New Aspects in the Treatment of Multiple Sclerosis
Vienna, March 09, 2002
Once again Schering sponsored a symposium, this year it was in Vienna and was attended by 500 leading European neurologists. The theme of the meeting was new aspects in the treatment of multiple sclerosis (MS). Many topics were covered, including the review of new clinical results and the presentation of new measurements for making a diagnosis of MS. Presentations were given by experts in the field of MS.
Welcome Address - Professor Günther Stock
Professor Günther Stock opened the symposium by reviewing the developments in the fields of multiple sclerosis (MS) and its treatment over the past year.
Professor Stock began with an introduction to interferons describing how they were once heralded as the ‘cure-all’ agents for viral infections and cancer. However, the only interferon that has proved of any clinical relevance is interferon beta, and it was approved in the United States for the treatment of relapsing-remitting (RR) MS in 1993.
Professor Stock then outlined Schering’s recent research initiatives in relation to the interferons. These include finding new indications for their interferon beta preparation, identifying new interferons, establishing how the interferon beta affects the cells in the brain and developing a new method of drug administration for their interferon beta preparation.
Recent pathological findings in MS – implications for diagnosis and therapy - Professor Hans Lassman
The exact mechanism for the cause of MS and what happens in the brains of people with MS has long been of interest to both physicians and people with MS. Professor Lassmann’s presentation was to review what is currently known and to present interesting new information. He outlined a three-step process for the disease progression of MS.
Inflammation
This is the first step of disease progression and is a flood of cells of the immune system into the brain. MS is an autoimmune disease; these immune cells have been inappropriately activated and this leads to nerve damage.
Demyelination
This is a complex process resulting in structures known as plaques forming in the brain. Demyelination, which is the loss of the protective coating around the nerve, begins with the inflammation that is common to all MS patients. However there is also an other step that is necessary for deymelination to occur. This step can be one of the following three and varies between people with MS.
Processes responsible for acceleration of demyelination:
• myelin-specific antibodies, which activate cells of the immune system
• substances released by cells of the immune system that induce a very low oxygen state (hypoxia) in the tissue, which causes additional nerve damage
• the person with MS having a genetic susceptibility making the tissue more vulnerable to damage caused by the cells of the immune system.
• Axonal damage and loss. Axonal loss is a feature of MS. Axons are a part of nerve cells, responsible for the transmission of nerve impuses. Initially, the axons within plaques are relatively well preserved and any axonal damage is in some part reversible, with some remyelination (replacement of the protective coating) occurring. However, there is also continuous axonal loss occurring at an extremely slow rate. When this loss exceeds the replacement, there is irreversible plaque formation and clinical disease progression.
A contribution to the discussion about why the variable step of acceleration of demyelination is so important has been given by Professor Lassmann who suggested that identifying particular markers for each of the different causes of demyelination might lead to new tools for the diagnosis and treatment of MS.
New diagnostic criteria for MS - Professor Alan Thompson
MS is a very difficult disease to diagnose, with many people being initially misdiagnosed. Professor Thompson presented the findings of ‘The International Panel on MS Diagnosis’, who reviewed the existing guidelines for MS diagnosis. He stated that these were not completely new criteria but part of an evolving process of existing criteria that began 20 years ago. The aim of the panel was to make the guidelines clearer and easier to use, with a view to ensuring that people with MS are diagnosed quickly.
The most significant change was in MRI diagnostic investigations, as this is a field of research that is changing at a very rapid pace. The panel recommended using some criteria that were suggested in 1997 by a group of radiologists led by Professor Barkhof, who was also speaking at this symposium. Significant changes to the criteria currently used to diagnose MS were suggested. The recommendations made included:
• to remove the potentially confusing definitions ‘probable MS’ and ‘clinically definite’ from the current phrases used in the diagnosis of the disease, and to replace them with the new terms ‘MS’, ‘possible MS’ and ‘not MS’
• to redefine a relapse as an event occurring 30 days from the onset of the last event, and not 30 days from the end of the last event.
This work of Prof Thompson has raised many questions, including whether or not the new criteria are practical and easy to use and whether or not they increase pressure for early MRI scans. This has been an important step in the evolution of the MS diagnostic criteria and areas have been highlighted that require further investigation in order to enhance the diagnostic criteria further.
Assessing treatment effects with MRI: present evidence and future perspectives - Professor Frederik Barkhof
The assessment of treatment effects with MRI was the topic of Professor Barkhof’s speech. He began by emphasising that MRI scans are very accurate and useful as a diagnostic tool.
Professor Barkhof expressed the impact of lesions, the areas of damage in the brain, and how MRI scans can be used to measure the dynamic nature of brain lesions and how the number of lesions a patient has changes over time in response to treatment and in relation to disease severity. The number of lesions that a person with MS has shows a significant link with clinical disability as measured by the expanded disability status scale (EDSS). Professor Barkhof showed that a 45% reduction in the development of lesions is seen in people with secondary progressive (SP) MS who have been taking interferon beta.
As well as lesion number, MRI scans can also show the amount of demyelination and axonal loss in the brain. Repeated MRI scans can show how these change in response to treatment. Professor Barkhof finished with a brief overview of brain atrophy and how it correlates with overall disability and cognitive function. He showed how MRI scans are used to view how the ventricles of people with MS are enlarged and the sulci are widened.
Secondary progressive MS, which patients to treat? - Professor Ludwig Kappos
There have been many clinical trials into the effectiveness of different drugs in the treatment of MS1-5. Professor Kappos spoke next and presented data from six such trials. He discussed whether or not to treat patients in the advance stages of SP MS with interferon beta, which is a current treatment for RR MS. He outlined the differences between RR and SP MS and posed the question whether or not the treatments for RR MS are suitable for these differences.
The results from four large clinical trials were analysed and the results of three showed that the therapeutic benefit of treatment is limited. Results from the clinical trial ‘European SP MS’ (EUSPMS) trial confirmed these initial findings6. However, additional studies showed that there are positive effects on quality of life associated with interferon beta treatment in patients with SP MS7.
Kappos says 2002: „The combined analysis of the two studies with Interferon beta-1b (EUSPMS and NASPMS8) shows that patients with active disease, evidenced by relapses, but also by more pronounced EDSS progression are those who would benefit most from this treatment. Other disease related characteristics like age, duration of MS, baseline EDSS values but also MRI parameters like T2 lesion load and Gadolinium enhancing lesions were less consistently associated with therapeutic effect.
The combined analysis of the results allowed Professor Kappos to draw the following conclusions:
• Patients with active disease, evidenced by relapses and more pronounced disability, are those who would benefit most from treatment with interferon beta
• SP MS should be treated earlier than it is at present
• Interferon beta treatment in SP MS is not as effective as in patients with RR MS
• Medical therapies based on other concepts should still be investigated for the treatment of SP MS.
Treatment of MS patients with interferon beta: observations from long-term treatment - Professor George P.A. Rice
Professor George Rice presented the results of another clinical trial, this time investigating the long-term treatment of MS patients with interferon beta. The aim of the study was to see how many patients were still taking the drug 12 years after the trial began in 1988, to study the long-term adherence to drug therapy and to monitor the evolution of neutralising antibodies (NABs). This was the longest ever trial conducted investigating the treatment of MS9.
The results were as follows:
• Remarkable compliance with the drug was seen, with 61% of patients still taking it after 12 years
• Side effects with the drug were minimal. However, skin necrosis (local skin death) was more common than expected (16% of patients), but was not seen as an impediment to long-term use of the drug
• The presence of NABs reduced over time and they were absent from all but 3 patients after 8 years.
• Long-term effectiveness of the drug was good.
The Independent Comparison of Interferon (INCOMIN) Trial: a multi-centre randomised trial comparing clinical and MRI efficacy of two interferon betas in multiple sclerosis - Professor Luca Durelli
The results of the Independent Comparison of Interferon (INCOMIN) trial were presented by Professor Luca Durelli10.
INCOMIN studied the effectiveness of two different interferon beta-1a and -1b preparations in the treatment of MS. Professor Durelli began with some background to the interferons, including conditions they are used to treat other than MS (hairy cell leukemia, bladder cancer and Kaposi’s sarcoma) and information on the differences between the two preparations.
During the first half of the trial it appeared as though both preparations were having the same level of effect in the people treated. However, during the second 6-month period one of the preparations (interferon beta-1b) emerged as more effective. In fact, half as many patients were presenting with new lesions compared with the other preparation.
Professor Durelli concluded by discussing the importance of this being an independent trial and not being sponsored by a drug company. He also said that longer follow-up work is required to see if this increased efficacy continues over time.
Pros and cons of early treatment – the BENEFIT study - Professor Xavier Montalban
Professor Montalban presented an introduction to the BENEFIT study, another clinical trial that began in the first week of March 2002. The BENEFIT study aims to investigate the effects of an interferon beta preparation given in different dosing regimens on MS. The trial will use the new criteria put forward by Professor Thompson for the use of MRI scans to measure how effective the drug is being.
This trial is being performed to investigate the emerging concept that much of the damage that occurs in MS is a result of processes in the first 5 years of the disease. Axonal damage and loss and brain atrophy is seen in patients with a first episode of MS, and recent investigations have shown that treatment with interferon beta can prevent some people with early MS from having a second attack. So, the theory being tested by this trial is that the early treatment of people with MS with interferon beta may prevent this early axonal damage.
Neurorehabilitation in MS - Professor Jürg Kesselring
The final speaker was Professor Kesselring, who ended the symposium with a speech from the perspective of people with MS. He began by presenting evidence from new studies in MS patients that showed that despite popular opinion among physicians, reduced disability and restoration of function are not the key outcomes of treatment that people with MS are looking for. People with MS want the symptoms that impact negatively on quality of life treated.
The symptoms that are important to people with MS are fatigue, pelvic MS, including urinary and sexual problems, loss of dexterity and mobility, cognitive and visual dysfunction and pain. These are the symptoms that they want treating.
Professor Kesselring highlighted a huge problem, which is raising awareness among physicians on the importance about treating such symptoms as fatigue, pain and depression, which have been neglected areas of treatment for a long time. A number of people with MS have either depressive symptoms or report feeling irritable most of the time or report crying often and for long periods. He also stressed the fact that disease progression is usually due to disease mismanagement. The simple things, such as kneeling down to speak to a person with MS who is in a wheelchair, to prevent them straining their neck, and providing them with footrests can make huge differences to their quality of life.
Professor Kesselring emphasised that although clinical trials are very important, MS is about more than MRI scans and plaques and that physicians should focus more on people with MS as individuals and what can be done to improve their quality of life.
References
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2 Paty DW, Li DKB et al. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II: MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:662-66.
3 Jacobs LD, Cookfair DL et al. Intramuscular IFNB 1a for disease progression in RRMS. Annals of Neurology 1996;39:285-94.
4 PRISMS Study Group: Randomised double-blind placebo-controlled study of interferon beta-1a in RRMS. The Lancet 1998;352: 1498-1504.
5 Johnson KP, Brooks BR et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicentre, double-blind, placebo-controlled trial. Neurology 1995;45:1268-76.
6 European Study Group on Interferon beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. The Lancet. 1998;352:1491-1497.
7 Freeman JA, Thompson AJ et al. Interferon-ß1b in the treatment of secondary progressive MS. Impact on quality of life. Neurology 2001;57(10):1870-1875.
8 Goodkin DE and the North American Study Group on Interferon Beta-1b in Secondary Progressive MS. The North American Study of Interferon Beta-1b in Secondary Progressive Multiple Sclerosis. Presented at: The 52nd Annual Meeting of the American Academy of Neurology; May 1, 2000; San Diego, Californien.
9 Rice GPA, Lesaux NE et al. Long-term safety, compliance and evolution of neutralizing antibodies in MS patients trested with interferon beta 1b. Multiple Sclerosis 2001;7 Suppl 1:S54, Abstract No. P-147.
10 Durelli L, Verdun E et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). The Lancet 2002;359,1453-1460.
