Thursday, 17 August 2017

Are MS drugs a waste of time......for progressive MS

Lorscheider J, Jokubaitis VG, Spelman T, Izquierdo G, Lugaresi A, Havrdova E, Horakova D, Trojano M, Duquette P, Girard M, Prat A, Grand'Maison F, Grammond P, Pucci E, Boz C, Sola P, Ferraro D, Spitaleri D, Lechner-Scott J, Terzi M, Van Pesch V, Iuliano G, Bergamaschi R, Ramo-Tello C, Granella F, Oreja-Guevara C, Butzkueven H, Kalincik T; MSBase Study Group. Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS. Neurology. 2017 Aug 9. pii: 10.1212/WNL.0000000000004330. doi: 10.1212/WNL.0000000000004330. [Epub ahead of print]

OBJECTIVE: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).
METHODS: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.
RESULTS: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results.
CONCLUSIONS: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

I'm back....(What! you didn't notice that I've not been around and that there were slow responses).

I been in the Third World.....................of internet access, with zero email and essentially no access to the web...with even the paid-for "high speed" (yeah right) net.


Where?..........yep you got it........in the USA. 

In a number of National Parks the internet access has been woeful

Who would have thought that a gas (petrol) station in the middle of nowhere, would turn out to be a cyber oasis compared to the dearth for International Travellers.


However, I saw an amazing example of "thinkhand" and why giving access to people in wheelchairs access to treatment to save upper limb function is something we really must do. 


If you look at the picture above you can see on the right of the top of the waterfall there is a platform, which is full of people watching the waterfall. This waterfall is 308 feet (94 metres), where the top is some 600 feet down the canyon.  


I was passed on the way up the canyon, by a hand-driven wheelchair, OK with some help from their partner and encouragement by the kids. They were at the top looking down by the time I got there. Why shouldn't we stop deterioration of loss of hand function.


Anyway more news from the MSBase people and they haven't done a post on this one but it is something the Pharmaceutical nihilists will be shouting out loud about why it is OK to do nothing. This study suggests that use of DMT does not influence the course of secondary progressive MS if used after onset.


ProfG will be sitting on a beach somewhere in the USA pondering what this means for his therapeutic lag idea, but more importantly what it could mean if hand function was the main outcome. 


The take home message of this story is more reason not to use DMT in SPMS. Which is not what we have been saying.

There were about 25% in the untreated ground that had MRI lesions and about 20% in the treated group (so not effectively treated)

However, you can see the (median) follow up was for only two years although it was longer for many people, and when the ASCEND trial of natalizumab looked  and there was no change in EDSS over two years. However if the trial was followed for 3 years then they was an influence. So the follow up in this study may not have been long-enough for the therapeutic lag effect to show itself, (if it existed, which it didn't when it was looked for).

Likewise, I really would like to see if you look at the effect of only highly-effective DMT/HSCT use and subsequent course of MS. Yes, I know that use of CRAB drugs is the real life situation, but the picture is going to be muddied if you include use of CRAB drugs. 

We know progression will often occur because this has already been seen with alemtuzumab and HSCT, but will the rate of decline change? 

H. Pylori: good, bad, ugly, or not quite sure?

Many people think that MS is triggered by exposure to infectious agents in our environment. The most well-known putative trigger is EBV, but there has also been debate surrounding the role of H. Pylori, an enteric pathogen better known for its role in causing peptic ulcers. Epidemiological evidence has been conflicting on whether H. Pylori infection protects against MS, increases the risk of MS, or has no association at all.

A nice new study systematically examined the amounts of anti-H. Pylori antibody in a big cohort of 139 pwMS, 39 pwParkinson's Disease, 21 pwAlzheimer's Disease, and 68 controls without any neurological diseases. The key advantage of this study is that they looked at antibodies against a wide range of H. Pylori antigens, the fragments of the bug exposed to the immune system.

The key findings were:
- Anti-flagellin antibodies were less common in MS than controls. 
- Anti-VacA antibodies were more common in SPMS than controls.
- Anti-p54, anti-p29-UreA and anti-p26 correlated with EDSS.
- Anti-p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA were less common in RRMS than control.
- Anti-p26 and anti-p17 correlated with number of relapses.

This is big news - it demonstrates that the antibody response to H. Pylori infection differs between pwMS and controls, between pwRRMS and pwSPMS, and is correlated with disease activity.

How do we interpret this?

There are a few possible explanations. My initial thoughts:
- Exposure to H. Pylori is protective against MS
- Exposure to VacA (a secreted bacterial protein) increases the risk of SPMS
- An underlying problem with immune regulation in people who are at-risk of developing MS affects the immune response to H. Pylori (this could be genetic e.g. MHC polymorphisms, environmental e.g. a consequence of EBV infection, etc...)
- DMTs affect the immune response to H. Pylori
- A combination of some/all of the above!

These don't explain why higher titres of certain anti-H. Pylori antibodies would correlate with disability and relapses. 

In short I'm not quite sure what these data mean but they are certainly interesting. If anti-H. pylori antibodies are protective then vaccination might even be on the cards as a preventative strategy.

Abstract
To assess whether Helicobacter pylori (Hp) antibody (ab) reactivity against individual Hp antigens is pathogenetically relevant to multiple sclerosis (MS), we systematically investigated prevalence and clinical significance of abs against 14 immunodominant and subdominant Hp antigens by ELISA and immunoblotting in 139 consecutive MS patients with relapsing-remitting (RRMS, n = 102) or secondary progressive (SPMS, n = 37). Sera from 39 patients with Parkinson’s disease (PD), 21 with Alzheimer’s disease (ALZ) and 68 healthy controls (HCs), were also tested. Anti-flagellin (18.3%) and anti-p41 (25.0%) abs in MS were less frequent than in HCs (39.4%, 48.5%, respectively). Abs against 5 of the 14 antigens were less frequent in RRMS than HCs, including p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA. Anti-VacA abs were more frequent in SPMS than in HCs (42.1 vs 12.1%, p = 0.019). Anti-p54, anti-p29-UreA and anti-p26 correlated with extended disability status scale (EDSS) (p = 0.017, p = 0.005, p = 0.002, respectively). Anti-p26 and anti-p17 correlated with the number of relapses (p = 0.037 and p = 0.047, respectively). This is the first comprehensive analysis of ab reactivities against most Hp antigens in MS patients. Ab responses differ between MS and HCs and between RRMS and SPMS, being more prevalent in SPMS than RRMS, thus suggesting an association between anti-Hp and the former type of MS.

Wednesday, 16 August 2017

Older people do less well



Guillemin F, Baumann C, Epstein J, Kerschen P, Garot T, Mathey G, Debouverie M; LORSEP Group.Older Age at Multiple Sclerosis Onset Is an Independent Factor of Poor Prognosis: A Population-Based Cohort Study.Neuroepidemiology. 2017 Aug 10;48(3-4):179-187.
BACKGROUND:Late-onset multiple sclerosis (LOMS) frequently features a primary progressive (PP) course, strongly predicting severe disability. In this population-based cohort, we estimated the prognostic role of age at multiple sclerosis (MS) onset, independent of PP course, on disability progression.
METHODS:The association of age at disease onset (adult, <50 years [AOMS], vs. late, ≥50 years [LOMS]) and time to Expanded Disability Status Scale (EDSS) score 4 and 6 was estimated by Cox regression modelling.
RESULTS:Among 3,597 patients, 245 had LOMS. Relapsing-remitting (RR) disease was less frequent with LOMS than AOMS (51.8 vs. 90.8%, p < 0.0001). PP course, LOMS and male gender predicted short time to EDSS 4 and 6. Worse outcome with LOMS (time to EDSS 4 and 6, HR 2.0 [95% CI 1.7-2.4] and 2.3 [1.9-2.9]) was independent of PP course or male gender. LOMS had greater impact on RR than PP disease (time to EDSS 4 and 6, HR 3.1 [2.3-4.0] and 4.0 [2.9-5.6]). Only LOMS predicted time from EDSS 4 to 6 (p < 0.0001).
CONCLUSIONS:Late onset MS was strongly associated with poor prognosis, independent of initial disease course, in predicting the disability progression along time.


ProfG has often said that "Age Matters" especially when it relates to brain health. As we age our repair and protective capabilities wane. This study supports this view and the the older you are there less well you do. However this is at a population level and there will be older people who do very well and younger people who do very badly.

Tuesday, 15 August 2017

Alternative solutions - treatment of acute relapse in steroid-unresponsive MS

Int J Mol Sci. 2017 Aug 11;18(8). pii: E1749. doi: 10.3390/ijms18081749.

Treatment of the First Acute Relapse Following Therapeutic Plasma Exchange in Formerly Glucocorticosteroid-Unresponsive Multiple Sclerosis Patients-A Multicenter Study to Evaluate Glucocorticosteroid Responsiveness.

Ehler J, Blechinger S, Rommer PS, Koball S, Mitzner S, Hartung HP, Leutmezer F, Sauer M, Zettl UK.

Abstract


Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

 Plasma exchange

Like you reading my post today, I too suffer from a little known, but commonplace condition called epistemophilia - meaning to have an insatiable thirst for knowledge. Google, Facebook, Twitter all present facts piecemeal as conclusive statements, but in academia, broadly speaking, the truth of knowledge is based on the strength of evidence.

Many of you know that steroids are used for the treatment of acute relapses, but how many of you knew that there were additional treatment options? Is there a plan B if you do not respond to steroids after a relapse? The answer is a 'yes'. Steroids remain the panacea for a variety of neurological conditions, but at the same time, particularly in inflammatory conditions, doctors have investigated other avenues; including intravenous immunoglobulins and plasma exchange. The latter, is the process of removal of the substrate of the blood, cleansing it of everything floating in it; circulating cytokines, antibodies, complement and immune complexes. Plasma exchange is a second-line option for those who don't respond to steroids. The optimal time period in which to see the peak effect of steroids is 7-10 days after a course, and deemed sub-optimal after 2 weeks. 

In this study, the authors evaluated responsiveness to steroids before and after plasma exchange to see whether subjects remain unresponsive to steroids after plasma exchange in a subsequent relapse or become steroid responsive again. They included 37 steroid-unresponsive subjects. For the first relapse they all received steroids. Only 5 subjects showed moderate improvement after steroids, remainder none. Whilst, follow up plasma exchange for the first relapse showed marked improvement in 12 (32.4%), moderate improvement in 18 (48.7%), and no effect in 7 (18.9%). All 37 subjects experienced a second relapse ~150 days later (range 31-2588 days). Steroids were given to 35/37 subjects, and achieved marked improvement in 10 (27%), moderate improvement in 24 (64.9%), and no effect in 3 (8.1%).

In summary, there is improved steroid responsiveness to the second relapse compared to the first, an interesting statistical difference from a clinical study. This is in part secondary to the use of plasma exchange in the initial relapse (see second set of bars in figure below). 

Mechanistically, steroids induce T cell apoptosis, whereas plasma exchange removes factors that are the paraphernalia of immune response (antibodies, cytokines, immune complexes etc.). This resetting may explain some of the regain in response to steroids at the second relapse. Unfortunately, the investigators didn't measure any biomarkers, so we don't know what changes were taking place at a biological level, which is disappointing. However, it's a study to be done for the future.

Figure: Different response to glucocorticosteroid (GCS) treatment before and after therapeutic plasma exchange (TPE) in 37 clinically isolated syndrome (CIS) and multiple sclerosis (MS) patients. Deterioration was defined as worsened target neurologic deficit or new neurologic symptoms, marked improvement as clinically significant improvement in function, moderate improvement as a definite change of the neurologic deficit without significant impact on function within the functional score, and no effect as unchanged symptoms.

Monday, 14 August 2017

Seeing is B-lieving

The success of B-cell-depleting therapies tells us that B cells play an important role in driving MS. We don't really understand how - they may be producing antibodies targeted against 'self', they may be recruiting other immune players like T lymphocytes and monocytes, or they may be doing both. 

There are many different types of B cell, each of which has a different set of roles in the immune system. 

So a sensible question to ask is whether the numbers and types of B cell present in the CSF - the spinal fluid - can predict the course of the disease.

A new study asked this question by looking at 128 pwMS and 40 people with other neurological disorders as their control group. They took samples of CSF - spinal fluid - and analysed the different subsets of B cells present. They then correlated this information with clinical details such as disease course and MRI findings.  

The numbers of mature B cells and plasmablasts (the precursors to long-lived antibody-secreting plasma cells) were raised in the group of people with bout-onset forms of MS (CIS, RRMS, SPMS) compared to PPMS and the control group. There was no difference in T cell numbers between the groups. 

CSF lymphocyte counts were not predictive of disability progression, conversion from CIS to RRMS.

This is very interesting. It implies that the CSF B cell profile is 'diagnostic' but not 'prognostic'. CSF B cells may be involved in driving relapses or may be a consequence of a 'leaky' blood-brain barrier in relapse-onset disease. What is odd and intriguing is that CSF B cells were not raised in PPMS. Given the success of ocrelizumab - a B cell depleter - in PPMS it is a bit counter-intuitive that this group did not show any evidence of having high CSF B counts. This may be because only two types of B cells, mature and plasmablasts, were examined here. In fact, the number of B lymphocytes in the CSF of the pwPPMS was slightly raised (although not statistically significant) compared to the control group. Given that the control group were also people with neurologic disorders, many of whom would be expected to have a degree of CNS inflammation, we may be missing a genuine difference here. Further studies are needed to examine the CSF of pwPPMS to determine whether there is a selective increase in specific B cell populations, such as the memory B's.


***

Abstract

Background

There is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS). The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF) B cell subtypes in disease evolution of patients with MS.

Materials and methods

128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3–10.8 years). 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS), 25 relapsing remitting MS- (RRMS), 2 secondary progressive MS- (SPMS) and 9 primary progressive MS- (PPMS) patients were included. The control group consisted of 40 patients with other neurological diseases (OND). CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS) and relapse rate.

Results

CSF mature B cells (CD19+CD138-) were increased in bout-onset MS compared to PPMS (p<0.05) and OND (p<0.001), whereas plasma blasts (CD19+CD138+) were increased in bout-onset MS (p<0.001) and PPMS (p<0.05) compared to OND. CSF B cells did not predict a progressive disease course, EDSS progression, an increased relapse rate or the conversion to CDMS. Likelihood of progressive disease course (p<0.05) and EDSS (p<0.01) was predicted by higher age at baseline, whereas conversion to CDMS was predicted by a lower age at onset (p<0.01) and the presence of ≥9 MRI T2 lesions (p<0.05).

Conclusion

We detected significant differences in the CSF B cell subsets between different clinical MS subtypes and OND patients. CSF B cells were neither predictive for disease and EDSS progression nor conversion to CDMS after a CIS.