. This system also appears to measure collective responses, at present (at least in sound), where you would want individual readings as (a) we currently randomise within cages, rather than having all animals in one treatment in CageA and the other Cage B (b) Not all animals develop disease at the same rate.

The authors "do not see this system as a complete replacement to the current clinical scoring methods (which can check on individual animals), but rather an additional tool that can be used alongside gold standard routines to assess beneficial drug responses in EAE". 

We have shown that the gold standard clinical scoring routines are less responsive to looking at recovery and have shown that animals move less as disease progresses. The merit may be a way to look at progressive deterioration over time and because of its constant monitoring small changes in loss of movement may be amplified, meaning experiments don't have to be as long...saving money on (mouse) hotel fees and less time in procedure for the beasties.

This is the type of approach that CRACK-IT aims to investigate. This is a NC3Rs programme aimed at developing practical approaches to address important issues to Industry, that have 3Rs potential.
Wonder how much the system costs?

People on fampridine are more responsive to stepping than walking

Koch MW, Patten S, Berzins S, Zhornitsky S, Greenfield J, Wall W, Metz LM.Depression in multiple sclerosis: A long-term longitudinal study.Mult Scler. 2014 May 22. pii: 1352458514536086. [Epub ahead of print]

OBJECTIVE:We aimed to evaluate the effect of slow-release (SR) Fampridine on multiple outcome measures reflecting different domains, and to compare the responsiveness of the Six Spot Step Test (SSST) and the Timed 25 Foot Walk (T25FW).
METHODS:For this study 108 participants were included. On day 0 they were tested with the T25FW, the SSST, the 9-Hole Peg Test (9-HPT), the 5 Times Sit-To-Stand test (5-STS) and the Symbol Digit Modalities Test (SDMT). Four weeks of treatment with SR Fampridine 10 mg BID was commenced. Participants were tested again after 26-28 days of treatment.
RESULTS:Mean changes observed were: SSST -3.4±6.4s (Faster) (p<0.001), T25FW -1.2±3.7s (p<0.001)(Faster, 9-HPT -1.2±6.0s (p<0.001)(Faster, 5- STS -3.4±7.2s (p<0.001) (Fasterand SDMT 1.4±4.8 a.u. (p=0.003) (better). Change on the SSST differed significantly from T25FW (SSST 17.0±19.6% vs. T25FW 11.2±17.1%, p=0.0013). Some 48.6% were found to have a meaningful change on the SSST compared with 25.7% on the T25FW. The response to treatment with SR Fampridine did not correlate with age, sex, Expanded Disability Status Scale and disease duration.
CONCLUSION: SR Fampridine treatment has significant effects on different domains including upper and lower body and cognition. Furthermore, the SSST is more responsive to the effect of SR Fampridine than is the T25FW.
We know that slow release Fampridine can may some of you walk better but if you do a different test that proportion can be bigger, however getting access to the drug is the big problem for many people.

Cortical shocks reduce fatigue

Stimulation of the cortex reduces MS-related fatigue. Interesting! #MSBlog #MSResearch

"Transcranial direct current stimulation (tDCS) is a form of neurostimulation which uses constant, low current delivered directly to the brain area of interest via small electrodes. It was originally developed to help patients with brain injuries such as strokes. tDSC has been reported to boost cognition in healthy adults. The pilot study below shows some benefit on MS-related fatigue. Very interesting and suggests that MS-related fatigue may be modifiable via cortical mechanisms. This work clearly needs to be expanded and tested in a large number of MSers and in more sites. I wonder if transcranial magnetic stimulation (TMS) of the cortex will have the same response? TMS is another way of stimulating the cortex using a magnetic field; it is easier to use and MSers prefer it. TMS is gainging widespread support to treat a large number of neurological conditions. Please watch this space; innovation is exciting."


Epub: Tecchio et al. Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation. J Neurol. 2014 May 23.

Background: MS-related fatigue is highly common and often refractory to medical therapy. 

Methods: Ten fatigued MSers received two blocks of 5-day anodal bilateral primary somatosensory areas transcranial direct current stimulation in a randomized, double-blind sham-controlled, cross-over study. 

Results: The real neuromodulation by a personalized electrode, shaped on the MR-derived primary somatosensory cortical strip, reduced fatigue in all patients, by 26 % in average (p = 0.002), which did not change after sham (p = 0.901). Anodal tDCS over bilateral somatosensory areas was able to relief fatigue in mildly disabled MSers, when the fatigue-related symptoms severely hamper their quality of life. 

Conclusion: These small-scale study results support the concept that interventions modifying the sensorimotor network activity balances could be a suitable non-pharmacological treatment for multiple sclerosis fatigue.

Monday, 26 May 2014

World MS Day 28th May 2014

A reminder that it is World MS Day on Wednesday. #MSBlog #MSResearch

If you have MS you may want to submit your One Day Wish.

Natalizumab PML Update May 2014

May 2014 natalizumab PML update. #MSBlog #MSResearch

"The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; I continue to be told by Biogen-Idec that if you are not a health professional you should not be reading this presentation. If you are a MSer you should be reading my previous post that has been designed for you."

Headline information

"As of the 6th March 2014 there have been 454 cases of natalizumab-associated PML. This represents an increase of 6 cases from last month; the number of cases each month continues to go down. The mortality associated with PML in this setting is currently 24%, i.e. 109 MSers have died as result of PML. Please note that the majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of well over 123,000 MSers been treated with natalizumab worldwide with over 320,000 years of natalizumab exposure."

"It is now clear that the numbers of MSers developing PML are falling due to the successful risk mitigation strategy that has been implemented Biogen-Idec with JC virus serological testing. This is a success story and it should be reassuring for MSers on natalizumab."

"Since NHS England gave us permission to switch high-risk natalizumab patients to fingolimod, we continue to de-risk our natalizumab-treated population. This is a big relief for me."

"The following is the most important headline data slide for MSers regarding risks based on the three identified PML risk factors:

  1. JCV serostatus
  2. Duration of treatment
  3. Previous exposure to immunosuppression

In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and this needs to be incorporated into future risk models."

"We have developed a simple infographic to help you intergrate all this information. You can download and print this infographic for your own information."

Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.

"The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch. In those MSers who are high risk and have elected to stay on natalizumab we have started doing 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 above."

CoI: multiple

Previous treatments influence fingolimod efficacy

What do you think of natalizumab sticky plaster analogy? #MSBlog #MSResearch

"The following study may alarm some of you; it show that MSers switching from natalizumab to fingolimod had a higher relapse rate than those switching from interferon-beta or glatiramer acetate. What the abstract does not tell you is that the MSers on natalizumab had an average wash-out period of 18 weeks, with a range from 12 to 24 weeks. What this study is documenting is MS rebound post-natalizumab. When you have no wash-out, or minimal wash-out (less than 8 weeks), between your last natalizumab infusion and starting fingolimod you prevent this rebound. This data is therefore not relevant to today's practice. This shows you how scientific publications often lag behind clinical practice."

"Why do you get rebound? That is an interesting question. It means that whatever is causing MS does not go away; it is still in the brain of MSers. By keeping out auto-aggressive cells with natalizumab you prevent them finding and attacking their target. By removing natalizumab you allow these immune cells to traffic back in the central nervous system find what they are programmed to find and attack it. Natalizumab withdrawal is the best and most predictable model of relapse we have in MS, that is human MS. I am sure the cause of MS is to be found by studying this phenomenon more carefully."

"One colleague described natalizumab as sticky plaster; it is fine whilst the sticky plaster is in place, but remove it and all hell breaks lose. This is why I find induction therapies so appealing; they target the peripheral immune response and don't rely on suppressing the immune cell trafficking."

Epub: Baldi et al. Previous treatment influences fingolimod efficacy in Relapsing-Remitting Multiple Sclerosis: results from an observational study. Curr Med Res Opin. 2014 May 15:1-23.

Objective: Fingolimod (FTY) is licensed as a disease-modifying treatment in highly active Relapsing-Remitting Multiple Sclerosis. The aim of the study was to evaluate the efficacy and safety of FTY in a real-life setting and to explore the possible role of clinical and MRI parameters, including previous treatment type, in predicting its efficacy. 

Methods: Clinical and MRI data was collected on 127 MSers assigned to treatment with FTY in six Multiple Sclerosis Centers in Emilia-Romagna, Italy, between August 2011 and June 2013. 

Results: During a mean follow-up period of 10 months (range 1-22), we observed a total of 47 relapses in 39 MSers (30.7%); new T2 lesions or Gadolinium-enhancing (Gd+) lesions were present at follow-up MRI in 32/71 patients (45%). EDSS at the end of the follow-up period was not different when compared to the baseline EDSS. Serious adverse events occurred in 3 MSers (2.4%). A higher proportion of MSers previously treated with natalizumab showed clinical (41%) or MRI activity (54%). Previous treatment with natalizumab increased the risk of a relapse within 30 days (versus immunomodulatory drugs; OR: 4.3; p=0.011) and at survival analysis (versus remaining MSers; HR: 1.9; p=0.046). Study limitations include a small population sample, a short observation period with variable timing of follow-up MRI and different baseline characteristics of MSers previously treated with natalizumab compared to those treated with immunomodulatory drugs.

Conclusions: This study confirms the efficacy of FTY in reducing relapse rate in MSers previously treated with immunomodulatory drugs, while it seems to be less effective in patients discontinuing natalizumab. Due to the short duration of follow-up is not possible to evaluate disability progression, however, no difference was observed between the groups.

CoI: multiple

MS on the Up in New Zealand

Pearson JF, Alla S, Clarke G, Taylor BV, Miller DH, Richardson A, Mason DF. Multiple sclerosis in New Zealand Māori. Mult Scler. 2014 May 22. pii: 1352458514535130. [Epub ahead of print]
The prevalence of MS in New Zealand in 2006 was 73.2 (age standardized per 100,000) while for those with indigenous Māori ancestry it was 3.6 times lower at 20.6. Earlier regional surveys (1968-2001) all reported much lower, or zero, prevalence for Māori than European. There was no evidence for differences in MS between those with and without Māori ancestry in either clinical features or latitude, confirming that Māori ancestry does not produce the reported increase in prevalence with latitude. It is likely that prevalence is increasing in low risk Māori; however, MS prognosis is independent of Māori ancestry.


Sunday, 25 May 2014

More long-term alemtuzumab data

Do you want your brain to age well? The choice may be yours. #MSBlog #MSResearch

"In response to a discussion yesterday around the open-label alemtuzumab data from Cambridge I am re-posting the 5-year extension data from the phase 2 Alemtuzumab trial. As you can see MSers treated with Alemtuzumab do a lot better than those treated with interferon over 5 years. As always this comes with a price, namely the risk of secondary autoimmunity."

"A delegate at the Top Seminars meeting in Sorrento confronted me with the argument that the FDA used when they turned down Alemtuzumab in the US, that there is no evidence alemtuzumab is better than Rebif in drug-naive MSers. You may recall that there was not statistically significant difference between those with sustained progression on the CARE-MS 1 trial. I said that is fine if you are only prepared to look at the tip of the iceberg and even then alemtuzumab was superior to Rebif in relapse reduction. However, when you dive under the surface and look at end-organ damage you will see that the rate of brain volume loss in year 2 was 0.25% on alemtuzumab and 0.5% on Rebif (slide 16 below).  Please remember that normal people lose between  0.1% and 0.4% of their brain volume per year after the age of 35."

"Which drug, alemtuzumab or interferon-beta, is preventing end-organ damage? Which drug will keep your brain healthy for old age? People always see what they want to see in the data."

"The natural conclusion of moving the therapeutic goal posts in MS to preventing end-organ damage is that you need to get on to the most effective DMTs as soon as possible in the course of the disease. I have tried to illustrate this in slides 50 to 56 below; only early highly-effective treatments can protect your brain sufficiently to give you a chance in old age."

Coles AJ, et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial. Neurology. 2012 Apr 3;78(14):1069-78.

OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline).

METHODS: Of 334 MSers originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months.

RESULTS: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia (autoimmune attack of platelets) occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab-treated MSer developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab.

CONCLUSIONS: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports.

CoI: Multiple

Getting rid of skin reactions in interferons

Hupperts R, Ghazi-Visser L, Martins Silva A, Arvanitis M, Kuusisto H, Marhardt K, Vlaikidis N; for the STAR Study Group.The STAR Study: A Real-World, International, Observational Study of the Safety and Tolerability of, and Adherence to, Serum-Free Subcutaneous Interferon β-1a in Patients With Relapsing Multiple Sclerosis.Clin Ther. 2014 May 5. pii: S0149-2918(14)00199-4.

BACKGROUND:Adverse reactions, particularly injection site reactions (ISRs), are common reasons for nonadherence to injectable multiple sclerosis (MS) treatments. Adherence to MS treatment is important to ensure good treatment outcomes.
OBJECTIVE: The aim of this study was to assess the local tolerability of subcutaneous (SC) serum-free interferon (IFN) β-1a in patients with relapsing MS over 1 year in a real-life, international setting. The study also assessed safety, disease activity, and adherence.
METHODS:This was a prospective, international, multicenter, observational study of 251 patients with relapsing-remitting MS treated with SC serum-free IFN β-1a 44 μg or 22 μg 3 times weekly for 12 months or until early discontinuation. The primary end point was the proportion of patients with ISRs. Secondary end points included proportion of patients with adverse events (AEs); annualized relapse rate (ARR); proportion of patients remaining relapse-free; and adherence to treatment.
RESULTS: During the observation period, 27.5% (69 of 251) of patients experienced non serious ISRs, which was consistent with the incidence reported in clinical studies. Five patients discontinued treatment and 2 patients suspended treatment because of ISRs. Mean age was 35.8 years; patients were predominantly white (94.8%), and two thirds (66.1%) were female. The overall incidence of AEs was 63.7% (160 of 251), and overall safety and tolerability were assessed as excellent, very good, or good in >85% of patients. More than 70% of patients remained relapse-free, and the mean ARR was 0.4. More than 90% of patients had very good or good adherence to treatment; a significantly greater proportion of these were relapse-free at 12 months compared with those with fair or poor adherence (77.6% vs 50.0%; P = 0.0107), and their ARR was significantly lower (0.3 vs 0.9; P = 0.0055). Patients with fair or poor adherence had 4.6 times higher odds of experiencing a relapse than those with very good or good adherence.
CONCLUSIONS: The incidence of ISRs and the overall safety profile in this observational study, in an international population in a real-life setting, confirm the good local tolerability of SC serum-free IFN β-1a reported in clinical studies. The association between good adherence and a lower ARR underlines the importance of good adherence. The good local and general tolerability of SC IFN β-1a may help ensure a high level of adherence, which is associated with better clinical outcomes

In mice we sometimes noticed that Interferons could cause adverse reactions and we worked out that this could be due to extra bits in the interferon preparation besides the interferons. This could be due to contaminating blood products used during making and formulating the drug.

Take your drugs and they work,don't take them and they don't. Any protein that is injected can become immunogenic, meaning that you can make an immune response against it and this can lead to unwanted "hypersenitivity" reactions...i.e. allergies. The amazing thing that Alemtuzumab a white blood depleting antibody can induce an immune response against itself. Get rid of blood products from beta interferon products, e.g. they can be used in growing the cells that make the protein drugs and they are less likely to cause skin reactions. Get rid of aggregates of proteins and they are less likely to cause skin reactions. Less skin reactions and the the more likely someone is to take their drugs.

The more likely they will work

Saturday, 24 May 2014

Blood counts don't predict disease activity

Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J.Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.
Neurology. 2014 May. pii: 10.1212/WNL.0000000000000520. [Epub ahead of print]

OBJECTIVE: To test the hypothesis that accelerated peripheral blood mononuclear cell recovery after alemtuzumab treatment of multiple sclerosis is associated with recurrent disease activity and to investigate the claim that CD4 counts greater than 388.5 × 106 cells/mL at 12 months can be used to identify patients who may benefit from further treatment.

METHODS: A total of 108 patients were followed for a median of 99 months (4 years) post alemtuzumab. Patients were classified as active or non-active after each cycle of treatment based on clinical relapse, increasing disability, or new T2/enhancing MRI lesions. These outcomes were correlated with CD4, CD8, CD19, CD56+ NK, and monocyte counts.

RESULTS: Of 108 patients, 56 (52%) relapsed at some point during follow-up. Mean annualized relapse rate after alemtuzumab was 0.17 vs 1.67 prior to treatment (equating to a 90% reduction). Of 108 patients, 28 (26%) met the criteria for sustained accumulation of disability. Median time to the lower limit of normal for CD19, CD8, and CD4 was 3, 19.5, and 32 months, respectively. There was no significant difference in the recovery of any cell population between patients with and without disease activity or accumulation of disability after treatment.

CONCLUSION: This study does not support the use of cell counts as biomarkers for identifying patients at greater risk of active disease following treatment with alemtuzumab.

How does Alemtuzumab work..many immunologists will claim because it inhibits T cell activity. Others argue that it could be because of B cell activity. After alemtuzumab treatment, T cells are depleted for over 1 year and closer to 2 years whereas B cells are only reduced for about 3 months after which time more B cells than normal are produced and is one reason a reason why Alemtuzumab may cause B-cell mediated autoimmune conditions because they return before T cell regulation recovers. But what is clear is that overall repopulation of white blood cells do not link to the return of disease activity. Does this mean white blood cells are not the problem. 

One could argue that it is cells in the brain that is important, however I suspect that a small subset of cells are causing the problem but the trees are lost because people concentrate on looking at the woods. 

In animals we know that if we deplete the white blood cell pool then this is necessary for activity and when they recover in numbers then disease returns. However these cells do not need to return to normal levels and rarely ever do recover. However, return of disease does not depend on absolute numbers of cells and disease can return when there are very few cells present.

Maybe we have to find ways to refine this further.