MS Abstracts 05d-2g5

Multiple Sclerosis is an Inflammatory DeMyelinating Disease of the Central Nervous System that may result in a wide range of Neurological symptoms and accumulating disability.

Its course is unpredictable resulting in a changing pattern of clinical need. Diagnostic criteria for Multiple Sclerosis require objective evidence for dissemination in space and time.

The diagnostic and management process should follow good practice guidelines with the person at the center of the process.

Appropriate support and information should be available from the time of diagnosis. Continuing education is key in enabling the person to actively participate in their management.

In the event of an acute relapse the person should have direct access to the most appropriate local service.

Provided medical causes have been excluded, corticosteroid treatment to hasten the recovery from the relapse should be considered. Management of an acute relapse should be comprehensive addressing any medical, functional, or psychosocial sequelae.

Leflunomide, a potent disease-modifying Antirheumatic drug used in the treatment of Rheumatoid Arthritis (RA), exhibits anti-Inflammatory, AntiProliferative and ImmunoSuppressive effects.

Although most of the beneficial effects of Leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist.

Because of mounting evidence for a prominent role of Dendritic Cells (DCs) in the initiation and maintenance of the Immune Response in RA, we analyzed the effect of the active metabolite of Leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle.

Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80.

Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of Uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite.

In addition, the ability of DCs to initiate T-Cell proliferation and to produce the proinflammatory Cytokines IL-12 and Tumor Necrosis Factor-alpha was markedly impaired by LEF-M treatment.

As a molecular mechanism, transactivation of nuclear factor-kappaB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M.

These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of Leflunomide in Inflammatory Diseases, including RA.

Chemokines and Chemokine Receptors play a key role in the transmigration of Leucocytes across the Blood-Brain Barrier (BBB).

CCR2 is the major receptor for CCL2, a potent Monocyte and T-Cell ChemoAttractant.

CCR2 and CCL2 have been consistently associated with a pathogenic role in Experimental Autoimmune Encephalomyelitis, using knockout and transgenic mice, Neutralizing Antibodies, Peptide Antagonists and DNA vaccination.

However, the significance of CCL2 and CCR2 in Multiple Sclerosis is enigmatic, because CCL2 levels are consistently decreased in the CSF of patients with this disease and other chronic NeuroInflammatory conditions, despite abundant expression within lesional Multiple Sclerosis tissues.

This study used an in vitro BBB model to test the hypothesis that CCL2 is removed from the ExtraCellular Fluid by CCR2-positive migrating cells as they cross the BBB, resulting in decreased CSF CCL2 levels.

We showed that CCR2-positive T-Cells and Monocytes migrated selectively across the in vitro BBB, and that CCL2 on the abluminal (tissue) side was consumed by migrating T-Cells and Monocytes.

Next, we used a new Anti-CCR2 Antibody to show that CCR2-positive MonoNuclear inflammatory cells could be readily detected in appropriate positive control tissues, but that CCR2+ cells were very infrequently found in Multiple Sclerosis lesions.

We then showed that CCR2 receptor density on T-Cells and Monocytes was specifically downregulated upon in vitro BBB transmigration in response to CCL2, but not irrelevant Chemokines.

These findings document a novel strategy for analyzing Chemokine Receptor function in inflammatory CNS disease, and support the hypothesis that CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB.

Meta-analysis was performed on the results of 75 comparisons from the 30 peer-reviewed publications that used proton Magnetic Resonance Spectroscopy (1H-MRSI) or Spectroscopic imaging to:

(i) quantify the mean concentrations of total Creatine (tCr, found in Neurons, Astrocytes and Oligodendrocytes), and/or total N-Acetyl groups (tNA, found only in Neurons).

In the lesional and/or non-lesional White Matter (WM) and/or the Gray Matter (GM) of patients with Multiple Sclerosis (MS) and

(ii) compare these values with those in the homologous tissues of normal controls (NC).

For mean [tNA] values, there was (i) a large-effect-sized overall decrease in patients' lesional WM relative to NC WM (25 comparisons), (ii) a medium-effect-sized overall decrease in patients' non-lesional WM relative to NC WM (36 comparisons) and (iii) a medium-effect-sized overall decrease in patients' GM relative to NC GM (14 comparisons).

Patients' mean [tNA] values were sometimes statistically normal but were never statistically increased. For mean [tCr] values, there was:

(i) no statistically significant overall change in the patients' lesional WM relative to NC WM (24 comparisons), although statistically significant increases and decreases were sometimes found,

(ii) a medium-effect-sized overall increase in patients' non-lesional WM relative to NC WM (33 comparisons) and (iii) no statistically significant overall change in patients' GM relative to NC GM (12 comparisons), although a significant decrease was found in one comparison.

Of 41 comparisons with statistically significant changes, 38 combined in a way that would probably result in decreased mean [tNA]/[tCr] ratios such that (i) 66% had statistically decreased mean [tNA] and statistically unchanged mean [tCr] values, (ii) 13% had statistically decreased mean [tNA] and statistically increased mean [tCr] values and

(iii) 21% had statistically unchanged mean [tNA] values and statistically increased mean [tCr] values.

Of the 25 comparisons that came from studies that also analyzed [tNA]/[tCr] ratios, the direction of change in mean [tNA] values and mean [tNA]/[tCr] ratios was concordant in 84%.

In comparisons that quantified both [tNA] and [tCr], there was a similar amount of variability in both measures in each of the different tissue types studied, both in patients and NCs.

Together, these results suggest that within-voxel tNA/tCr ratios can be interpreted as valid and accurate surrogate measures of 'Cerebral tissue integrity' - with decreased tNA/tCr ratios indicating some combination of NeuroAxonal disturbance, Oligodendroglial disturbance, and Astrocytic proliferation.

These results also suggest that, although within-voxel tNA/tCr ratios are not perfect indicators of [tNA] content, they do represent a practical compromise to acquiring surrogate measures of within-voxel NeuroAxonal integrity.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS). In the last 12 years, there has been a proliferation of studies elucidating the Immune mechanisms that mediate tissue damage in MS.

Interferons (IFNs) have an important role in regulating Innate and Adaptive Immune Responses. They decrease ProInflammatory responses such as the Autoimmunity in MS, but other Autoimmune responses such as Systemic Lupus Erythematosus (SLE) may be exacerbated.

This review offers a general overview of the biological properties of IFNs, effects on Immune Cells, and clinical effectiveness in MS treatment. IFN signaling is complex, from Receptor binding events to the generation of effector mechanisms that dampen inflammation.

Immune cell function is altered in MS. IFN treatment of MS patients ameliorates Immune dysfunction, but not completely. The incomplete resolution of Immune dysfunction by IFNs partly explains their significant, but modest therapeutic effects.

This observation also suggests that there are Immune mechanisms in MS that are resistant to IFN therapy.

In MS, abnormalities may exist at several points along the IFN signaling pathway, including molecular defects in the IFN second messenger system. Currently, several studies are ongoing evaluating ways of potentiating IFN effects.

IFNs were the first agents to show clinical efficacy in treatment of MS. More than a decade of experience with IFNs has showed continued clinical efficacy over time. In the near future, IFNs will continue to play a major role in MS.

Objectives
To compare the responsiveness of the Multiple Sclerosis Impact Scale (MSIS-29) with other self report scales in three Multiple Sclerosis (MS) samples using a range of methods.

To estimate the impact on clinical trials of differing scale responsiveness.

Methods
We studied three discrete MS samples: consecutive admissions for rehabilitation; consecutive admissions for steroid treatment of relapses; and a cohort with Primary/Progressive MS (PPMS).

All patients completed four scales at two time points: MSIS-29; Short Form 36 (SF-36); Functional Assessment of MS (FAMS); and General Health Questionnaire (GHQ-12).

We determined:

(1) the responsiveness of each scale in each sample (effect sizes):

(2) the relative responsiveness of competing scales within each sample (relative efficiency):

(3) the differential responsiveness of competing scales across the three samples (relative precision); and

(4) the implications for clinical trials (samples size estimates scales to produce the same effect size).

Results
We studied 245 people (64 rehabilitation; 77 steroids; 104 PPMS). The most responsive physical and psychological scales in both rehabilitation and steroids samples were the MSIS-29 physical scale and the GHQ-12.

However, the relative ability of different scales to detect change in the two samples was variable. Differing responsiveness implied more than a twofold impact on sample size estimates.

Conclusions
The MSIS-29 was the most responsive physical and second most responsive psychological scale. Scale responsiveness differs notably within and across samples, which affects sample size calculations. Results of clinical trials are scale dependent.

Macrophage Migration Inhibitory Factor (MIF) has been implicated in the pathogenesis of Inflammatory and Autoimmune Diseases. The role of MIF in the progression of Experimental Autoimmune Encephalomyelitis (EAE) was explored using MIF(-/-) mice.

Wild-type mice showed a progressive disease course, whereas MIF(-/-) mice exhibited acute signs but no further progression of clinical disease.

MIF(-/-) mice displayed markedly elevated CortiCosterone levels and significant decreases in the Inflammatory Cytokines TNF-, IFN-γ, IL-2, and IL-6 before, during, and after EAE onset.

Taken together, these findings support that MIF is an important mediator of EAE progression through GlucoCorticoid antagonism and up-regulation of the inflammatory response.

Background
Natalizumab, a humanized MonoClonal AntiBody against alpha(4) Integrin, inhibits Leukocyte adhesion and migration into inflamed tissue.

Methods
We conducted two controlled trials to evaluate Natalizumab as induction and maintenance therapy in patients with active Crohn's Disease.

In the first trial, 905 patients were randomly assigned to receive 300 mg of Natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10.

In the second trial, 339 patients who had a response to Natalizumab in the first trial were randomly reassigned to receive 300 mg of Natalizumab or placebo every four weeks through week 56.

The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).

Results
In the first trial, the Natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks.

Continuing Natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P< 0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo.

Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the Natalizumab group in the second trial.

In an open-label extension study, a patient treated with Natalizumab died from Progressive Multifocal Leukoencephalopathy, associated with the JC virus, a human PolyomaVirus.

Conclusions
Induction therapy with Natalizumab for Crohn's Disease resulted in small, nonsignificant improvements in response and remission rates.

Patients who had a response had significantly increased rates of sustained response and remission if Natalizumab was continued every four weeks.

The benefit of Natalizumab will need to be weighed against the risk of serious adverse events, including Progressive Multifocal Leukoencephalopathy. (Clinical Trials, gov numbers, NCT00032786 and NCT00032799.)

Copyright 2005 Massachusetts Medical Society.

Current treatments of Relapsing/Remitting Multiple Sclerosis (RRMS) with ImmunoSuppressive or ImmunoModulatory drugs have been shown to modify the course of the disease in a significative number of patients.

However, in many cases, the response to either Interferon-beta (IFN-ß) or Azathioprine (AZA) treatments was not satisfactory and new therapeutic approaches are needed.

We studied clinical and MRI efficacy, safety and tolerance of AZA and IFN-ß-1a combined therapy in 23 patients with clinically definite RRMS, who had not previously been responsive to either monotherapies.

Our cases were divided into three subgroups:
1. 8 previously untreated patients (subgroup A) with at least 2 years of natural course of the disease
2. 8 patients (subgroup B) previously treated with AZA for 2 years and
3. 7 patients (subgroup C) previously treated with IFN-ß-1a for 2 years. The baseline Expanded Disability Status Scale (EDSS) ranged from 2 to 4 in all subgroups

All patients completed 2 years of combined treatment with a dose of AZA adjusted to reduce Lymphocyte count down to 1,000 +/- 100/microl in association with IFN-ß-1a at a dose of 6 MIU every other day.

The mean number of relapses during the combined treatment period was significantly lower than that observed before combined therapy in all the three subgroups.

Also, the mean Delta EDSS score was significantly lower during combined treatment than in monotherapy in subgroups B and C.

Moreover, after 2 years of combined treatment, the number of new T₁ HypoIntense lesions, the number and volume of proton density/T₂ HyperIntense lesions and the Gadolinium enhancement of T₁ HypoIntense lesions were significantly lower than before combined treatment.

After 2 years of treatment, this combination therapy appears to be safe and well tolerated and no serious side effects were reported.

Despite some limitations of our study design, the information regarding efficacy, safety and tolerance of the association of AZA and IFN-ß is most encouraging.

Copyright 2004 S. Karger AG, Basel

Disease-Modifying Treatments (DMTs) for Multiple Sclerosis (MS) are now widely available, and their beneficial effects on relapse rates, Magnetic Resonance Imaging outcomes and, in some cases, relapse-related disability have been shown in numerous clinical studies.

However, as these treatments are only partially effective in halting the MS disease process, the search for improved treatment regimens and novel therapies must continue.

Strategies to improve our therapeutic armamentarium have to take into account the different phases or parts of the pathogenesis of the disease.

Available treatments address systemic Immune dysfunction, Blood-Brain Barrier permeability and the inflammatory process in the Central Nervous System.

Currently, patients who fail to respond adequately to first-line DMTs are often considered as candidates for intensive ImmunoSuppression with cytostatic agents or even Autologous Stem Cell Transplantation. However, new approaches are being developed.

Combination therapies offer an alternative approach that may have considerable potential to improve therapeutic yield and, although likely to present considerable challenges in terms of trial design, this certainly seems to be a logical step forward in view of the complex pathology of MS.

Several new drugs are also being developed with the aim of providing more effective, convenient and/or specific modulation of the inflammatory component of the disease.

These treatments include humanized MonoClonal AntiBodies such as the Anti-VLA-4 AntiBody Natalizumab, inhibitors of IntraCellular activation, signalling pathways and T-Cell proliferation, and oral ImmunoModulators such as Sirolimus, Teriflunomide or Statins.

There remains, however, an urgent need for treatments that protect against DeMyelination and Axonal loss, or promote ReMyelination/regeneration.

Due to the chronicity of MS, the therapeutic window for NeuroProtective agents is wider than that following stroke or acute Spinal Cord Injury, and may therefore allow the use of some drugs that have proven disappointing in other situations.

Novel potential NeuroProtective agents such as alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid antagonists and Ion-Channel blockers will be entering Phase II trials in MS in the near future, and it is hoped that these agents will mark the start of a new era for DMTs for MS.

Background
The Anti-CD20 Monoclonal AntiBody Rituximab effectively depletes B-Lymphocytes and has been successfully used in the therapy of Immune-mediated disorders of the Peripheral Nervous System.

A limited effect of Rituximab on B-Lymphocytes in the CerebroSpinal Fluid compartment of patients with Primary/Progressive Multiple Sclerosis (MS) was recently reported.

Objective
To determine the effect of Rituximab on clinical, Magnetic Resonance Imaging, and Immunological variables in a patient with Relapsing/Remitting MS.

Design
A patient with Relapsing/Remitting MS was treated with Rituximab.

The patient was repeatedly examined clinically and by Magnetic Resonance Imaging. The frequency of peripheral blood and CerebroSpinal Fluid B-Lymphocytes was assessed by flow cytometry before, during, and after Rituximab therapy.

Results
Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on Magnetic Resonance Imaging were also reduced. B-Lymphocytes were depleted in the Cerebrospinal Fluid and peripheral blood.

Conclusions
Our data demonstrate beneficial clinical effects of Rituximab in Relapsing/Remitting MS, mediated through modulation of Humoral Systemic and Central Nervous System intrinsic immune responses.

Clinical trials should determine optimal therapeutic strategies for patients with Relapsing/Remitting MS.

Background
Subclinical Multiple Sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated Magnetic Resonance Imaging (MRI) changes consistent with MS.

And 'MRI relapses' are several times more common than clinical relapses.

Case Description
A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's Disease study, where his father was the proband.

MRI indicated multiple areas of abnormal signal intensity in a PeriVentricular and Gray-White Matter junction distribution.

Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand.

MRI now indicated a further area of high signal intensity in the Right Posterior Cord at the level of C5/C6.

There was mild Pyramidal distribution weakness in the right leg with an Extensor Plantar Response on the same side.

Over the next five years there has been mild progression in Weakness and Fatigue and intermittent Lhermitte's Phenomenon.

At no stage has there been a history of relapse, CerebroSpinal Fluid examination was normal and Evoked Responses (Visual and SomatoSensory) are normal.

Conclusion
This case demonstrates the phenomenon of SubClinical MS, unusually supported by prolonged clinical and MRI follow-up.

The patient eventually became symptomatic nine years after MRI diagnosis and is following a Primary/Progressive course.

Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of Primary/Progressive MS.

And, is compatible with the later onset seen in this subgroup of patients.