Tuesday, 26 September 2017

Should RIS (radiologically isolated syndrome) be treated?

Mult Scler. 2017 Sep 1:1352458517729462. doi: 10.1177/1352458517729462. [Epub ahead of print]

Radiologically isolated syndrome should be treated with disease-modifying therapy-Yes.

Okuda DT


Radiologically isolated syndrome should be treated with disease-modifying therapy – No

Andrés Labiano-Fontcuberta, Julián Benito-León First Published September 14, 2017


MS treatments are a caveat emptor. Global consumerism has hit the MS market succeeding in banishing moderation, thereby legitimising price hikes in the name of competition. It, therefore, falls to the responsible clinician to take the moral and ethical high ground. So, if science gives us the opportunity to treat early, regardless of cost, wouldn't it be wrong not to follow its instruction? Is, there an alternative viable option - realistically speaking? A transformative approach to early treatment in MS should therefore not be swept under the table. A pragmatic approach that demands an unequivocal demonstration of efficacy is not an approach to take in the path to a cure.

Okuda, above argues that MRI lesions in radiologically isolated syndromes (RISs) are very typical to those seen in MS in terms of appearance, frequency and distribution in the brain. Of those scanned 24% demonstrate contrast enhancing lesions on their baseline scan - it is well know that this cohort has further increased risk for future contrast enhancing lesions on subsequent head scans (Hazard ratio=3.4). Early DMT use, therefore, is a sound strategy for preventing further disease evolution.

"An estimated 11,000 axons are transected per cubic centimeter of contrast enhanced tissue".

Okuda, however, concludes with the realities of DMT use in MS: "Relating radiological features specific to in situ demyelination may be challenging at times. However, how truly accurate are clinical descriptions of experiences by patients that we routinely use to fulfill the clinical component of the diagnostic criteria in those with established MS? Would our concerns for treatment in RIS subjects be different if the costs of DMT were not so exorbitant or if the treatments provided were substantially safer than our current offerings?"

The counter argument for not treating RIS is provided by Labino-Fontcuberta and Benito-Leon. They argue on the point that the current risk-benefit ratio of DMTs is unfavorable for treating early. The current evidence is that ~ 7/10 RIS cases may not go onto develop MS in the next 5 years. In this case, a greater number would need to be treated to avoid developing MS, than is necessary. The authors appeal to a greater understanding of the nature of the disease at the RIS stage before we as a community offer treatments for it. 

"Emerging data suggest that in RIS, the clinical and pathological damage of magnetic resonance imaging (MRI) lesions might be compensated by more efficient reparative mechanisms".
 
I leave it to you to draw your own conclusions - are you for or against early treatment in RIS?

Monday, 25 September 2017

#ThinkSpeak & #NewsSpeak: social medicine the great disruptor

We are in the process of 'professionalising' the Barts-MS blog, by reducing the number of posts and improving the quality and relevance of each post for pwMS. As part of this transition, I will be moving all of my #ThinkSpeak posts, which are not directly relevant to MS onto Medium, a relatively new and evolving social media platform. Although the #ThinkSpeak post '#SocialMedicine the great disruptor' that I posted on Medium is underpinned by many ideas that I have developed on this blog I don't think its content is appropriate for this site.


#NeuroSpeak: treating MS in patients with PML

Teriflunomide is the drug of choice for treating MS in patients recovering from PML. #NeuroSpeak #CharcotProject

Summary: This post summarises the scientific principles for treating multiple sclerosis in patients who have PML as a complication of natalizumab treatment. I make the case for using DMTs that are not immunosuppressive and highlight the antiviral effects of Teriflunomide that make it the DMT of choice. 

At the grand round at Imperial College on Friday, a case of natalizumab-associated PML was presented. The patient had developed IRIS and was deteriorating. The question was posed about MS rebound contributing to some of the later deterioration in functioning and how to treat MS in this situation. 

It is clear that you cannot use an MS DMT that causes immunosuppression, particularly one that targets T-cells, in this situation. Patients with PML need their CD8+ cytotoxic T-cell to recover from PML. In my opinion, this only leaves 4 drugs that have a suitable profile:

(1) Interferon-beta: IFNbeta is not immunosuppressive and has many activities that are anti-viral. However, a lot of people who are on natalizumab may have failed IFNbeta in the past. IFNbeta has also been shown not to be that effective in preventing MS rebound post-natalizumab. 

(2) Glatiramer acetate: GA is not immunosuppressive, is only moderately effective in treating MS, is not effective in preventing MS rebound post-natalizumab and has a delayed onset of action. Therefore, it would not be the ideal agent to prevent MS rebound post-alemtuzumab in a patient with PML.

(3) Teriflunomide: Teri is not immunosuppressive as defined by the regulators, it has a complex mode of action that includes general anti-viral activity. Interestingly, leflunomide, a prodrug that is converted into teriflunomide, has been shown to have antiviral effects against BK virus (see below), that is very closely related to JCV, the cause of PML. In addition, there is some emerging evidence that Teri may cross the blood-brain barrier and hence may be able to inhibit JCV with the CNS. At the last AAN there was a poster of a switch study showing that Teri, post-natalizumab, was able to hold back rebound MS disease activity in the majority of patients and overall these patients did well.

(4) Daclizumab: Dac is not immunosuppressive, as defined by regulators, and only drops CD8 cell numbers by ~10%. Therefore, antiviral responses, for example against JCV should be intact. Dac also expands the NK, or natural killer, cell population that have anti-viral effects. We are in the process of doing a switch study to assess the effectiveness of Dac post-natalizumab to see how effective it is in preventing post-natalizumab rebound. Daclizumab also has a rapid-onset of action making which makes it an ideal agent post-natalizumab. However, as Dac reduces IL2 signalling in activated T-cells it may blunt effector T cell responses, i.e. reduce their reactivity, which makes me concerned about using it in patients with active JCV infection and PML. 

My recommendation, therefore, to the team looking after this patient particular patient was to use high dose Leflunomide (40mg per day) until JCV was not detectable in her CSF and then to switch her to Teriflunomide 14mg per day. The choice of Leflunomide dose is based on that used to treat BK-virus associated nephropathy. In my opinion, the team looking after this patient have little to lose; her JCV viral load in the spinal fluid was dropping so the IRIS (immune reconstitution syndrome) was at least taking care of the JC virus. However, she needs something to take care of MS without impacting on her immune system and at the same time assisting with the treatment of her PML.


With regard to Teriflunomide, there is an increasing number of reports of how well pwMS are doing on teriflunomide long-term. Teriflunomide is the only DMT that works significantly better second, or third, line than it does as a first-line treatment (see figure below). I have hypothesised that these observations may be due to teriflunomide's mode of action as an anti-viral agent. Professor Julian Gold and I are in the process of exploring this hypothesis under the umbrella of the Charcot Project. We will let you know as soon as we have data available.  




Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006 Mar 15;81(5):704-10.



BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.

METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy.

RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added.

CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Morita et al. Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review. J Clin Virol. 2016 Sep;82:133-8. doi: 10.1016/j.jcv.2016.07.015.

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomidetreatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.


CoI: multiple

Delayed Repopulation white cell population after stopping DMF

Bhupendra O. Khatri, Sergey S. Tarima, Benjamin Essig, Jean Sesing, Tayo Olapo. Delayed lymphocyte re-population following discontinuation of dimethyl fumarate and after switching to other disease modifying drug therapies MSARDS DOI: http://dx.doi.org/10.1016/j.msard.2017.09.014

Background:Dimethyl fumarate (DMF) reduces absolute lymphocyte counts, CD4, and CD8 counts, without significantly affecting total white blood cell counts. However, the recovery rate of these cells after discontinuation of DMF is unknown. The effect of subsequent disease modifying therapies (DMTs) on re-population rate is also unknown.
Objectives:To study the re-population rate of absolute lymphocytes, CD4, and CD8 counts back to baseline after discontinuation of DMF. 2. To measure the effect of subsequent DMTs on the re-population rate of these cells after DMF therapy. 3. To study the effect of the duration of exposure to DMF on repopulation of these cells.
Methods:A retrospective chart review of subjects who had discontinued DMF and in whom, CBC with differential, CD4 and CD8 counts were available at baseline, discontinuation and at follow-up (n=113).
Results: DMF causes a significant drop in absolute lymphocyte, CD4, and CD8 counts. Re-population of these cells after discontinuation of DMF is significantly delayed, irrespective of whether or not a subsequent DMT is used, although there is a difference in re-population rate among DMTs. The re-population rate is also dependent on the duration of time patients have been exposed to DMF; longer exposure was associated with more delayed recovery.
Conclusion:During this 30 month study period, re-population rates were significantly delayed post-DMF, irrespective of what subsequent DMT the patients received. Furthermore, no recovery of lymphocyte counts occurred in patients who were started on fingolimod or alemtuzumab after DMF was discontinued; in fact there was a continued decline in all of the cell populations studied.



As I have been saying for some time, when you start a DMT you have to think of what next after the DMT, as many will fail particularly the lower efficacy agents. DMT is higher efficacy agent. It is an immune depleting agent, which is pretty good at getting rid of CD8 T cells. It is moderate at removing memory B cells so that affects its ranking in my mind. But what else does it do. It is evident that some people who take DMF, deplete their cells and they do not functionally recover for some time, suggesting that DMF must hit the baby T cells so that there is little to repopulate with.
This offers a conundrum of when is best to start, because you don't want to wait too long before starting the next treatment so rebound does not occur, but if you are adding a lymphopenia inducing drug when you are lymphopenic are you going to be more susceptible to infections?
Worth knowing and discussing with your neuro before the switch.  ProfG maybe can expand on the DMF switch when he wakes up in Trumpland.

Sunday, 24 September 2017

Up in Smoke

Palacios N, Munger KL, Fitzgerald KC, Hart JE, Chitnis T, Ascherio A, Laden F. Exposure to particulate matter air pollution and risk of multiple sclerosis in two large cohorts of US nurses. Environ Int. 2017 Sep 19;109:64-72.

BACKGROUND:Air pollution is thought to raise the risk of neurological disease by promoting neuroinflammation, oxidative stress, glial activation and cerebrovascular damage. Multiple Sclerosis is a common auto-immune disorder, primarily affecting young women. We conducted, to a large prospective study of particulate matter (PM) exposure and multiple sclerosis (MS) risk in two prospective cohorts of women: the Nurses Health Study (NHS) and the Nurses Health Study II (NHS II).
METHODS: Cumulative average exposure to different size fractions of PM up to the onset of MS was estimated using spatio-temporal models. Participants were followed from 1998 through 2004 in NHS and from 1988 through 2007 for NHS II. We conducted additional sensitivity analyses stratified by smoking, region of the US, and age, as well as analyses restricted to women who did not move during the study. Analyses were adjusted for age, ancestry, smoking, body mass index at age 18, region, tract level population density, latitude at age 15, and UV index.
RESULTS: We did not observe significant associations between air pollution and MS risk in our cohorts. Among women in the NHS II, the HRs comparing the top vs. bottom quintiles of PM was 1.11 (95% Confidence Intervals (CI): 0.74, 1.66), 1.04 (95% CI: 0.73, 1.50) and 1.09 (95% CI: 0.73, 1.62) for PM10 (≤10μm in diameter), PM2.5 (≤2.5μm in diameter), and PM2.5-10 (2.5 to 10μm in diameter) respectively, and tests for linear trends were not statistically significant. No association between exposure to PM and risk of MS was observed in the NHS.
CONCLUSIONS: In this study, exposure to PM air pollution was not related to MS risk.

Phew pollution is not a risk factorof MS,...an makes a change from finding risks...what next?

Can we find something else that doesn't link with MS:-)

But wait like buses, no sooner than one paper on pollution we have two.

Amy M. Lavery, Amy T. Waldman, T Charles Casper, Shelly Roalstad, Meghan Candee, John Rose, Anita Belman, Bianca Weinstock-Guttman, Examining the Contributions of Environmental Quality to Pediatric Multiple Sclerosis

Background Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade.
Objective:To examine potential environmental factors in pediatric MS using geographic information systems (GIS).
Methods:Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects’ geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or ≥20 miles from the recruiting center), using logistic regression.
Results Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p=0.90 <20 miles from center; p=0.43 ≥20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR=2.83; 95%CI 1.5, 5.4) and those who reside ≥20 miles from a referral center (OR=1.61; 95%CI 1.2, 2.3).
Conclusion: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.

So in this study in childhood MS, risk was not associated with environmental (air, water etc) quality per say..so I thought replication within a day of the above and hopefully the need for no more studies on this:-), but then we had the air quality bit and it says in children living in poor air quality are affected so I spoke too soon. 

You were 3 times more likely to have MS if you live near to the MS hospital in a poor quality area the risk and was one and half times if living more than 20 miles (32km) away. 

So I'm not sure what to make out of this.....numerous other studies on air pollution on the way....:-( 

Do parents with kids with MS move to be nearer treatment centres?

or is it god forbid cars and all the air pollution they cause. 

We have been demonising the hubble ciggie for along time, but should we be ditching the motor...as driving kills!

Will new car adverts have to feature the pictures of car accidents and ill children as a health warning.

Should America start to use public transport for the sake of their children or...Maybe too much heresy for one day:-).