MS Forum/MS over the past 17 years.
Abstract: At its final meeting, the MS Forum Executive Committee reviewed highlights of where things stood prior to the immunomodulatory era, and how things have evolved subsequently. What the future might hold was discussed in a second session. Prior to 1990: Genetic predisposition to multiple sclerosis (MS), as determined by human leukocyte antigen expression, was established and an environmental trigger (Epstein-Barr virus?) was suspected, as was lack of sunshine. Substantial evidence for activated T-cells as relapse initiators had accumulated. Defective regulatory cell function that correlated with disease activity was shown. Adrenocorticotropic hormone lessened relapse severity as did its steroid replacement. A trial of cyclosporine, a T-cell inhibitor, in progressive MS failed. The drug, not the patients chosen, was blamed. 1990-2010: Approval of interferon-beta (IFNB)-1b was followed promptly by IFNB-1a, glatiramer acetate, mitoxantrone and then by natalizumab and fingolimod. All reduce MS attack frequency and new lesion accumulation. None have reduced disability progression in progressive MS. Brain atrophy, cognitive loss and axonal interruption in progressive MS depend on innate immune system activation rather than on T-cells. New strategies are needed.

KEY WORDS:

Multiple sclerosis, Human leukocyte antigen, Epstein-Barr virus, Depression, T-cells
Article Type: Clinical report
Subject: Multiple sclerosis (Genetic aspects)
Multiple sclerosis (Environmental aspects)
Multiple sclerosis (Risk factors)
Antigens (Health aspects)
Epstein-Barr virus (Company sales and earnings)
Author: Arnason, B.G.W.
Pub Date: 11/01/2010
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: Nov, 2010 Source Volume: 17 Source Issue: 3
Topic: Event Code: 830 Sales, profits & dividends Computer Subject: Company earnings/profit
Product: SIC Code: 2836 Biological products exc. diagnostic
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 256365666
Full Text: Introduction

Interferon-beta (IFNB)-1b (Betaferon[R]/Betaseron[R]) was the first immunomodulatory agent approved for the treatment of multiple sclerosis (MS). In 1993, IFNB-1b was shown to reduce the frequency and severity of MS relapses. The MS Forum was founded that same year. Several aims were defined from the outset.

One was to increase awareness and improve understanding of MS. A second was to bring together workers in different disciplines and from multiple nations to foster interaction and cross fertilization. A major goal was to offer educational materials relevant to the clinical management of MS patients to practising clinicians and to other healthcare workers. To this end, the MS Forum sponsored a series of workshops in which experts from diverse fields were brought together to review topics pre-selected by the Executive Committee. In all instances there was new information, often coming from basic science, which was distilled into a non-technical monograph designed for a non-expert audience. The hope was constant, that the information provided might have a favourable impact on patient care. Twenty-three monographs were published over 17 years. Typically, 6000 copies of each were printed and many more were downloaded online from the MS Forum website (www.msforum.net), which, as of last year, counted 9565 visits from people from 102 countries.

In addition, the MS Forum presented 17 symposia, most at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress. There were approximately 85 presenters over the years, and between 700 and 2000 attendees per event for a total estimated attendance of 16,000. Many symposia were interactive and Continuing Medical Education (CME)-accredited. Emphasis was directed towards practical management of challenging cases, often with healthy differences of opinion amongst the panelists and between members of the audience. The MS Forum also sponsored numerous regional events including the Pan-Asian MS Forum and expert meetings that led to the formation of the Pan-Asian Committee on Treatment and Research of Multiple Sclerosis (PACTRIMS) and the Latin-American Committee on Treatment and Research of Multiple Sclerosis (LACTRIMS). AS well as these regional symposia such as meetings of MS Forum Europe and MS Forum Canada were sponsored as well. Modern Management slide kits created from the information and outcomes presented and concluded from these activities have been provided over the years to those requesting them.

Last, but importantly, the MS Forum took responsibility for The International MS Journal. Since its founding, the journal has been published on behalf of the MS Forum. The Editors-in-Chief have been members of the MS Forum Executive Committee, but the Editorial Board has had wide representation from the MS Forum membership. Articles published typically have been by invitation of the Editors-in-Chief with input from the Editorial Board. Review Articles have dealt with the biochemical, immunological, pathophysiological, radiological and clinical aspects of MS and related conditions with emphasis on key points rather than the minutiae, with the goal of clarity of presentation for non-expert audiences. The journal is now in its seventeenth volume with more than 50 issues published to date. There have been 368 authors and 420 articles as of last year. This issue of the journal will be its last since the MS Forum, its original aims largely accomplished, is being dissolved.

The final meeting of the MS Forum Executive Committee was held in January 2010. Committee Members took this bitter-sweet occasion to present selective overviews of where things stood prior to the era of immunomodulatory treatments for MS, how things have evolved from 1993 to the present, and what the future might hold.

Where we were Prior to 1990

In 1985, the epidemiology section of McAlpine's Multiple Sclerosis (1) contained the following statements: 1) 'speculation concerning possible causative factors has outrun the evidence'; 2) 'one can be certain that the pattern of frequency represents the interaction of both genetic and environmental influences'; 3) North-to-South gradient correlates best with winter sunshine 'and it might be most appropriate to seek differences between exposure to sunlight in cases and controls in childhood'. Vitamin D deficiency is mentioned specifically. Cod liver oil (i.e. vitamin D) was first advocated as a treatment for MS a century earlier in the 1880s; 4) Age of onset is consistent with an influence exerted by one or more of 'those acute virus infections that confer lifelong immunity' since this is 'one situation in which a rapid fall in susceptibility of a population occurs with age'; 5) 'Heterophile antibody (a marker for recent Epstein-Barr virus [EBV] infection) occurs only in a restricted age group, broadly speaking between 6 and 25 years of age. The age distribution is symmetrical and is reminiscent of the age incidence curve of MS, although a decade earlier'; 6) 'Some stocks are susceptible, others less so, to geographic influences.' These statements, all correct, have a remarkably modern ring to them.

Two double-blind, randomized, placebo-controlled trials of adrenocorticotropic hormone (ACTH) were conducted in relapsing MS patients in the 1960s. The first trial, reported in 1961, compared 22 patients on ACTH over 3 weeks with 18 who were on placebo. Benefit was reported for ACTH at 3 weeks. (2) Despite the small size of the study the conclusion reached proved to be correct. The second trial ran from 1965 to 1968. (3) One hundred and three patients with rapidly worsening MS were given ACTH over 2 weeks. Improvement with ACTH treatment, as compared with 94 patients on placebo, was shown at 7, 14 and 21 days. Note that the first large scale successful, well-conducted, placebo-controlled treatment trial in MS was initiated 45 years ago and ACTH in a gel formulation was approved as a treatment for MS exacerbations 40 years ago.

Some 20 years later, 32 MS patients experiencing an acute exacerbation were given ACTH daily for 14 days and compared with 29 patients given intravenous methylprednisolone 1 g daily for 3 days. (4) Disability lessened to the same extent in both groups at 3, 7, 14 and 28 days after starting treatment and at 3 months. Glucocorticoid replaced ACTH as the preferred treatment for acute MS relapses based on the belief, widely held at the time, that the beneficial effect of ACTH in MS depended wholly on its ability to induce glucocorticoid release from the adrenal gland.

This conclusion may have been premature. A beneficial effect of glucocorticoid treatment over the longer term has never been shown clearly in MS nor has ACTH been revisited. It is now evident that ACTH binds to five different melanocortin receptors of which only one is involved in glucorticoid release; (5) that ACTH is synthesized and released by immune system cells, in particular by monocytes/macrophages; (6) and that melanocortin receptors are expressed on monocytes/macrophages pointing to autocrine and paracrine, glucocorticoid independent, feedback loops. (7) It is also evident that systemically administered ACTH provokes brisk adrenalindependent acetylcholine release from vagus nerve endings (8) and of adrenal-independent noradrenaline release from sympathetic nerves (9) with both neurotransmitters exerting major inhibitory actions on pro-inflammatory cytokine release by monocytes/macrophages. (10,11) Several other hormones, originally thought to be restricted to particular organs, have subsequently been shown to alter immune system function, but they too, as with ACTH, have been little studied in MS.

T-cells play a major role in MS relapses (see below). Cyclosporin exerts a selective and reversible inhibitory effect on T-cells but is not directly anti-proliferative. The drug inhibits synthesis of Interleukin-2, IFN[gamma] and the recently discovered IL-17. All three are major pro-inflammatory cytokines released by activated T-cells. (12) Cyclosporin is very effective in preventing graft rejection. The drug was tested in the 1980s in 273 MS patients with mild to moderately severe neurological disability (Expanded Disability Status Scale [EDSS] 3.0-7.0) and 274 placebo controls and was given for 2 years. (13) All patients had progressive disease and it was reasoned that given their disability such patients had the greatest need for treatment. The thought being why treat early when disease might remain benign?

The cyclosporin study in progressive MS was a complete failure; no significant effect on time to sustained progression or on a composite score of activities of daily living was observed. The fault was promptly assigned to the drug, almost surely incorrectly, with the corollary that knocking out T-cells does not work in MS. Yet, in another trial of cyclosporin there was a 50% reduction in attack frequency in relapsing-remitting MS (RRMS) patients. The finding was set aside because progressive MS patients in another arm of the same study did not benefit from cyclosporin treatment. (14) In retrospect this was a big mistake. The failure by the MS research community, myself included, to recognize that the mechanisms responsible for progressive MS are quite different from those responsible for MS attacks has had a woeful cost. Looking back, the clues were there, but they did not register. Only when trials of drugs that had proven effective in reducing MS attack frequency, one after another, failed dismally to alter the course of progressive disease, was it belatedly and grudgingly accepted that mechanisms operative in progressive MS differ not merely in magnitude, but rather in kind from those operative in RRMS. Twenty years were lost before it became evident that altogether new approaches to the treatment of progressive MS were needed. Ruefully, one might ask what clues are out there today that we are missing?

Despite the preceding information, a fair bit was known about the immunology of MS before the era of immunomodulatory agents. Early on, discrete human leukocyte antigen (HLA) gene products were found to increase risk for MS several-fold. (15,16) Each antigen-presenting cell expresses a limited number of HLA alleles. Each HLA allele offers a finite number of antigens to T-cells. Contact between an HLA-presented antigen and a T-cell with surface receptors for that particular antigen triggers activation restricted to that T-cell. Given this, the existence of, at most, a limited number of MS-related antigens was implicit and a role for activated T-cells in disease pathogenesis almost certain. (17) Indeed, activated T-cells are persistently present in MS in both the blood and the cerebrospinal fluid and far more so when disease is in relapse than when it is not. (18)

A defect in immune regulation was also recognized many years ago. Deficient [CD8.sup.+] [CD28.sup.-] T-suppressor cell function was noted during MS attacks with suppressor cell function restored during remissions. (19,20) The ability of IFNB-1b to activate [CD8.sup.+] T-cells provided one of the rationales for a clinical trial of the agent, and the ability of interferon to augment [CD8.sup.+] [CD8.sup.-] T-suppressor cell function was duly documented over the course of the pivotal IFNB-1b trial that led to its approval. (21) It was also established early on that upper respiratory viral infectious illnesses predispose to MS relapses, presumably because immune responses to viruses in deep cervical nodes kindle a spill-over reactivation of nervous system-specific memory T-cells left over from prior MS attacks. (22) What was not known, or anticipated, was that quasi-total T-cell ablations, while profoundly lessening attack frequency in RRMS, would fail utterly to slow disability progression in primary or secondary progressive MS. (23) This dichotomy points to a minor role, at best, for T-cells in progressive MS and, given the recent documentation of persistent monocyte/macrophage/microglial activation in progressive disease, (24-26) signals a shift in dominant operative immune mechanisms from the adaptive to the innate immune system as the disease evolves. The above does not exclude an ancillary role for the innate immune system at disease onset in MS which might explain why currently approved treatments, even when given early, are only partially effective.

1990 to 2000

This was the 'decade of the brain' and several major advances in the treatment of RRMS occurred. Approval of IFNB-1b was followed in quick succession by that of intramuscular IFNB-1a (Avonex[R]), subcutaneous IFNB-1a (Rebif[R]) and glatiramer acetate (Copaxone[R]).

Long-term safety of all these agents was established in RRMS, as was benefit in terms of reduction in attack frequency and less persuasively in progression of disability over time. Marked reduction in magnetic resonance imaging-detected disease activity was shown as well. Patient despair gave way to hope and hope fostered compliance with therapy. Even so, long-term compliance with treatment remains a problem to this day.

Little by little, the desirability of beginning therapy as soon as the diagnosis is secure has gained adherents; it has now become widely accepted, although not by all, that very early therapy maximally delays onset of progressive disability. Initial enthusiasm for systemic therapy has been tempered by the realization that all currently approved immunomodulating and immunosuppressive agents are only partially effective, even when treatment is started at disease onset. There remains an urgent need for treatments based on other concepts including protection against neurotoxicity, protection from neurodegeneration and better promotion of repair.

Progress was made during the 'decade of the brain' in symptomatic treatments. Modafanil (Provigil[R]) was shown to be quite helpful in the management of fatigue. (27) Better recognition of depression symptoms in MS and the realization that episodic irritability, anxiety and panic occur early, often, and more so when disease is in relapse has led to increased long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants. SSRI antidepressants counteract the activation of the serotonin transporter induced by IFN[gamma] released by central nervous system (CNS)-invading T-cells. (28) Additional MS-relevant actions of SSRI antidepressants include reversal of the hypothalamo-pituitary-adrenal dysregulation frequently encountered in MS (29) and a restoration of the deficient brain-derived neurotrophic factor (BDNF) synthesis by immune system cells seen in progressive MS. (30,31)

2001 to 2010

Recognition that Devic's disease (aka neuromyelitis optica) and its variants are distinct from MS constitutes a significant advance. The demonstration that antibodies directed against the aquaporin-4 water channel provide a marker for Devic's disease was seminal. (32) These antibodies likely have a role in attacks of the disease, perhaps in conjunction with a T-cell-dependent opening of the blood-brain barrier. Devic's disease does not respond to the immunomodulatory treatments that favourably alter RRMS, but may respond to other therapeutic approaches. Among MS treatment failures, are there even now some with unrecognized conditions that masquerade as MS?

New gene mapping methodology has permitted screening of large populations with recent identification of multiple additional MS susceptibility genes. (33) All are immune-system genes and each, unlike HLA alleles, increases risk minimally (odds ratios 1.10-1.30) so that their importance remains uncertain. There has been a resurgence of interest in a role for EBV, the cause of infectious mononucleosis, as the instigator of the MS process. There is no effective vaccine for infectious mononucleosis. Might such a vaccine eradicate MS if given in childhood?

Also of renewed interest is a potential role for lack of exposure to sunlight, and hence vitamin D deficiency as a contributor to MS pathogenesis. Vitamin D has immunosuppressive properties and expression of the MS-associated MHC class II allele HLA-DRB1* 1501 is regulated by vitamin D. (34) On the other hand, while ultraviolet light exposure protects in experimental allergic encephalomyelitis (EAE), protection does not depend on vitamin D. (35) EAE is the prototypic animal disease model for MS. Ultraviolet light activates additional skin-expressed immunosuppressive molecules beyond vitamin D, including [alpha]-melanocyte stimulating hormone and ACTH, (36) so that low vitamin D levels, when found in MS, might be a marker for low levels of something else.

The past decade has brought a heightened awareness of cognitive deficits, axonal severing, globally decreased neuronal metabolism and frank loss of neurons in MS and especially so in secondary progressive MS (SPMS). Such deficits bespeak an urgent need to develop treatment strategies that exploit the latent neuroprotective potential of CNS-invading inflammatory cells. Perhaps equally important will be a better understanding of the roles played by brain microglia in neurodegeneration and neural repair and how to lessen the former two and increase the last.

Important here will be the roles of neurotransmitters which neurotransmitters may damage or protect neural elements directly. They also may do so indirectly by altering astrocyte, oligodendrocyte and microglial functions. Thus, failure by astrocytes to sequester glutamate may promote the toxicity of this neurotransmitter for neurons (37) while excess glutamate produced by activated immune-system cells can be toxic for oligodendrocytes. (38) To the contrary, acetylcholine may be neuroprotective inasmuch as binding of acetylcholine to the [alpha]7-nicotinic acetylcholine receptor expressed by microglia inhibits release of pro-inflammatory cytokines. (39,40) Cortical acetylcholine deficiency has been documented in EAE as an accompaniment of cognitive impairment. (41) Absent the restraining influence of acetylcholine, cortical microglia might be expected to increase production and release of pro-inflammatory cytokines and thereby contribute to cognitive impairment.

Microglia express [beta]2-adrenergic receptors; noradrenaline, when it binds to these receptors potently inhibits production and release of pro-inflammatory cytokines by brain microglia. (42) p2-adrenergic agonist drugs are protective in EAE (43) and are possibly protective as add-on therapy in RRMS. (44) [beta]2-adrenergic agonists restore defective [CD8.sup.+] T suppressor cell function in SPMS. (45) The locus coeruleus is the sole source of noradrenergic innervation to the cortex. Decreased locus coeruleus metabolism correlates with impaired cognition in MS. (46) If impaired locus coeruleus metabolism lessens noradrenaline release, as seems likely, a potentially harmful increased release of pro-inflammatory cytokines by microglia might well ensue. Neurotransmitter agonists and antagonists, little studied in MS thus far, may yet prove to have therapeutic potential.

Key Points

* HLA-endowment has long been recognized as a major risk factor for MS. Recent screenings have identified additional genes that predispose to MS. All are immune system genes and each increases risk only slightly, but there may be synergistic interactions among them.

* MS relapses are driven by activated T-cells. Ablation of T-cells has minimal effect on worsening of disability in progressive MS. Progressive MS depends on the innate immune system and is independent of T-cells.

* Monocytes and the macrophages and microglia that derive from monocytes are innate immune system members. They express receptors for both excitatory and inhibitory neurotransmitters. Engagement by acetylcholine of the [alpha]-7 nicotinic acetylcholine receptors expressed by microglia inhibits microglial secretion of pro-inflammatory cytokines, as does engagement by noradrenaline or other [beta]2-adrenergic agonists of microglial [beta]2-adrenergic receptors. These properties may be exploitable therapeutically.

* Depression in MS is characterized by irritability, anger, anxiety and sometimes panic. CNS-invading T-cells secrete IFN[gamma], and IFN[gamma] activates the serotonin transporter. SSRI antidepressants do the opposite and are effective in treating depression in MS. SSRI antidepressants also correct hypothalamo-pituitary-adrenal axis overactivity which is common in MS and restore the deficient BDNF synthesis by immune system cells seen in progressive MS.

Conflicts of Interest

No conflicts of interest were declared in relation to this article.

Received: 22 September 2010

Accepted: 23 September2010

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BGW Arnason

Department of Neurology and The Brain Research Institute, University of Chicago, Chicago, Illinois, USA

Address for Correspondence

Barry GW Arnason

Department of Neurology

Surgery Brain Research Institutes

5812 South Ellis Avenue

SBRI J209 (MC 2030)

Chicago, IL 60637

USA

Tel: +1 773 702 6386

Fax: +1 773 702 9060

E-mail: barnason@neurology.bsd.uchicago.edu
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