Friday, 28 February 2014

Clinic Speak: switching from natalizumab to fingolimod

Rebound post-natalizumab can be prevented or reduced by early switch to fingolimod. #MSBlog #MSResearch #ClinicSpeak

"The study below confirms the results of the TOFINGO study, MSBase and several smaller studies, which show that if you have a wash-out period when switching from natalizumab you are  more likely to have a relapse  than if you don't have a washout. Why? Natalizumab has a circulating half-life close to 2 weeks; the half-life describes the period of time it takes for the levels to drop by 50%. It therefore takes about 10-12 weeks (5-6 half lives) for natalizumab levels to drop to low enough levels to allow lymphocytes to start trafficking back into the brain and spinal cord. If these cells are autoimmune cells they will set-up an local inflammatory response and trigger a relapse. This process takes several weeks. This is why we see rebound disease activity (relapses or MRI activity) about 3-4 months after stopping natalizumab. Therefore it is not a good idea to stop natalizumab without starting another DMT to prevent this rebound. Unfortunately, interferon beta and GA have not proven to be very effective post-natalizumab. What about oral drugs? We don't have data yet on teriflunomide (Aubagio) or BG12 (Tecfidera). However, fingolimod has been studied and provided it is started with 8 weeks of stopping natalizumab it can prevent most of the rebound. The sooner you start it the better. At the Royal London Hospital we have adopted this practice for sometime now. If the switch is in a JCV positive MSers we do an MRI for new white matter lesions and lumbar puncture to analyse the spinal fluid for JCV DNA. If these test are clear the likelihood of asymptomatic PML is low and we start fingolimod. This typically occurs at around week 3 or 4 after the last infusion of natalizumab. As it takes about 6 weeks for fingolimod to take an effect by the time natalizumab is out of your system fingolimod is working."

"If you are being switched from natalizumab to fingolimod and your neurologist wants to do a prolonged washout ask him/her why?"

"What is most intriguing about stopping natalizumab is the rebound activity that is often very severe and greater than that what was seen prior to starting natalizumab. Why? I suggest you read my post from last year on this topic; it generated a lot of discussion about MS and its potential cause."

Rebound activity post-natalizumab; image from Arch Neurol. 2011;68(2):186-191.

Cohen et al. Switching From Natalizumab to Fingolimod in Multiple Sclerosis: A French Prospective Study. JAMA Neurol. 2014 Feb 24. doi: 10.1001/jamaneurol.2013.6240.

IMPORTANCE: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of MSers to our knowledge.

OBJECTIVE: To collect data from MSers switching from natalizumab to fingolimod.

DESIGN, SETTING, AND PARTICIPANTS: A survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod.

MAIN OUTCOMES AND MEASURES: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod.

RESULTS: Thirty-six French MS tertiary referral centers participated. In total, 333 MSers switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for MSers receiving natalizumab. Twenty-seven percent of MSers relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). MSers who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of MSers relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). 

CONCLUSIONS AND RELEVANCE: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

CoI: multiple

TED Chandran Repairing the brain

Can we get repair in MS? Heres an old TED (Click on Old Ted for  a working link to the video)  from our 
Friend Dr Chandran from Edinburgh who has been leading 
some of the UK effort in this Area.

Thursday, 27 February 2014


INSPIRE Study update: we are almost there; 19 study subjects recruited and 5 to go. #MSBlog #MSResearch

"In response to several requests, the following is a recruitment update on the INSPIRE Study."

A Phase II Baseline Versus Treatment Study to Determine the Efficacy of Raltegravir (Isentress) in Preventing Progression of Relapsing Remitting Multiple Sclerosis as Determined by Gadolinium-enhanced MRI

There is accumulating research evidence that Human Endogenous Retrovirus (HERV) and herpes viruses (in particular Epstein-Barr Virus) are involved in the pathogenesis of MS. People with active MS have higher levels of HERVs than people either without MS or who have other neurological conditions. It has been shown that HERVs may produce neurotoxic proteins/antigens associated with MS activity and disease progression. This is the first clinical trial investigating the hypothesis that the antiretroviral drug raltegravir may suppress HERV activity and ameliorate progression of relapsing remitting MS. Raltegravir is an integrase inhibitor which blocks retroviral replication. A recent experimental study suggests that raltegravir may also be active against herpes viruses.

Eligible participants (see Inclusion/Exclusion Criteria) will be observed for 3 months having monthly brain Gadolinium enhanced MRIs and blood/urine/saliva sampling (baseline). Then they will be treated with raltegravir (one 400mg pill taken twice a day) for 3 months. During treatment period participants will continue to have monthly MRIs and blood/saliva/urine sampling. Participants will have monthly clinical and neurological examinations and they will complete questionnaires assessing response to treatment. Participants will have screening and study visits at The Royal London Hospital, Whitechapel. Monthly MRIs will be performed at the Institute of Neurology, UCL, Queen Square, London.

Inclusion Criteria:
  1. Patients between 18-55 years of age.
  2. Diagnosis of MS, according to the revised McDonald Criteria 2010.
  3. EDSS score of 0-6.0 inclusive.
  4. Documented at least one relapse within the past 12 months or at least one Gd-enhanced lesion on the brain MRI detected within 3 months prior to screening date
  5. Gd-enhanced lesion on screening MRI (if MRI not used to meet screening criteria above).
  6. Female patients of childbearing potential will be expected to be on appropriate contraception (hormonal or barrier method of birth control; abstinence) from time of consent until 6 weeks after treatment discontinuation. (the repeated administration of gadolinium and MRI are not recommended during pregnancy). NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  7. Females of childbearing potential must have a negative urine pregnancy test prior to every MRI scan/ within 7 days prior to being registered for protocol therapy.
  8. Must give written informed consent and authorize the release and use of protected health information, as required by local law.
  9. Able and willing to undergo blood, saliva and urine sampling at regular intervals as defined by the protocol.
  10. Able and willing to receive Gadolinium enhanced MRI's at regular intervals as defined by the protocol.
  11. Able to comply with study requirements.
Exclusion Criteria:
  1. Pregnant or breastfeeding or unwilling to use contraception.
  2. Treatment with immunosuppressive, immunomodulatory or experimental treatments within the last 6 months of enrolment in the study, but excluding pulsed intravenous or oral steroids for treatment of MS relapse.
  3. No pulsed intravenous or oral steroids in the 30 days preceding the baseline assessment.
  4. Patients presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil <1.5 or platelet count < 100, or thrombocytopenia < 1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the patient.
  5. Presence of human immunodeficiency virus antibodies.
  6. Patients receiving proton pump inhibitors (e.g. omeprazole/esomeprazole)
  7. Patients with active hepatitis B or/and C with liver function tests >2.5 times ULN
  8. Exposure to any other investigational drug within 30 days of enrolment in the study.
  9. Prior history of malignancy unless an exception is granted by the Chief Investigator.
  10. History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
  11. Patients treated with Rifampicin in past four weeks. Identifier: NCT01767701

"Hopefully, the results will be available with the next 12 months."

Additional reading: raltegravir

CoI: multiple, this trial is being funded by Merck. Please note you cannot self-refer for this study. If you are interested in taking part in a clinical trial seek advice from a member of your MS team. 

Clinic Speak: why do you use complementary or alternative medicines?

Do you use complementary or alternative medicines? Why? #ClinicSpeak #MSBlog #MSResearch

"What is complementary or alternative medicine (CAM)? CAM is any practice that is put forward as having the healing effects of medicine but is not based on evidence gathered using the scientific method. CAM consists of a wide range of health care practices, products and therapies, using alternative medical diagnoses and treatments which typically have not been included in the degree courses of established medical schools or used in conventional medicine. Examples of alternative medicine include homeopathy, naturopathy, chiropractic,energy medicine and acupuncture."

"In the study below 62% of MSers used CAMs in 2002, which dropped to 23% in 2009. Poor economic state and progression of MS was associated with less CAM use. I assume because of MSers being unable to afford CAMs and their perceived lack of efficacy, respectively. What is interesting is that CAM usage was particularly prevalent at EDSS stages of 3.5-4.0. Why? This is the stage of the EDSS scale when MSers mover from minimal to moderate impairment and when secondary progression sets in for MSers with relapse-onset disease. This is also when MSers realise that their disease is progressing and traditional medicine is letting them down or failing them."

"I always tell recently diagnosed MSers that they will go through an emotional roller-coaster ride similar to Kübler-Ross's five stages of grief. These can be memorised by the acronym DABDAA."

D - Denial (I don't have MS, you must have made a mistake)
A - Anger (Why me? What have I done to deserve getting MS?)
B - Bargaining (Are you sure I have MS? Can you please re-investigate me to make sure you have the right diagnosis? If I stop smoking and go onto this diet will my MS go away? What can I do to get rid of this disease?)
D - Depression (I fell terrible, my life is ruined, I am going to end-up in a wheelchair.)
A - Acceptance (I have MS, what can I do about it? How am going to get on with my life despite having MS?)
A - Anxiety (I can't sleep at night. I keep waking up and worrying about losing my job. How am going to look after my children? What if my partner leaves me? What is going to happen to me? Will my children get MS? Should I start a family? How am I going to meet anyone?)

"What I have noticed is that when MSers transition from the minimal to the moderate impairment phase they tend to go through these emotional phases again. I think this is when you realise that your MS is not so benign and it is likely to lead to progressive and irreversible disability. It is at this stage that you realise that traditional medicine has failed and you start looking around for alternatives. I personally don't have problem with my patients seeking CAMs, provided they can afford it and the CAMs they use don't come with too many risks. I an convinced that the process of being proactive, and self-disciplined, about a therapy is in itself helpful; it is my impression that it improves your mood and gives you hope. On the other hand being passive and accepting of the status quo is associated with low mood and poor motivation. This is why I personally subscribe to the holistic approach  to managing MS; this involves traditional medicine, lifestyle measures (diet, exercise, sleep hygiene, stopping smoking, mental activity, etc.) and CAMs if you so choose. What I don't do is prescribe or recommend CAMs; as a Western-trained neurologist I am card-carrying evidence-based practitioner and try an avoid adopting practices that are not evidence-based or have a compelling scientific rationale."

BACKGROUND: Complementary and alternative medicine (CAM) in chronic progressive diseases, like multiple sclerosis (MS), is highly prevalent. Up to now there are no satisfying longitudinal analysis about changes in using of CAM accompanied by influencing parameters like disease duration, stage of impairment or socioeconomic factors. This study captured the using of CAM of MSers in combination with disease progression.

METHODS: 119 MSers were asked about CAM utilization, sociodemographic and disease factors within the context of a semistructured interview at an interval of seven years. The depressive status was ascertained with the Beck's Depression Inventory (BDI). Differences of users and non-users were checked with diverse statistical tests.

RESULTS: Comparing both isolated measurements at second point, less MSers used CAM accompanied by worse socioeconomic situation and progression of the disease. MSers use CAM in a stage of illness, characterized by the Established Disability Status Scale (EDSS) between 3.5 and 4.0 points, signifying a transition from moderate to severe impairment, and a shorter duration of illness in comparison to non-users. Types of used CAM have been changed over seven years. Relaxation techniques and traditional Chinese medicine (TCM) are the favorite therapies at second measurement

DISCUSSION: As the key result of the study MSers use CAM in an early stage of the disease. Their EDSS lies between 3.5 and 4.0 points and they suffer medial two years shorter from MS than non-users. CAM could be an important appliance to cope with the disease.

CoI: multiple

Remyelination of cortical lesions may not always repair

Rodriguez EG, Wegner C, Kreutzfeldt M, Neid K, Thal DR, Jürgens T, Brück W, Stadelmann C, Merkler D. Oligodendroglia in cortical multiple sclerosis lesions decrease with disease progression, but regenerate after repeated experimental demyelination. Acta Neuropathol. 2014 Feb 25. [Epub ahead of print]

Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA+ mature oligodendrocytes and Olig2+ oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA+ and Olig2+ cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA+, but not Olig2+ cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS.

So you can repeatedly demyelinate a rat and it will remyelinate its grey matter, in MS it is suggested that early lesions. Likewise remyelinate but chronic (older) ones may not and some of the myelin forming precursors were reduced in the chronic lesions. At some point the repair potential becomes exhausted. However yet again we have pathologists who can't agree. 

Cortical remyelination: a new target for repair therapies in multiple sclerosis. Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, Chomyk AM, Yong VW, Fox RJ, Kidd GJ,Trapp BD.Ann Neurol. 2012;72(6):918-26. Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient

The truth is likely to be somewhere between the two. Some people will repair very well and others will not and they maybe at risk to more cognitive problems. Maybe if they used a different strain or age of rat they may have got a different result. However the commonality with the white matter is if there are not myelinating precursors in the lesions then they don't repair as well.In rats repeated demyelination was met with repair and so in support of ProfG's view that one of the best early repair strategies is get rid of the inflammation and the brain will repair itself.

Troll-Free Zone.

Although we appear to be a Troll-Free Zone, we still get the odd person spilling some bile. Their posts however end up in spam or go straight to the bin.

This online report about Internet trolling shows that they (trolls) show narcissism (egocentrism and preoccupation with prestige), machiavellianism (tendency to deceive and manipulate), psychopathy (lack of empathy and inhibition), and sadism (pleasure of inflicting pain or humiliation on others).

Maybe "stupidity" is another trait, as they must realise the hard work sending the insults is futile and they simply waste their own time.

Wednesday, 26 February 2014

Survey results: bone marrow transplantation

Are MSers really this willing to take risks? #MSBlog #MSResearch

"In response to my posts on bone marrow transplantation (BMT) and brain atrophy after BMT in MSers I have the following interim results of our one question survey. Could  this really be correct? Almost 50% of MSers are prepared to take the risks of BMT. Only 32% said no. If these result are correct I have seriously underestimated the risk MSers are prepared to take in the hope of a potential cure for their disease."

"Please have your say!"

ClinicSpeak: body temperature and fatigue

Will lowering your body temperature help your fatigue? #ClinicSpeak #MSBlog #MSResearch

"The study below is very interesting. Its findings are in line with some of my own anecdotal observations in MSers and has potentially major implications for all MSers. In short RRMSers have a higher body temperature than controls and this is associated with worse fatigue."

"Why would RRMSers have a higher body temperature? Maybe they have MS lesions in the area of the brain that controls body temperature; i.e. the hypothalamus. This is unlikely as this should be a greater problem in SPMSers who generally have a higher lesion load and are therefore more likely to have lesions in the hypothalamus; in this study SPMSers did not have a raised body  temperature. In fact hypothermia, or a low body temperature, does occur in MSers from lesions in the brain's temperature control center or hypothalamus and I have only ever seen this rare complication of MS in SPMSers. I suspect the most likely explanation for the raised body temperature in MSers is that it is due to active inflammation in the brain. Inflammatory MS lesions produce chemical signals called cytokines that may explain the raised body temperature. Interleukin-1 (IL-1) and TNF-alpha are the main cytokine culprits when it comes to raising your body temperature. These cytokines bind to nerve cells in the hypothalamus and stimulate the so called sickness behaviour refelex; this includes fatigue, hypersomnalence (tiredness), a rise in body temperature and a change in your metabolism to conserve energy. If this is the case then MSers could use their body temperature as a way to monitor if their MS is active or not? A corollary to this would be if that if you went on to a highly-effective DMT that shut down inflammation in the brain it should lower your body temperature. I think this would be an interesting and cool study to do. May be we could crowd source this and do the study via the web? I have some ideas how it can be done."

"Some of my clinical anecdotes that are congruent with the results of the study below are: (1) I have several MSers I look after who take anti-pyretics (medication to lower your temperature) as a means of treating their fatigue. Some use paracetamol or acetaminophen and others ibuprofen; they swear by it. (2) Women with MS often complain of worse fatigue during menstruation; a period in  their menstrual cycle associated with a slight higher body temperature. (3) Flu-like symptoms associated with interferon-beta therapy, which cause a mild pyrexia, exacerbates fatigue. (4) Warm environments, exercise and infections all of which raise body temperature exacerbate fatigue. (5) Despite the poor evidence-base a large number of MSers swear that cooling improves their fatigue; one of my patients has had a walk-in butchers fridge installed in her home; it easily takes her wheelchair. She spend 4 to 5 half-hour sessions in the fridge every day; she claims this is the only way she can cope with her fatigue."

"There are some small trials supporting these observations; i.e. that aspirin, a widely used anti-pyretic helps MS-related fatigue. Could the latter be due to effect of aspirin on body temperature?"

"How could a raised body temperature cause fatigue? I have discussed this in many previous posts; the one on Uhthoff's phenomenon explains it best."

"Have any of you noticed that anti-pyretics helps your fatigue? I would be interested in finding out."

Sumowski & Leavitt Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure. Arch Phys Med Rehabil. 2014 Feb. pii: S0003-9993(14)00126-9.

OBJECTIVE: To investigate whether resting body temperature is elevated and linked to fatigue in RRMSer.

DESIGN: Cross-sectional study investigating (a) differences in resting body temperature across RRMS, SPMS, and healthy groups, and (b) the relationship between body temperature and fatigue in RRMSers.

SETTING: Climate-controlled laboratory (∼22°C) within a non-profit medical rehabilitation research center.

PARTICIPANTS: Fifty RRMSers, 40 matched healthy controls, and 22 SPMSers.


MAIN OUTCOME MEASURE(S): Body temperature was measured with an aural infrared thermometer (normal body temperature for this thermometer is 36.75°C), and differences were compared across RRMS, SPMS, and healthy persons. RRMSers completed measures of general fatigue (Fatigue Severity Scale; FSS), as well as physical and cognitive fatigue (Modified Fatigue Impact Scale; MFIS).

RESULTS: There was a large effect of group (p<.001, ηp2=.132) whereby body temperature was higher in RRMSers (37.04°C±0.27) relative to healthy controls (36.83 ± 0.33; p = .009) and SPMSers (36.75°C±0.39; p=.001). Warmer body temperature in RRMSer was associated with worse general fatigue (FSS; rp=.315, p=.028) and physical fatigue (pMFIS; rp=.318, p=.026), but not cognitive fatigue (cMIFS; rp=-.017, p=.909).

CONCLUSIONS: These are the first-ever demonstrations that body temperature is elevated endogenously in RRMSers and linked to worse fatigue. We discuss these findings in the context of failed treatments for fatigue in RRMS, including several failed randomized controlled trials (RCTs) of stimulants (modafinil). In contrast, our findings may help explain how RCTs of cooling garments and antipyretics (aspirin) have effectively reduced MS fatigue, and encourage further research on cooling/antipyretic treatments of fatigue in RRMS.

MS is increasing in New Zealand

Alla S, Pearson J, Debernard L, Miller D, Mason D. The Increasing Prevalence of Multiple Sclerosis in New Zealand. Neuroepidemiology. 2014 Feb;42(3):154-160. [Epub ahead of print]

Background: New Zealand (NZ) has a high prevalence of multiple sclerosis (MS). Worldwide, the prevalence of MS appears to be increasing. 
Objectives: To review all published prevalence studies undertaken in NZ to determine whether the prevalence of MS in NZ is increasing. Methods: PubMed, Medline, Scopus, Web of Knowledge, EMBASE, AMED and CINAHL were searched to identify studies reporting the prevalence of MS in NZ. Prevalence rates from the National MS Prevalence study in 2006 were compared with earlier prevalence rates for the same regions using Poisson regression. 
Results: Prevalence rates reported in the earlier regional studies ranged from 23.6 to 68.5/100,000 population; in the same regions in 2006, the range was 47.6-134.2/100,000 population. Prevalence rates were significantly increased in all regions studied except for the Bay of Plenty. The increase in prevalence was seen in both sexes. The sex ratio remained constant over time. 
Conclusions: In studies spanning almost 40 years (1968-2006), the prevalence of MS within the same regions of NZ has significantly increased whereas the sex ratio and latitudinal gradient have remained stable.
You can read the conclusions

Tuesday, 25 February 2014

More on BMT, neurotoxicity and brain atrophy

BMT accelerates brain atrophy rates and disability progression in SPMS. #MSBlog #MSResearch

"My post on bone marrow transplantation (BMT) yesterday generated some discussion about brain atrophy. The BMT procedure requires chemotherapy to ablate or wipe-out your immune system to allow stem cell transplantation. The chemotherapy drugs that are used are neurotoxic, i.e. they damage the brain. In MSers who already have pre-existing damage their nerve cells are more susceptible to chemotherapy damage. The following study I was involved shows that when SPMSers are given chemotherapy they undergo increased neuronal loss, which is associated with faster progression on the EDSS and greater brain atrophy. The data speaks for itself. The picture below is what we call a survival curve of EDSS progressions and you can see that the MSers who had high serum levels of the neuronal toxicity marker neurofilament were much more likely to progress than those who did not have raised neurofilament levels. Similarly, brain atrophy rates in SPMSers were in the order of 2.1% per year in those who had a BMT compared to only 1.2% per year in SPMSers who did not have a BMT; the upper limit of normal for brain atrophy in healthy adults is generally accepted to be 0.4% per year. The bottom line is that if you have SPMS BMT is likely to accelerate your disease progression. As a result of these observations and other data most MSologists have stopped doing BMT in SPMS and limit it to those with RRMS. However, with the advent of highly-effective DMTs such as alemtuzumab, natalizumab, fingolimod and the anti-CD20s in development it is hard to justify BMT in view of its risks."

"I qualified as a neurologist, in the UK, in 1998 and got my first job at the Royal Free Hospital in London. At the time the Royal Free was pioneering BMT in other autoimmune diseases. Due to the environment at the Royal Fee I did due diligence on BMT in MS and came to the conclusion at the time that the risks outweighed the benefits of the treatment. In the 1990s the mortality of MSers undergoing BMT was ~5%, i..e 1 in 20 MSers who had a BMT would die from the procedure. Since then the mortality rates have dropped to about 0.5-1.0%; that is still a chance of 1 in 100 to 1 in 200 of dying from the procedure. Would you take this risk?"

"BMT is an induction therapy and hence offers you a potential chance of a cure; that is if MS is an autoimmune disease. BMT is one of the ongoing 15-20 year experiments testing this hypothesis."

Petzold et al. Evidence for acute neurotoxicity after chemotherapy. Ann Neurol. 2010 Dec;68(6):806-15.

OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients' quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.

METHODS: This prospective study included MSers with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMSers matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).

RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT MSers and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL MSers or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).

INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.

CoI: Prof. G was a co-author on this study.

Not all viruses are associated with MS

Herpesviruses, including human herpesvirus-6 and varicella zoster virus, have been implicated in the disease aetiology of multiple sclerosis. These viruses are capable of reactivation, reminiscent of the relapsing-remitting nature of multiple sclerosis. However, viral DNA has also been reported present in healthy controls, often at similar prevalence rates. This study aimed to determine whether prevalence could be associated with different stages of activity of the disease as well as the inflammatory status of the patients. Polymerase chain reaction assays were used to screen for human herpesvirus-6 and varicella zoster virus DNA in blood from 31 Caucasian patients with multiple sclerosis and 30 healthy age, sex and race matched control subjects. The patients were screened for inflammation using C-reactive protein as a marker and were also categorized according to their remitting/relapsing status. Results were positive for human herpesvirus-6 in blood from only one patient (3.2%) and human herpesvirus-6 DNA was not present in any control subjects. Varicella zoster virus was not detected in either the patients or control subjects. Similar to some other studies we saw an absence or very low viral positivity in blood from both patients and controls. These findings were irrespective of relapse episodes, increased inflammatory status or duration of the disease. Results therefore do not support a causative role for either human herpesvirus-6 or varicella zoster virus in the disease aetiology of multiple sclerosis, but rather that prevalence in patients may be linked to that of the general population

This papers for a causal link between MS and two different viruses and comes up short in both cases as there are too many people with MS who don't have evidence of infection. This has constantly been the case for HHV-6 so it it is either one of many causative agents or more likely a secondary effect that this virus has been spotted in MS.

Monday, 24 February 2014

Bone marrow stem cells to replace the immune system effectively silences RRMS

Are you prepared to have a bone marrow transplant? #MSBlog #MSResearch

"Bone marrow transplantation (BMT) using your own stem cells is the ultimate human experiment in an autoimmune disease. The hypothesis is simple; let's ablate or destroy your immune system and then let your immune system reboot from scratch using harvested stem cells. It sounds straight forward but it is not. firstly, it is very difficult to destroy your immune system so  that when it reboots there is a chance the autoimmune cells will repopulate, i.e. your MS will return. Whilst you are waiting for your immune system to recover you are at high risk of complications from the treatment, i.e. infections, bleeding and anaemia. During this period you need bone marrow support. I did my house job on a haematology oncology ward and I used to look after the bone marrow transplant patients. Boy do they get sick and sick quickly. BMT is not for the faint hearted."

"It is very difficult, if not impossible to do randomised double-blind placebo-controlled trials to test BMT as a treatment strategy. Therefore we have to rely on observational data and compare it with natural history data of MS to get an idea of its effectiveness. The Swedish study below is in keeping with other country-wide data; BMT is a very effective treatment for highly-active RRMS. The problem is if you use this treatment in SPMSers that don't so as well; i.e. it may stop relapes and MRI activity but it does not stop non-relapsing progressive disease. In fact the chemotherapy that is used to ablate the immune system is often neurotoxic (damages neurons) and may make hasten disease progression. We showed in collaboration with the group in Rotterdam that chemotherapy in BMT increases the amount of neurofilament released into the peripheral blood and the level of neurofilaments correlated with disease progression. Neurofilaments are a structural protein inside neurons and axons and are released when the neuron or axon are damaged."

"Would you take the risk of BMT? You need to remember  that BMT is the ultimate induction therapy and potentially offers a cure. Similarly, to alemtuzumab therapy, we need to wait 15 to 20 years to see if these MSers rendered NEDA (no evident disease activity) are cured or will they come back with SPMS?"

"How does this fit in with the EBV hypothesis? Not sure, but BMT destroys the B-cell pool and hence targets EBV. There are some reports of people becoming EBV negative post BMT. So the fact that BMT works as a treatment for MS does not exclude EBV as a potential cause of MS."

Burman et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014 Feb 19. 

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive MS. No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated MSers constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish MSers treated with HSCT.

METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two MSers were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 MSers had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 MSers (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

RESULTS: At 5 years, relapse-free was 87%; MRI event-free 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

Pain in MS

Fernández-de-Las-Peñas C, Ortega-Santiago R, Ortíz-Gutiérrez R, Caminero AB, Salom-Moreno J, Arendt-Nielsen L. Widespread Pressure Pain Hypersensitivity in Patients with Multiple Sclerosis with and Without Pain as Sign of Central Sensitization.Clin J Pain. 2014 Feb 12. [Epub ahead of print]

OBJECTIVE:To determine the presence of widespread pressure hyperalgesia in multiple sclerosis (MS) patients with and without pain and its association with pain and fatigue.
METHODS:One hundred and eight (n=108) individuals with definite MS, 49 men and 59 women (mean age: 44±8 y) and 108 age- and sex matched healthy controls (mean age: 44±9 y) were included. Fifty patients (n=58, 54%) reported pain and 50 (46%) did not exhibit pain. Pressure pain threshold (PPT) was bilaterally assessed over supra-orbital, infra-orbital, mental, median, radial and ulnar nerve trunks, C5-C6 joint, second metacarpal and tibialis anterior muscle by an assessor blinded to the subject's condition. The intensity of pain was assessed with a numerical pain rate scale (0-10), fatigue was determined with the fatigue impact scale (FIS), and depression was evaluated with the Beck Depression Inventory (BDI-II).
RESULTS:The ANCOVAs revealed that PPT were significantly decreased bilaterally over the supra-orbital, infra-orbital, mental, median, ulnar, and radial nerve trunks, C5-C6 joint, second metacarpal and tibialis anterior muscles in patients with MS compared to healthy controls (all, P<0.001). No significant differences existed between MS patients with pain and those without pain (all P>0.944). Patients with pain exhibited higher fatigue and depression than those patients without pain (P<0.05). PPT was not associated with any clinical variable, i.e., pain, depression, or fatigue).
CONCLUSIONS: Our study found widespread pressure pain hyperalgesia in individuals with MS as compared to healthy controls. No differences existed between MS patients with pain and those without pain in the presence of widespread pressure sensitivity. Current results suggest that MS is associated with sensory hyper-excitability of the central nervous system or dysfunction in endogenous pain modulatory systems.

Pressure hyperalgesia means that touch has becomes painful where it had not been painful before. In this study the pain threshold dropped as a consequence of MS in the face trunk and arms, This sensation results from the development altered nerve impulse signalling in pain pathways 

Sunday, 23 February 2014

More on brain atrophy

Brain atrophy predicts disability progression and cognitive impairment. #MSBlog #MSResearch

"In response to my post yesterday on 'Brain atrophy: the ultimate outcome in MS' I thought it would be worthwhile revisiting the pivotal IFNbeta-1b (Betaseron/Betaferon) long-term follow-up data. In the 16-year follow-up baseline 3rd ventricular width, a crude measure of brain atrophy, correlated with disability progression and cognitive impairment at 16 years. Please note that the abstract states it does not correlate with physical disability progression; however in the table in the paper the p-value is significant albeit it with a low R-squared value. For those of you who are not statisticians this means that brain atrophy at baseline is not a very good predictor of EDSS progression but does explain a small component of it."

"Unfortunately, the on-study changes in the MRI variables did not explain much change at 16 years; why not? Firstly, IFN-beta-1b subsequently was not been shown to affect brain atrophy, the drug is only a moderately effective DMT and the placebo-controlled part of the trial was relatively short. I therefore would not put too much weight on this studies conclusions. With the more effective DMTs on study changes are predictive of long-term outcomes; despite the follow-up being shorter than 16 years at present. What is also important to note is that the average disease duration of the MSers in this IFN-beta-1b study, when it started, was over 8 years, which is far too far along the disease course to have a major impact. We need to hit this disease earlier before too much reserve capacity is lost to have an impact. This study supports the concept of brain atrophy being the integrator of end-organ damage in MS; those who came into the study with end-organ damage did worst."

"Who wouldn't want to protect their brain from shrinking?"

Note the enlargement of the 3rd ventricle between the two scans. This is a crude index of brain atrophy that can be seen in serial scans done as part of routine clinical care. 

"Please note the highlighted text in the abstract below."

Goodin et al. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.

BACKGROUND: Evaluating the long term benefit of therapy in MS is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established.

METHODS: In a MSer cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome.

RESULTS: Baseline disability correlated with both physical (R(2)=0.22; p<0.0001) and cognitive (R(2)=0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R(2)=0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R(2)=0.12; p<0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R(2)=0.21; p<0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome.

CONCLUSIONS:  Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course. Trial registration number http://Clinical, study registration NCT00206635.

Laquinimod trìal data published 2 Years after the contents released to Investors

Vollmer TL, et al. J Neurol. 2014 A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis.

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated

This is the phase III data from laquinimod and the disappointing news based on effects on relapse rate is that it is not very good and in fact worse than beta interferon. However as Prof G has already pointed out the interesting thing is that there was a much better effect on progression of disability and begs the question if this is a neuroprotective drug that can be added onto a more effective DMT.

See recent posts
Multiple Sclerosis Research: EMA's CHMP says no to laquinimod....24 Jan 2014
Multiple Sclerosis Research: Why the results of laquinimod are so ... 07 Jan 2014

The ALLEGRO Trial was reported in mid 2012 but ProfG first posted on the results of the BRAVO trial in November 2011 and "The City" got the news in August 2011 so it is clear that Bankers and Shareholders get their information first and the science media gets the scraps a few years later, especially when the news being spun is not good news.
In response to this News of a "Failed-based on Relapse Rate" Relapsing Remitting MS drug "You" made a comment
" a patient rather take a relapse once every third year or so, if I can stop the disability progress. That is the main aim for me as a patient – not the relapses itself!"
"BRAVO study with laquinimod was imbalanced at baseline. The active laquinimod arm was in worse shape than the placebo arm, according to relevant MRI active disease markers at baseline"

What use is rehab?

What components of rehabilitation are helpful from the perspective of individuals with multiple sclerosis? Salminen AL, Kanelisto KJ, Karhula ME. Disabil Rehabil. 2014. [Epub ahead of print]

Purpose: To investigate the helpful components of rehabilitation from the point of view of people with multiple sclerosis (MS). Methods: Sixteen focus groups were conducted for 68 adults with MS, who were 6 months through their 2-year multi-professional group-based out-patient rehabilitation programs in three regions of Finland. Data were analyzed using qualitative inductive content analysis combined with counts of the coded data. 

Results: Participants described 20 helpful components of rehabilitation that were clustered to themes of the rehabilitee himself/herself, structures of everyday life, information, activity, environmental interventions, social relationships and support. The most frequently described components of the seven main themes were peers, advice, physical exercise, assistive technology and home adaptations, and personal responsibility. 
Conclusions: The helpful components of both in-patient and out-patient rehabilitation that are of particular importance to people with MS are diverse and show the relevance of ICF in rehabilitation and the need for a comprehensive view in rehabilitation. The importance of peers and peer support should be taken into account in rehabilitation planning and related recommendations. The findings show that helpful rehabilitation for people with MS is not a set of mechanistic interventions but requires good social relationships and support. 
Implications for Rehabilitation: Helpful components of rehabilitation for people with MS are diverse and show the need for a comprehensive and individual view in rehabilitation. Professionally guided peer support should be offered as a part of rehabilitation. Interventions related to assistive technology and home adaptations should be an obvious part of rehabilitation. It is important to support people with MS to preserve identity as an active person and to take personal responsibility in their own rehabilitation.

What do you think?

Saturday, 22 February 2014

Brain atrophy: the ultimate outcome in MS

Brain atrophy the integrator of MS-related end-organ damage. #MSBlog #MSResearch

"I have started thinking about MS as my cardiology and nephrology colleagues think about the heart and kidneys, respectively. They talk about end-organ damage and try and prevent it. When it comes to the heart and kidney it is easy to measure this with functional outcomes. In MS the brain and spinal cord function is much more difficult to measure, because of mutiple pathways and the ability for the damaged nervous system to adapt to damage (plasticity). Therefore a good measure of this is change in volume of the brain; i.e. brain volume loss is a good integrator of end organ damage in MS. This study below confirms other data sets that in MSers who progress they lose much more brain volume than those who don't progress. This is an important point and we therefore should be targeting normalisation of brain volume loss as the ultimate treatment aim in MS after we have switched off inflammation. This is why we want to keep the definition of NEDA (no evident disease activity) open to change. For us to incorporate brain volume loss into NEDA we need to standardise the measure of brain volume loss and get all MS Centres to do the necessary MRI scans to measure it. A question for your neurologist next time you see him/her is to ask if you have progressive brain atrophy. Some centres are already measuring this routinely, but this is a very small number."

Please compare the size of the central black areas between the 18 month scans and the baseline; this is how much brain volume loss can occur in a RRMSer in 18 months. 

Epub: Jacobsen et al. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry. 2014 Feb 19.

OBJECTIVES: To identify MRI biomarkers associated with long-term disability progression in patients with multiple sclerosis (MS), and to define the rate of evolution of global, tissue-specific and regional atrophy in patients with MS over long-term.

METHODS: MRI of the brain and clinical neurological assessment was performed in 81 patients at time of first visit and after 5 and 10 years of follow-up. MRI was acquired on 1.5 T scanners. T1-lesion and T2-lesion volumes (LVs) were calculated. Global and tissue-specific atrophy changes were longitudinally assessed, using a direct measurement approach, by calculating percentage volume changes between different time points. Regional tissue volumes for the subcortical deep grey matter (SDGM) structures were also obtained. Disability progression was defined as an increase in Expanded Disability Status Scale of ≥1.0 compared to baseline at 5-year and 10-year follow-up.

RESULTS: Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.

CONCLUSION: This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.

Being Unhelpful

You are given the option of saying posts are unhelpful, helpful; or very helpful

Recently we have been getting a few too many "unhelpfuls". 
Whilst this may be the last option open to a troll, you may have some justified reason for this. 

In the interests of feedback it would be helpful to say why it is unhelpful., remembering we are about Good and BAD news...

CCSVI Saturday

All is quiet on the CCSVI Front

INTRODUCTION: Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of the internal jugular veins (IJVs) and/or azygos veins with disturbed flow and formation of collateral venous channels. The presence of CCSVI has been associated with multiple sclerosis (MS). Percutaneous venous angioplasty (PVA) has been proposed to improve extracranial outflow; however, a non-invasive, post-procedural follow-up outcome measure has not been established.
AIM OF THE STUDY: To evaluate the short-term haemodynamic follow-up of CCSVI after PVA using color Doppler ultrasound (CDU) and to investigate whether hemodynamic variation correlated with clinical variation.
MATERIALS AND METHODS: Forty-five patients affected by MS with confirmed CCSVI underwent IJVs PVA. Venous haemodynamic (VH) parameters indicative of CCSVI and the Venous Haemodynamic Insufficiency Severity Score (VHISS) were evaluated by CDU at baseline and 3 months post-PVA. Concurrently, the MS-related disability status (EDSS) was evaluated.
RESULTS: The VH parameters and VHISS 3 months after IJVs PVA significantly decreased: the VH parameters -32.1% and the VHISS -33.8% (p < 0.001). The EDSS score 3 months after IJVs PVA was significantly lower than the baseline (-5.5%, p < 0.001). Using the median value of the VHISS variation as the cut-off, we were able to identify two groups of patients: responders, group A; and non-responders, group B. The EDSS score variation at 3 months was 0.310 in group A and 0.275 in group B (p = 0.746).
CONCLUSIONS: CCSVI endovascular treatment can induce an improvement in VH parameters and the VHISS. The neurological disability score (EDSS) also improved after PVA; however, there was no correlation to the VHISS variation after PVA, MS type and duration.

So some good news for the campaign

Friday, 21 February 2014

Efficacy and safety of natalizumab after 5-10 years

Are we ready for the early highly-effective paradigm shift? #MSBlog #MSResearch 

"I have been discussing the TOP results for several years; they show that MSers derive the most benefit from natalizumab when it is started early and as a first-line therapy. In addition the lower the disability at baseline the greater your chances of improving or recovering; low disability implies reserve capacity to allow recovery. It will be interesting to see if the EMA are swayed by this data and allow MSers who are JCV-ve access to this drug as a first-line therapy. At present it is mainly used as a second-line drug in those with highly-active or severe rapidly-evolving MS. 

"I don't think these results will be unique to natalizumab, but simply represent the impact of highly-effective therapies when used early. The question is whether or not the wider MS community are ready for a paradigm shift to this approach."

"Please note that although the EDSS flat-lined over 5 years this is an average and that some MSers will have improved, some will have stayed the same and some would have deteriorated. However, the observation of flat-lining over a 5 year period is remarkable; I am keen  to see if this will continue over the next 5 years and whether or not those started early on natalizumab will be protected from developing SPMS."

"Please note that I have numerous conflicts of interest in relation to this study and my commentary above."

Epub: Butzkueven et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry. 2014 Feb

BACKGROUND: Clinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting.

OBJECTIVE: To evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in RRMSers. 

METHODS: The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings.

RESULTS: In this 5-year interim analysis, 4821 RRMSers were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 MSers and at least 2 years in 2496 MSers revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11-44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years. Lower annualised relapse rates were observed in MSers who used natalizumab as first MS therapy, in MSers with lower baseline EDSS scores, and in MSers with lower pre-natalizumab relapse rates. Mean EDSS scores remained unchanged up to 5 years.

CONCLUSIONS: Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated MSers with RRMS in clinical practice.

CoI: multiple

Slow burning inflammation may be a indicator of future progression

Background: Absence of clinical and radiological activity in relapsing-remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution.
Methods: Cerebrospinal fluid (CSF) levels of interleukin 1beta (IL-1beta), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4 years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded.
Results Median follow-up of RRMS patients was 5 years. Detection of CSF IL-1beta levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1beta in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1beta. Patients with undetectable IL-1beta in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1beta had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1beta.
Conclusions: Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1beta in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients.

We have recently shown in EAE that you can block relapsing disease but you can still get "slow burning" nerve loss from the outset. In some strains it takes just on attack to get this in motion in others many more attacks before for frank clinical progression starts. It is of interest in this study in MS they looked by MRI and clinical parameters to see that disease had gone into complete remission (so NEDA = No evident disease activity by ProfGs standard). However was it real remission?

In this study they did a spinal tap and then looked for a molecule called interleukin-1 (IL-1), which is a protein that is involved in the production of an inflammatory response and has been implicated in the formation of nerve damage. So despite the belief that the disease was incomplete remission, there was evidence of a grumbling glial (the likely source of the IL-1) response. This would be associated with low grade inflammation, suggesting that in this group there may be "slow burn" occurring. This invisible inflammatory flame burns nerves, and smouldering away creeps burning but with not enough intensity to start a fire, such that the damage is obvious.

So what had happened 5 or more years down the line. 

Well every one had been put on DMT and they worked or failed at the same rate irrespective of whether IL-1 originally was detected or not.

However, when  disability was looked at it was found those people with IL-1 in their cerebrospinal fluid were more likely to have progressive disease.

So maybe setting off the "slow burn" is associated with the development of progression. Therefore putting out the fire is needed. This is what DE-FLAMES aims to do. It is amazing that even in a point-in-time could have impact many years down the line. It would need serial CSF to determine whether IL-1 and the slow burn was persistent or not...Maybe this can be measured in DE FLAMES as a marker of treatment activity.

However, it points to looking outside the T cell and probably B cell box to get at the problem! 

Maybe we have already, as some of the DMT may block the IL-1 cytokine pathway.