Wednesday, 27 July 2016

MS a B cell disease.....Wait a minute on not quite yet, T cells are hanging on

Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, Krane M, Lange R, Pfannes K, Subklewe M, Gürkov R, Bradl M, Hohlfeld R, Kümpfel T, Meinl E, Krumbholz M. Features of Human CD3+CD20+ T Cells. J Immunol. 2016 Jul 13. pii: 1600089. [Epub ahead of print]

Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3+CD20+ T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells co-expressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3+CD20+ T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8+ and CD45RO+ memory cells and in CCR7- cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20+ B cells. Taken together, human CD3+CD20+ T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.

As ocrelizumab arrives MS is being described as a B cell disease, but to feed a lifeline to the T cell brigade it has been shown that a small subset of T cells express CD20 and these get depleted. Is this why rituximab/ocrelizumab works? I am not sure. However it seems that B cell depletion can reduce antigen presenting cell function and this is maybe why it works. Maybe it is because it is removing EBV infected B cells

B Regulatory Cells

Piancone F, Saresella M, Marventano I, La Rosa F, Zoppis M, Agostini S, Longhi R, Caputo D, Mendozzi L, Rovaris M, Clerici M.B Lymphocytes in Multiple Sclerosis: Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity. Sci Rep. 2016 Jul 14;6:29699. doi: 10.1038/srep29699.

B lymphocytes contribute to the pathogenesis of Multiple Sclerosis (MS) by secreting antibodies and producing cytokines. This latter function was analyzed in myelin olygodendrocyte protein (MOG)-stimulated CD19+ B lymphocytes of 71 MS patients with different disease phenotypes and 40 age-and sex-matched healthy controls (HC). Results showed that: 

1) CD19+/TNFα+, CD19+/IL-12+ and CD19+/IFNγ+ lymphocytes are significantly increased in primary progressive (PP) compared to secondary progressive (SP), relapsing-remitting (RR), benign (BE) MS and HC; 

2) CD19+/IL-6+ lymphocytes are significantly increased in PP, SP and RR compared to BEMS and HC; 

3) CD19+/IL-13+, CD19+/IL-10+, and CD19+/IL-10+/TGFβ+ (Bregs) B lymphocytes are reduced overall in MS patients compared to HC. B cells expressing BTLA, a receptor whose binding to HVEM inhibits TcR-initiated cytokine production, as well as CD19+/BTLA+/IL-10+ cells were also significantly overall reduced in MS patients compared to HC. Analyses performed in RRMS showed that fingolimod-induced disease remission is associated with a significant increase in Bregs, CD19+/BTLA+, and CD19+/BTLA+/IL-10+ B lymphocytes. 

B lymphocytes participate to the pathogenesis of MS via the secretion of functionally-diverse cytokines that might play a role in determining disease phenotypes. The impairment of Bregs and CD19+/BTLA+ cells, in particular, could play an important pathogenic role in MS.
Just as we know of effector and regulatory T cells there are effector and regulatory B cells. As we are depleting B cells it is important to realise that regulatory cells may get depleted. Animal studies indicate that CD20 B cell depletion can inhibt enhanced or do nothing to EAE, depending on the timing of administration. On balance CD20 B cell depletion and CD19 B cell depletion appears to inhibit relapsing MS but Acaticept that was also supposed to deplete B cells appeared to make MS worse, presumably because it affects B regulatory cells.

Tuesday, 26 July 2016

NewsSpeak & OffLabel: maybe off-label prescribing will be come a global reality?

 When it comes to putting your money where your mouth is the US is right up there! #NewsSpeak #OffLabel

"The Patient-Centered Outcomes Research Institute (PCORI) will fund four comparative clinical effectiveness studies in MS (see below). Well done to all the successful PIs."

"Let's hope the rituximab data is good enough for NHS England  to adopt off-label prescribing in MS; at present they won't. At last, we will know which of the two heavy-weight orals, fingolimod or DMF, is superior. It is good news for the field that someone is prepared to fund an independent head-2-head study. The importance of this trial cannot be underestimated; with fingolimod coming off-patent we need new data to over-turn the 2nd-line indication we have for prescribing fingolimod in Europe. A cheap small-molecule oral therapy, with high-efficacy, will almost certainly lower the entry level price for treating MS. However, I am a bit disappointed that teriflunomide was not included in this head-2-head study; when you look at the subgroup analyses I think teriflunomide is more efficacious long-term than the headline results of the phase 3 trials indicate. I predict teriflunomide would have a reasonable chance of holding its own in terms of efficacy against both DMF and Fingolimod. Another point is that teriflunomide is also coming off-patent soon; so another cheap entry level drug to mix it up."


Four Studies to Assess Effectiveness of Multiple Sclerosis Treatments Receive $19.6 Million in Funding from PCORI: Studies will give patients evidence to help them choose among therapies. PCORI July 19, 2016

Press release

WASHINGTON, D.C. (July 19, 2016) – The Patient-Centered Outcomes Research Institute (PCORI) Board of Governors today approved nearly $20 million to fund four comparative clinical effectiveness research (CER) studies that will assess several therapies used to treat multiple sclerosis (MS) or its symptoms.

Two studies will compare the benefits and harms of various treatments collectively known as disease-modifying therapies (DMTs) that aim to reduce MS attacks or slow the disease’s progression. Another will evaluate the effectiveness of medications used to treat fatigue, a common, often debilitating problem for people with MS. The fourth will assess whether people with MS in rural and low-income areas can get similar benefits from rehabilitation therapies if they are provided via telehealth versus in a clinic.

The studies will be designed and conducted with significant input from patients, family caregivers, and other healthcare stakeholders. Each will include people with MS; nurses, physicians or other clinicians; or representatives of other stakeholder groups on their research teams. The four awards were among 35 totaling $153 millionapproved today by PCORI’s Board.

“PCORI is delighted to make these new awards addressing crucial evidence gaps and questions of vital interest to the more than 400,000 people in the U.S. living with multiple sclerosis,” said PCORI Executive Director Joe Selby, MD, MPH. “These studies will provide significant new evidence to help patients, their families and their clinicians decide more confidently which of the therapies available to them will work best given their needs and preferences.”

"These PCORI awards are a welcome and much-needed infusion of new MS research funding for important real-world questions about treatment strategies and their effectiveness," commented Bruce Bebo, PhD, Executive Vice President, Research, at the National Multiple Sclerosis Society, a group representing patients that will be an engaged stakeholder partner in several of the studies. "The projects should provide important evidence for the best ways to address troubling symptoms like fatigue, and the potential for using technology to deliver needed rehabilitation approaches to people in remote areas," he added.

The four projects approved today are:

Rituximab: An $8.5 million study comparing the effectiveness of rituximab, a biologic drug, to other commonly used disease-modifying therapies in individuals with the relapsing-remitting form of the disease. Rituximab is increasingly being used as an MS therapy in Sweden and the United States. The study will be based at Karolinska Institute in Sweden and conducted in collaboration with Kaiser Permanente Southern California. In particular, it will assess the comparative safety outcomes of the medications.

Excercise -based rehab: A $5.8 million study of whether patients get as much benefit from an exercise-based rehabilitation program delivered via Internet or telephone as when the therapy is provided in a clinic. Evidence shows that exercise, yoga, and other such therapies can alleviate symptoms and improving function, but clinics that can provide such services are scare in rural and low-income areas. The trial, led by a research team based at the University of Alabama at Birmingham, will be conducted in Alabama and Mississippi.

Fatigue: A $1.9 million study of three medications frequently used to relieve fatigue in people with MS. There is little evidence about how well these drugs – amantadine, modafinil, and methylphenidate -- work compared to one another in providing relief for MS-related fatigue. The trial will be led by a team based at the University of California at San Francisco.

Fingolimod vs. DMF: A $3.3 million award for the first pragmatic trial comparing the benefits and harms of the oral DMTs fingolimod and dimethyl-fumarate. These drugs are commonly used to treat MS and are believed to be similarly effective, but both have side effects and they have not been compared directly to one another. The trial will be led by a research team based at the Foundation of the Carlo Besta Neurological Institute in Milano, Italy, and include sites in the United States, Europe, and Israel.

The new studies address evidence gaps and questions that people with MS and other healthcare stakeholders identified as their top priorities through PCORI’s process for topic selection. A multi-stakeholder workshop in April 2015 brought together patients and participants representing groups advancing research on the disease as well as clinicians, government agencies, industry, and health insurance plans to refine the questions that became the focus of PCORI’s funding announcements.

All of the awards are approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

Progressive dwindling

PLoS One. 2016 Jul 21;11(7):e0159210. doi: 10.1371/journal.pone.0159210.

Progressive Dwindling in Multiple Sclerosis: An Opportunity to Improve Care.

Martin JE, Raffel J, Nicholas R.

Abstract

INTRODUCTION:

In the general ageing population, 40% of deaths occur following a prolonged trajectory of "progressive dwindling," characterised by chronic accumulation of disability and frailty, and associated with increased dependency and reduced reserves. Those who progressively dwindle are poorly catered for by current healthcare systems and would benefit from a coordinated approach to their medical and social care, known as formative care. People with multiple sclerosis (pwMS) may be more likely to progressively dwindle, and may be appropriate targets for formative care pathways.

OBJECTIVES:

To determine the proportion of pwMS who follow a progressive dwindling trajectory prior to death. To relate trajectory to place of death, and examine what factors predict the progressively dwindling trajectory.

METHODS:

A retrospective observational study of 582 deceased pwMS enrolled in the UK MS Tissue Bank, including death certificates and extensive clinical summaries.

RESULTS:

73.7% of pwMS had a "progressively dwindling" trajectory of dying. This was predicted by those who reach MS disease milestones earlier. 72.5% of pwMS died an MS-related death, which was predicted by an aggressive disease course from onset. Those who progressively dwindled were equally likely to die in hospital as those with other trajectories to death.

CONCLUSIONS:

The progressively dwindling trajectory of dying is very common in pwMS, and can be predicted by earlier disease milestones. Pathways could target pwMS in these years prior to death, to improve care.


 Tipping point

This article brings to the surface the problem with MS research - an enterprise focused on basic science research, or what I call pop science that ignores the immediate needs of our patients. Moreover, frustratingly, what we preach in public is very different from our private thoughts. There is very little impetus to work towards finding solutions for progressive disease. You note, that I don't mention cure. We should be aiming towards the tipping point; the small changes (Sisyphus effect) that have a big impact (snowball effect).

Progressive dwindling is the progressive chronic illness before death. Broadly speaking, in an aging population four broad trajectories of dying have been described (Bowman and Meyer 2004):
  • 20% sudden deaths e.g. heart attack
  • 20% follow a rapid decline e.g. cancer
  • 20% as a result of acute exacerbations of chronic disorders e.g. infective exacerbation of chronic obstructive airways disease.
  • 40% follow a prolonged period of 'progressive dwindling' e.g. Alzheimer's, progressive MS (Figure 1)
Figure 1: cause of death in 582 people with MS (UKMSTB - UK MS Tissue Bank Jan 1998-Feb 2015)

The care pathway for the latter 40% is haphazard at best, focused predominantly at the major centers with access to multidisciplinary teams. There is little in the way of formative care provision in order to improve quality of life. This need is more pressing in MS than any other neurological disorder as it spans most of adulthood.

Martin et al. point out that those who progressively dwindled had an earlier age of onset, progression (earlier achievement of disease milestones suggesting aggressive disease course) and were wheelchair bound.  Moreover, they were more likely to die in hospital (not at a hospice, as in cancers) than in their own residence, which may be interpreted as failure of care.

This research points to a disconnect between active treatment (DMTs) and end of life care in MS with progressive dwindling occurring for several years. This is a serious concern as this research points to at least 74% people with MS having this trajectory before death (NB: this figure may be biased as it is retrospectively collected, and is from a brain bank database). A more formative strategy is needed that can deal early with care planning and readily with complex care needs and increased rates of cognitive disability.

Monday, 25 July 2016

Th17 important in MS

Bühler U, Fleischer V, Luessi F, Rezk A, Belikan P, Graetz C, Gollan R, Wolf C, Lutz J, Bar-Or A, Siffrin V, Zipp F. Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment. Mult Scler. 2016 . pii: 1352458516658559. [Epub ahead of print]

OBJECTIVE: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity.
METHODS:Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients (n = 33), untreated RRMS patients (n = 13), and healthy controls (n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients.
RESULTS: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed.
CONCLUSION: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug's mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology


MS is caused by Th17 cells becuase this now dogma. So when we give natalizumab there are more CD4, IL-17 cells in the blood and the numbers correlate with T1-hypointense lesion.Therefore this validates the value of Th17 in disease pathogenesis. 

However, proof is really getting rid of CD4+, IL-17+ T cells and it having an impact on MS.

However, so far depletion of CD4 T cells did not have a marked impact on MS lesions (although depletion levels were correlated relapse) and interleukin 17 neutralising antibodies reduced gadolinium lesions by about 50%. This gets the Th17ers mouths watering but remember beta interferon is much more effective than that and so many things do much better.

We need to be cautious until this action is shown