2009 European Charcot Foundation Symposium

The 2009 European Charcot Foundation Symposium gathered many world opinion leaders in MS in Lisbon for a 3 day meeting to discuss “A new treatment era in multiple sclerosis: options, challenges and risks”.

Prof Lassmann
. In brain lesions in secondary progressive MS (SPMS), about 65% of cells are clonally expanded MHC class I CD8+ T cells that seem to escape apoptosis and outnumber CD4+T cells 10:1. There was little surprise that ustekinumab (anti-p40 IL-12/IL-23 antibody) trial in MS showed no benefit.Associated with the active demyelination, activated microglia/astroglia and cellular infiltrates are found in most types of lesions, there is evidence for oxidative damage from reactive oxygen species (ROS/RNI) and involvement of the mitochondrial complex IV in acute Balo type lesions (Mahad Brain 2008). The axonal injury is characterized by dissolution of the cytoskeleton, calpainopathy and disturbance of axonal transport. Na+ overload is observed, as in a channelopathy, which is the base for trials that block Na+ as a strategy for neuroprotection: Na+/Ca++ channel blockers, GluR blockers both in low doses (Frischer Brain2009). Overall, despite integrity of BBB, there is active inflammation: compartmentalization of inflammation in SP.
Prof Comi. The use of imaging techniques such as MTR can show sequential changes in new Gad enhancing lesions. This made it possible to see that in the same patients different lesions recover differently. The enhancement with a ring distribution is associated with worse evolution than when there is nodular enhancement and periventricular lesions evolve in a worse way than subcortical lesions (could it be because of the preferential location of stem cells in the periventricular area?)
Unlike Lassmann, he thinks there is imaging evidence for dissociation between inflammation and degeneration. In MRI, one can see evidence for primary anterograde and retrograde axonal degeneration in the NAWM.
He also emphasized the role of OCT (optical coherence tomography) in optic neuritis and CIS in particular.

Prof Edan. There emphasis on the difference between neurodegeneration due to focal or diffuse inflammation.
A bigger change in T2 lesion volume in the 1st 5 years is correlated with who will progress to SP stage (Fisniku LK & Miller).
In MS with progressive onset, phase I (time from EDSS 0 to EDSS 3) is much shorter that in RR-MS.
Both PP-MS and initially RR MS start phase II (EDSS 3 to EDSS 6) at about the same age.
At the end of day, the debate could reach a consensus about whether inflammation drives or is independent of neurodegeneration. Based on brain post-mortem pathology, there is inflammation behind the BBB; this compartment is not targeted by most drugs: even drugs with BBB penetration such as cladribine only achieve a concentration of about ¼ of the peripheral blood concentration, which may explain why SP-MS trials disappointment. Based on clinical cohorts and MRI studies, there is imaging evidence for neurodegeneration very early on in disease and in locations that do not seem to be affected by focal inflammation.

Novartis sponsored a Satellite Symposium
on “Fingolimod: SP1 receptor modulation” chaired by Prof Giovannoni.
Prof Antel. Fingolimod is a pro-drug that needs a converting enzyme to be activated; this enzyme is present in the blood and in the central nervous system. This drug is thought to work both on the inflammatory component of MS but also to have CNS effects. Fingolimod is a lipophiic molecule that crosses the BBB and binds to myelin. Interestingly, this raised the question whether the myelin pool is available to act on inflammatory cells. Nevertheless, it is measurable in the CSF.
S1P1 receptor is present in neural cells and astrocytic S1P1 signalling is critical for EAE. Physiologically, it is thought to modulate endogenous repair mechanisms; in mice cerebellar cultures, the oligodendrocyte precursor cells (OPC) put out and retract processes, depending on the timing and dose of the drug, with an impact on myelin maintenance and remyelination. This effect was not always protective.
In the periphery, fingolimod prevents naïve and central memory T cells to egress from lymph nodes; only naïve T cells (CCR7+CD45RA+), central memory T cells (Tcm or CCR7+CD45RA-) and B cells are affected, but effector memory T cells (Tem or CCR7-CD45RA- and CCR7-CD45RA+) are spared. This means that only selective T cell subsets are present in the circulation and they retain their functional properties.

Prof Vermersch. In the trials with fingolimod, the primary outcomes that were assessed were T1 hypointense lesion load, general atrophy and the visual system (anterior visual pathway / RNFL / macular volume).
The OCT was used to measure retinal nerve fibre layer (RNFL) thickness, which has been associated with relapse rate and progression in 52 PwMS, as well as associated with disease activity (measured as a 1 point increase in EDSS) and disability. The OCT measures were also correlated with MRI assessment of normalised brain volume.
The OCT uses a superluminescent diode as a near-infrared light source, uses interferometry measures and is able to penetrate significantly deeper into the scattering medium, for example ~3× deeper than confocal microscopy. It measured macular thickness and volume, but can also measure retinal ganglion density of different retinal regions.
In CIS patients, the temporal area of the retina was thinner, but not the average. In most measures, it was the external areas that showed significant differences, but this is similar to all types of damage, it is not specific for CIS/MS.
In contrast with MRI general brain volume, this measure was not affected by high dose pulsed steroids.

Prof Havrdova. Clinical trials with fingolimod
Initial results from the 2-year phase III FREEDOMS 1 study (~1300 patients) show that oral fingolimod was significantly superior to placebo in reducing both relapses and disability progression in patients with RRMS. There was no significant difference in efficacy between 0.5 mg and 1.25 mg doses. It reduced the relapse rate by 54% for the 0.5 mg dose and 60% for the 1.25 mg dose compared to placebo (both p<0.001). In addition, it reduced the progression of disability by 30% for patients on 0.5 mg (p=0.024) and 32% for those on 1.25 mg (p=0.017) compared to placebo over two years.
Results from the 1-year TRANSFORMS study (largest head-to-head Phase III study, vs Avonex) showed a reduction in relapse rates of 52% and 38% for fingolimod 0.5 mg and 1.25 mg respectively compared to interferon beta-1a (both p<0.001)
FREEDOMS II, currently under way, is a 2-year placebo-controlled Phase III study, similar to FREEDOMS 1.
INFORMS in PPMS patients in on-going.

Profs Kappos, Vermersch, Hartung and Montaban
discussed what to do in CIS or fulminant MS, the role of new drugs in RRMS and in progressive disease.
When CIS becomes MS with McDonald’s criteria through MRI in the first year, it seems reasonable to treat, as these are the patients at higher risk of developing a clinical relapse earlier.
The challenges with fulminant MS
Definition: 1. Rapid sequence of relapses with intervals shorter than 30 days or
2. A single catastrophic clinical manifestation with tumour-like MRI appearance – Marburg type – with encephalopathy that may be fatal and usually on the first attack.
Histology: greater number of T cells that recognise deiminated epitopes, increased citrullination in human MBP and developmentally immature MBP. If they have a Lassmann-Lucchinnetti type II pattern, there is good recovery with plasmapheresis (and possibly rituximab), but not if they are type I or III (Balo type). It must be stressed, however, that the existence of the Lassmann- Lucchinnetti classification has recently been questioned and is not accepted by all MS neuropathologists.
The differential diagnosis includes gliomas, multifocal gliomas, gliomatosis cerebri, lymphoma or rarely sarcoidosis. Treatment: high dose pulsed steroids: 1 to 5g of methylprednisolone daily for 5 to 10 days, followed by tapering
1. MRI shows no Gad+ve lesions and less T2 lesion load → Clinical and MRI follow-up → DMT
2. MRI with Gad +ve lesion or increased T2 lesion load → mitox 6 months → DMT
3. Clinical aggravation (15 days) → plasmapheresis (5 sessions) → mitox 6 months/rituximab (pattern II)

The future anti-B-cell therapies were mentioned: ocrelizumab (humanized anti CD20 monoclonal antibody) and ofatumumab (Arzerra – HuMax-CD20, human mab, approved for non-responsive CLL, targets a different anti-CD20 epitope); atacicept (soluble form of the TACI receptor that binds to two ligands, BLyS and APRIL, that are implicated in B-cell survival, maturation and antibody production – not good in phase II MS trial), belimumab (Benlysta or LymphoStat-B is a fully human mab that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator -BLyS, also known as B-cell activation factor of theTNF family -BAFF.

The role of the new drugs in RRMS is a matter of intense debate: while some groups would offer them as first line treatment considering increased efficacy and easier administration other groups would use them in cases of failed IFNβ/glatimer acetate because of increased potential for serious side-effects.

There are still no positive trials for progressive MS. The OLYMPOS trial of rituximab in SPMS, MAESTRO (MBP8298 or dirucotide) in SPMS, and most of the trials have got the inadequate selection of patients, and bad outcome measures to show benefits.

Prof Meinl. The group has tested for antibodies against myelin glycoproteins, in particular neurofascin – an adhesion molecule required for the clustering of voltage gated Na+ channels at the node of Ranvier – as they are targets for auto-ab in MS patients. NF 186 and NF 155 may be implicated. The ab induces axonal injury in the animal model. There are detectable contactin-2 auto-abs in MS patients and the ab mediates gray matter pathology in animals. The ELISA technique is not optimal and they developed a FACS based technique and are testing their samples.

Prof Fujihara. The identification of NMO-Ig as anti-AQP4 antibodies and their presence in the serum of patients with neuromyelitis-optica was a major step in the research of neuroinflammation. Not unlike MS patients, patients with NMO have relapses of neurological deficits, usually with worse outcome. The a-AQP4-abs have been shown to destroy the AQP4 in the foot processes of astrocytes and the disease is now an independent entity, with more aggressive treatment. The highlights were the features of pain as a typical symptom, the possibility that abs become negative after steroid treatment and the presence of the typical antibodies many years prior to clinical attacks.

Prof Hemmer
. The mechanisms of pathogenic antibodies target 1. Inactivation of extra-cellular proteins, 2. Receptor blockade, 3. Cytotoxicity (through complement deposition or NK cell activity). The pathogenic antibodies bind in a conformational way to epitopes of the target protein. They have been testing for a-MOG abs in children and the younger the children are, the more a-MOG-abs they detect.
Also, in a study of children with demyelinating disease, the ones that went on to develop MS were the ones who were a-EBV-abs positive.

Dr Monica Calado-Marta

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