2004 overview: Developments in clinical MS research
In this overview Dr Morten Blinkenberg, Denmark, discusses some of the issues in multiple sclerosis that attracted special interest in 2004.
An overview of the most important news in clinical MS research during the last year will inevitably require a substantial selection of the many interesting studies. In the following paragraphs I will bring some key learning messages to you that I find significant, and have influenced my view upon different aspects of the disease and treatment.
First I would like to focus on pathophysiology and the intriguing paper by Barnett et al. (ref. 1), who studied MS cases with an acute lethal course. The authors describe predominance of lesions with oligodendrocyte apoptosis and microglial activation in myelinated tissue, with sparse inflammatory activity. The question this paper rises, is whether the described changes is an early pathological feature of MS, and the inflammatory changes merely an epiphenomenon.
Lesions with predominance of oligodendrocyte-pathology have previously been characterized, and arguments for MS being an oligodendrocyte disease has been put forward, although not approached as in the paper by Barnett et al. The issue is very interesting and will definitely inspire new studies in this field.
An interesting point was made regarding vitamin D and incidence of MS. Munger et al. (ref. 2) show that women who used supplemental vitamin D have 40% reduced risk of developing MS. There is reason to believe that sustained exposure to sunlight may in part explain the geographical difference in MS incidence, due to natural vitamin D synthesis. The question that remains is to what degree vitamin D has a disease modifying effect.
Theoretically there is evidence supporting this hypothesis, mainly because of the anti-inflammatory properties of vitamin D, but also because increased disease activity has been described on MRI during the dark winter season in tempered regions. It would be of great interest for the MS community to shed light on this issue, since vitamin D supplements could represent an easy and economically feasible treatment option.
This is also the case for statins. The drug has an immunomodulatory (in vitro) effect that to some degree resembles that of beta-interferon. It has been shown that statins have marked effect on EAE (experimental autoimmune encephalomyelitis), which is an animal model of MS. Furthermore, an open label clinical trial (ref. 3) describe a decline in number and volume of MRI Gadolinium enhancing lesions of approximately 40% compared with pretreatment MRI.
Statins are orally administrated and safe to use, which are interesting features compared with existing MS therapies. It is clear that double blind and placebo-controlled studies are needed in this field, which have already been initiated.
Beta-interferon and biological response
A lesson was learned about beta-interferon (b-INF) and biological response. Sorensen et al. (ref. 4) show that relapse rate was higher in antibody-positive patients, with a neutralization capacity of more than 20% (NAB+). There was no measurable effect on disability, but time to first relapse was increased 244 days in NAB negative patients.
There are still a lot of unanswered questions to the antibody story, one of these being the clinical consequences of non-persistent NAB+ patients. It is evident that we need more studies in this field and preferably supply NAB measurements with markers of biological b-INF response, such as e.g. myxovirus resistance protein A (MxA). Future therapy in MS will indeed depend more on stratification of response to different treatments in order to improve efficacy.
Stem cell transplantation
In aggressive MS, treatment with stem cell transplantation has drawn attention, although evidence of effect has been insufficient. The prospective study by Saiz et al. (ref. 5) to some degree account for this, but unfortunately show that autologous stem cell transplantation (ASCT) is not a cure for MS, which might have been expected.
The probability of progression-free survival after ASCT was 86% and the probability of disease activity-free survival was 46%, which indeed is very optimistic. A question that needs to be answered, before ASCT should be offered in a clinical context, is to what degree it differs from high dose chemotherapy alone. This is currently being studied in a randomized trial comparing ASCT with mitoxantrone.
Results from the two phase III Natalizumab multicenter-studies should be mentioned in this overview although data has not been published yet. United States Food and Drug Administration (FDA) has approved the use of natalizumab for the treatment of relapsing MS, which will have a major impact on the use of existing treatment regimens.
Natalizumab is a recombinant humanized monoclonal antibody that binds to a4-integrin and thereby prevent migration of leukocytes into CNS and establishment of the inflammatory lesion.
The one-year data from the (two-year) AFFIRM study, show reduction in the clinical relapses rate (primary endpoint) by 66 % relative to placebo (p<0.001) and an annualized relapse rate of 0.25 for patients treated with natalizumab versus 0.74 for placebo.
One year MRI data show that 60 % of patients treated with natalizumab developed no new or newly enlarging T2 hyperintense lesions compared to 22 % of placebo-treated patients (p<0.001).
No gadolinium enhancing lesions was seen in 96 % of natalizumab-treated patients compared to 68 % of placebo-treated patients (p<0.001). The proportion of patients who remained relapse free was 76 % in the natalizumab-treated group compared to 53 % in the placebo-treated group (p<0.001).
The SENTINEL trial included patients with disease activity on b-INF 1a, who were randomized to add-on therapy with natalizumab or placebo to their standard regimen. This study also achieved the one-year primary and secondary endpoints although the results are not as compelling as in the AFFIRM trial.
In this way, natalizumab seem to be a superior drug in terms of efficacy and safety. The full two-year data for both studies are awaited with great interest in 2005.
Daclizumab is another humanized monoclonal antibody that may be used in the treatment of MS. Daclizumab limits T-cell expansion by blocking of IL-2 signaling (anti - CD 25) and this immuno-modulatory effect is used in organ transplantation. An open label phase II trial by Bielekova et al. (ref. 6) show promising results as add-on therapy in 10 MS patients with treatment failure of b-INF.
Daclizumab was well tolerated with no major side effects. The authors find a 78% decrease in new contrast enhancing lesions on MRI and 70% decrease in total contrast enhancing lesions compared with baseline.
Larger randomized trials are needed in order to determine the efficacy of the drug.
Reason to be optimistic
There is indeed reason to be optimistic about future therapy for MS patients, with a great variety of drugs and treatment options. Disease outcome can be improved and efficacy of new drugs is getting better.
Still, the only disease modifying approach is immune therapy, which is based on the assumption that inflammation is the most important determinant for neuronal death in MS.
We do not know to what extent this is true, or if there are other determinants that are important for the initiation and evolvement of the disease. It is evident that we need to know more about the pathophysiology of MS and I hope the coming year will bring more answers than questions in this regard.
1. Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion. Ann Neurol 2004; 55 (2); 458-68.
2. Munger KL et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004; 62 (1); 60-5.
3. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363 (9421); 1607-8.
4. Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003; 362 (9391); 1184-91.
5. Saiz A, Blanco Y, Carreras E, Berenguer J, Rovira M, Pujol T, Marin P, Arbizu T, Graus F. Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS. Neurology 2004; 62 (7); 282-4.
6. Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, McCartin J, Wurfel J, Ohayon J, Waldmann TA, McFarland HF, Martin R. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U S A 2004; 101 (23); 8705-8. (OBS: Free full text article)
Published on CNSforum 31 Dec 2004