Multiple Sclerosis: The Big Questions--the MS Forum Workshop.
|Article Type:||Conference notes|
(Care and treatment)
Multiple sclerosis (Conferences, meetings and seminars)
Neurology (Conferences, meetings and seminars)
Epidemiology (Conferences, meetings and seminars)
|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|
|Geographic:||Geographic Scope: Switzerland Geographic Code: 4EXSI Switzerland|
22-24 January 2010
The following is a synopsis of the MS Forum Workshop, Multiple Sclerosis: The Big Questions held in Zurich, Switzerland on 22-24 January 2010. The topics of the presentation and presenters at the workshop were:
Many of the talks, however, contained overlapping material. Therefore, this synopsis was not written sequentially and does not include the material of each presenter in its entirety.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), which typically recurs episodically at unpredictable intervals (also referred to as 'acute attacks' or 'flares'). These inflammatory episodes, which usually last days to weeks, cause injury to the myelin sheaths surrounding the nerve axons, to the oligodendrocytes themselves and, to a somewhat lesser extent, the nerve cells and nerve-cell processes. Both acute and chronic inflammation, as evidenced by elevations in total protein concentration, mononuclear cell counts, and the gammaglobulin (Immunoglobulin [IgG]) fraction, are typically found in the cerebrospinal fluid (CSF) of individuals, especially during acute clinical attacks. In the northern parts of North America and Europe, where the disease is most common, the prevalence is approximately 0.1-0.2% of the population (i.e. 100-200 per 100 000 population) and the incidence is approximately 5-6 per 100 000 population per year. Women are affected approximately two to three times more often than men. The disease generally becomes clinically apparent between the ages of 20 and 40 years, although it can begin either earlier or later in life. Thus, some cases have begun (clinically) as early as the first year of life, whereas others may become symptomatic only in the sixth or seventh decade. Moreover, some individuals with pathologically verified MS (~0.1% of routine autopsies) may be discovered incidentally. This means that, over their entire lifetime, as many as half of patients with pathological MS never experience clinical symptoms of sufficient severity to bring them to medical attention.
One of the main purposes of studying the epidemiology of MS is to gain insight to the underlying causes of the disease. Indeed, if the principal mechanisms of disease pathogenesis were to be understood clearly, then it might be possible to entertain notions of either a cure for existing disease or the primary prevention of future disease. Much of our current understanding of disease pathogenesis has been derived from basic science investigations of animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and this important work has provided considerable insight into both the remarkable complexity of the mammalian immune system and the mechanisms underlying its dysfunction in these models. Nevertheless, MS is a disease of humans without any known, naturally occurring, counterpart in any nonhuman species. For this reason, the clues to disease pathogenesis provided by a study of basic epidemiological facts regarding MS is essential to a comprehensive understanding of this illness.
Environmental Factors in the Pathogenesis of MS
Both the genetic background of an individual and environmental events that they experience during their lives are known to be critical components of MS pathogenesis. For example, as noted earlier, an individual from northern North America or northern Europe has a lifetime risk of developing MS of approximately 0.1-0.2%. The risk for an individual with an affected family member increases in rough proportion to the genetic similarity between themselves and the proband, reaching a risk of more than 200 times the general population risk for a monozygotic (MZ) twin of an MS proband. Despite this strong genetic predisposition, however, it is clear that genetics is not the only factor. If it were, the proband-wise concordance-rate for MZ twins would be much closer to 100% than to the 20-30% reported in northern populations. Consequently, it is clear that, in addition to any genetic contributions, there must be environmental and/or epigenetic factors that also contribute in important ways to MS pathogenesis.
Environmental Factors Near Birth
The first finding is the presence of the so-called 'maternal effect' in MS. Epidemiological support for such 'maternal effect' is provided by three independent observations. The first is that half-siblings (i.e. siblings who share one, but not both biological parents), who are concordant for MS, are twice as likely to share the mother as they are to share the father. Such a circumstance suggests that MS susceptibility is transmitted from mother to child through some mechanism other than the passage of nuclear genes. An environmental exposure, occurring either in the intrauterine period or soon thereafter, is one possibility.
The second observation is that the MS concordance rate for fraternal twins seems to be almost twice that for full siblings. Such a disparity cannot be attributed to mitochondrial inheritance, genetic imprinting or epigenetic factors because, on average, these factors should be similar for both siblings and fraternal twins sharing the same biological parents. Rather, this discrepancy must be due to environmental events occurring during the shared intrauterine or early post-natal period.
The third observation relates to the month-of-birth effect for MS that has been reported in studies from Canada and northern Europe. In these northern hemisphere countries, significantly more MS patients are born in May and fewer are born in November, compared with other months of the year. By contrast, in the southern hemisphere (Australia) this pattern is reversed such that the peak risk occurs in November/December and the nadir occurs in May/June.
This month-of-birth effect provides unequivocal evidence for an early environmental event, involved in MS pathogenesis that is time-locked to birth. In addition, this environmental event is periodic and appears to be coupled to the solar cycle. Perhaps importantly, mothers of May babies spend much of their pregnancy during the winter months (with less sun exposure) compared to mothers of November babies who are pregnant over the summer. One possible explanation for such circa annum periodicity to MS susceptibility might be variations in vitamin D levels due to the differences in maternal sun exposure while the child is in utero. Other events such as seasonal infections might also explain such periodicity although, because a child is typically not infected in utero, any such association would need to be indirect.
Environmental Factors During Adolescence
A second environmental factor is suggested by observations in people who migrate from one geographical region to another with differing MS risks. For example, when an individual moves (prior to their adolescent years) from an area of high MS prevalence to an area of low prevalence (or vice versa), their MS risk becomes similar to that of the region to which they moved. By contrast, when they make the same move after adolescence, their MS risk remains similar to that of the region from which they moved. These observations indicate that there is an environmental event, which is involved in MS pathogenesis that occurs sometime between birth and adolescence.
Environmental Factors During Adult Life
Third, the initial clinical symptoms in MS are generally delayed considerably (often by decades) following the period when the maternal factor and the migratory factor take place suggesting that subsequent environmental events are responsible for the timing of symptom onset.
Over the years many potential environmental triggers have been postulated to be linked to MS pathogenesis. Of these, Epstein-Barr virus (EBV) infection and vitamin D deficiency have been attracting the greatest current interest for their potential role in MS pathogenesis. EBV is a double-stranded linear DNA virus of the herpes family. It is a very common infection of humans, with more than 90% of the population becoming infected at some time. EBV infection has been consistently linked to MS, especially when it causes symptomatic mononucleosis, and in fact, there is evidence of prior EBV infection in essentially 100% of adult-onset MS cases (Table 1). If correct, this indicates that prior EBV infection is a necessary (but not a sufficient) condition for MS to develop. Such a strong association is very difficult to ignore. However, because EBV infection does not occur in utero, it is presumably not the early 'maternal' factor but, rather, is a better candidate for the adolescent factor, which is when symptomatic mononucleosis typically occurs.
Vitamin D is produced by the conversion of 7-dehydro-cholesterol into vitamin D3, in the presence of ultraviolet B (UVB) radiation. However, it is not a vitamin in the usual sense of a biochemical that is prevalent in our diets and participates in specific biochemical reactions. Rather, vitamin D is essentially absent from our diets and it acts as a transcription factor, controlling the expression of thousands of nuclear genes throughout the body. It is involved in immune system development and maturation, its deficiency is associated with other autoimmune diseases, and it is coupled to the solar cycle in temperate regions. As a result, vitamin D deficiency is a strong candidate for the 'maternal' factor in MS pathogenesis. Moreover, the recent finding that vitamin D regulates the HLA DRB1 * 1501 allele (by far, the allele most closely associated with MS susceptibility) establishes a clear connection between vitamin D and MS pathogenesis.
It is of note that MS epidemiology has changed in important ways over the past several decades. Thus, the incidence (prevalence) of MS is increasing in many parts of the world, especially in women. As a consequence of this, the sex ratio has been altered (Figure 1). Because MS genetics seems unlikely to have shifted in so short an interval, these observations presumably relate to a change in the environmental determinants of MS or to a gene-environment interaction. In fact, there is now evidence that the month-of-birth effect results from a gene-environment interaction. For example, the trans-generational difference in MHC transmission of the DRB1 * 1501 allele (in women) implies that there are epigenetic changes related to MS pathogenesis. Moreover, the month-of-birth effect seems to be derived entirely from those individuals who carry the DRB1 * 1501 allele. Thus, although the rising female to male ratio (Figure 1) has to be environmental, it could also be a reflection of the gene-environment interaction localized to the major histo-compatibility complex (MHC) on chromosome 6. Moreover, other gene-environment interactions are suggested by the fact that women are responding to the environment changes responsible to the increasing incidence of MS (whatever these are) to a far greater extent than men (Figure 2).
At present it is not possible to pinpoint the responsible change involved in MS pathogenesis. Many widespread environmental changes are known to be taking place such as increasing atmospheric concentrations of C[O.sub.2], C[H.sub.4] and other pollutants; increasing global temperatures; a depletion of stratospheric ozone; and a greater dietary consumption of trans fats. Interestingly, one recent change (potentially relevant to the possible role of vitamin D deficiency) is that people are increasingly encouraged to avoid prolonged sun exposure and to use sunblock to prevent skin cancer. Nevertheless, sunblock with sun protective factor (SPF)-15 blocks approximately 94% of the incoming UVB radiation and higher SPF levels block even more. As a result, any widespread use of sunblock and sun avoidance will exacerbate any population deficiency of vitamin D synthesis and, presumably, will increase the likelihood of diseases related to vitamin D deficiency.
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Primary and Secondary Prevention of MS
Clearly, if factors such as vitamin D deficiency or EBV infection become established as critical environmental components involved in the pathogenesis of MS, it would be possible to entertain the notion of the primary prevention of MS. For example, although it would take decades to learn the answer, if vitamin D deficiency in utero were important for disease pathogenesis, then pre-natal supplementation could be used to prevent the disease in at least some individuals. Similarly, if EBV was a necessary component of the causal chain leading to MS, a vaccine against this agent (if developed) might reduce substantially the incidence of MS.
At present, however, in the absence of proven primary causes, it is probably more appropriate to focus on the possibility of the secondary prevention of MS. In this context, the term 'secondary prevention' is meant to imply that the intervention (whatever it is), although not preventing the development of the disease, nevertheless, prevents the progression of the disease once it has begun. The current 'standard' disease-modifying therapies (DMTs) such as glatiramer acetate (GA) and interferon-beta (IFNB) have been clearly shown to reduce the short-term outcomes of relapse rate, disability scores and magnetic resonance imaging (MRI) evidence of disease. They also probably reduce the long-term outcomes of the development of secondary-progressive MS, or the need for assistance with ambulation. In addition, the use of these therapies early on in the course of the disease seems to be more effective than therapy offered later. Consequently, these agents, in some sense, can be said to provide some level of secondary prevention, especially when administered early in the disease course. To accomplish this form of secondary prevention, however, we would need to identify 'at-risk' patients very near the beginning of their disease. To do this would require screening of asymptomatic individuals. In the circumstances of a disease like MS, where the disease prevalence is low (~0.15% of the population), where our current treatments are, at best, only modestly effective, and where our best screening test (MRI) is very expensive, realistically there is no way, to make the screening of asymptomatic patients cost-effective. Naturally, it will always be possible to identify some 'at-risk' individuals at the clinically isolated syndrome (CIS) stage or even before the onset of symptoms at the radiographically isolated syndrome (RIS) stage of illness when an individual has been imaged for reasons unrelated to MS.
Even in these circumstances, however, because of the perceived inconvenience of injectable agents, there is likely to be some reluctance to begin a partially effective therapy in circumstances where the diagnosis and course of disease have yet to be established. Perhaps, as newer therapies with better efficacy and more convenient routes or schedules of administration become available, the idea of secondary prevention of MS may become a more realistic goal.
Therapeutic Targets and Opportunities
Several new approaches to disease management of MS patients are either now available or soon will be (Figure 3). These include oral agents that act in the periphery to trap immune cells in secondary lymphoid organs (fingolimod), intravenous agents that target specific cell-surface antigens on T or Bcells (rituximab, ofatumumab, ocralizumab, daclizumab, alemtuzumab), oral cytotoxic agents (cladribine), IV agents that block the influx of immune cells into the CNS across the blood-brain barrier (natalizumab), and oral agents that act within the CNS to dampen the inflammatory response (laquinimod, BG-12, fingolimod). Each of these agents (presumably) has a different mechanism of action and, in general, these new agents are highly effective at lowering the biological activity of MS as determined by outcomes such as relapse rate, clinical disability and MRI measures of disease. However, these new agents also have the potential for serious complications, which may limit their use as first-line therapies.
For example, it is now well established that the monoclonal antibody natalizumab (anti-[alpha]4 integrin) is associated with the occurrence of progressive multifocal leuko-encephalopathy (PML) in a small number of cases. The rate of this complication seems to increase with increasing exposure such that, after 2 years of continuous therapy, it may approach 0.2%. Nevertheless, of those patients who have developed PML, all 20 who have been assessed (thus far) have had antibody evidence of JCV virus (JCV) infection prior the start of natalizumab. This finding indicates that the risk of developing PML for a person who lacks antibody evidence of a prior JCV infection is markedly reduced (and possibly zero). Therefore, incorporation of this antibody testing into the therapeutic algorithm should make the use of natalizumab therapy as a first-line agent possible in some circumstances.
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Other new agents, presumably, also carry risk. For example, PML has occurred in the setting of the monoclonal antibody rituximab (anti-CD20) therapy although the extent to which this is due to concomitant medications is unclear. Similarly, intravenous cladribine (used for treatment of hairy cell leukaemia), similar to other cytotoxic agents, has been associated with the occurrence of infections and of secondary malignancies, but how this experience translates to the treatment of MS with the oral agent is not known. The monoclonal antibody alemtuzumab (anti-CD52) has remarkably good efficacy data, being significantly (>70%) more effective than three times weekly IFNB-1a on measures of sustained disability and relapse. However, the frequent occurrence of other autoimmune diseases (idiopathic thrombocytopenic purpura, Graves' disease) and occasional occurrence of malignancies raise some concerns about long-term safety. The sphyngosphine-1-phosphate (S1P) inhibitor fingolimod was recently approved by the US Food & Drug Administration. During the clinical trials of this agent the drug seemed, in general, well tolerated and very efficacious, although the occurrence of two deaths (disseminated herpes zoster, herpes encephalitis) raises some question about safety. Much of these potential toxicities for the new therapies in MS are, thus, unclear at present. Nevertheless, because of the apparently improved efficacy of many of these new agents compared to our current therapies, establishing the cost/benefit of these novel therapeutic approaches will become increasingly important.
Protection and Repair of the CNS
If one thinks broadly about MS therapies there are several different approaches that might be considered, each of which overlaps with the others to varying degrees. The first therapeutic approach involves the use of drugs, which limit the extent of damage, and which improve and speed the recovery from the acute inflammatory episodes or attacks of MS. The second broad category is the symptomatic therapies, which are used to ameliorate specific symptoms resulting from injury to the CNS, but which have little impact on the underlying disease. The third and currently most important approach, involves the use of DMTs, which are actually felt to alter the biology of the disease. These therapies might work, for example, by lowering the number and frequency of attacks or by slowing accumulation of axonal loss. The fourth therapeutic area (and, arguably, the one most urgently in need of development) is those therapies that protect the nervous system from irreversible damage and those that promote its repair.
One of the challenges in the development of this strategy, however, is to reach a consensus about how we define protection and repair. For example, neuroprotection might be considered as either the preservation of neural tissue and function or the prevention of tissue damage, which is independent of any direct impact on the ongoing insult. Similarly neural repair might be considered as either the direct repair of injured tissue in situ or the reversal of acquired disability by the promotion of tissue regeneration and replacement. Also, do we want to protect the neurons, the oligodendrocytes, the glia; do we want to stop the astrogliosis, maintain a normal metabolism, enhance (endogenous) restorative mechanisms, supply trophic support; or some mixture of all of these goals? Obviously, how we define our goals will determine how we should proceed in the development of these potential therapeutic strategies. In addition, the boundaries between disease-modifying, reparative, and protective strategies is somewhat blurred (Figure 4). Thus, agents like GA and IFNB are thought to have both neuroprotective properties, as well as disease-modifying properties although where you draw the line between the two is unclear.
Another factor that has slowed the development of clinically available agents in the class is that the complex interactions between the modulation of the immune response and the restorative mechanisms create challenges and make the impact of interventions hard to predict. Thus, for example, we know that there is a close correlation between inflammation and neurodegeneration although, at the same time, we know that inflammation also contributes in important ways to protection and repair. Moreover, whether the destructive or protective role of inflammation prevails likely depends on the stage and type of lesion. Nevertheless, several strategies (targeting many different components of the inflammatory cascade) are currently under active investigation. These strategies include the use of stem cells, sodium channel blockers and anti-epileptic drugs, glutamate antagonists, anti-Nogo antibodies, LINGO antagonists, neurotrophic growth factors, erythropoietin, cannabinoids, minocycline, fluoxetine and hormonal agents. Whether these approaches yield promising avenues for more definitive clinical trials will need to await the results of these preliminary studies.
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In the past several decades, the field of MS has been characterized by the marked and significant advances we have made in our understanding of this disease. Beginning in the early 1990s, we introduced the first unequivocally effective DMT for this condition. Now, 20 years later, we have numerous new and highly effective agents with novel mechanisms of action already approved and several others closely following. We have made considerable advancement in our understanding of the genetic and environmental factors involved in disease pathogenesis and we can now reasonably entertain notions about the possibility of primary and secondary disease prevention. Finally, we have made strides at identifying new therapeutic targets to develop the protective and reparative treatments that are so needed by our patients with fixed disabilities. As a result, we can now look forward with hope that the next couple of decades may bring about a cure or prevention for this illness.
Conflicts of Interest
No conflicts of interest were declared in relation to this article.
Received: 16 November 2010
Accepted: 17 November 2010
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Department of Neurology, University of California, San Francisco, CA, USA
Address for Correspondence
Douglas S Goodin
MS Center at the University of California
350 Parnassus Avenue
Tel: (415) 514-2464
Fax: (415) 514-2470
1. The MS Epidemic George Ebers 2. Pathogenesis of MS Douglas S Goodin 3. Secondary Prevention of MS Ernest Willoughby 4. Therapeutic Targets and Opportunities Ralph Gold 5. Neuroprotection Sten Fredrikson 6. Neural Repair Reinhard Hohlfeld
Table 1. Prevalence of antibodies to EBV in the sera of patients and controls Study EBV+ EBV+ MS Cases (%) Controls (%) Sumaya et al (1) (1980) 155/157 (98.7) 76/81 (93.8) ([double dagger]) Bray et al (2) (1983) 309/313 (98.7) 363/406 (89.4) ([double dagger]) Larsen et al (3) (1985) 93/93 (100) 78/93 (83.9) ([double dagger]) Sumaya et al (4) (1985) * 104/104 (100) 23/26 (88.5) Shirodaria et al (5) (1987) 26/26 (100) 24/26 (92.3) ([double dagger] [double dagger]) Munch et al (6) (1998) 137/138 (99.3) 124/138 (89.9) ([dagger]) Myhr et al (7) (1998) * 144/144 (100) 162/170 (95.3) Wagner et al (8) (2000) 107/107 (100) 153/163 (93.9) ([dagger]) Ascherio et al (9) (2001) 143/144 (99.3) 269/287 (93.7) ([dagger][dagger]) Sundstrom et al (10) (2004) 234/234 (100) 693/702 (98.7) Haahr et al (11) (2004) ([dagger]) 153/153 (100) 50/53 (94.3) Ponsonby et all (12) (2005) ([double 136/136 (100) 252/261 (96.6) dagger][double dagger]) Total 1741/1749 (99.5) 2267/2406 (94.2%) Study P value Sumaya et al (1) (1980) 0.05 ([double dagger]) Bray et al (2) (1983) 0.0001 ([double dagger]) Larsen et al (3) (1985) 0.0001 ([double dagger]) Sumaya et al (4) (1985) * 0.007 Shirodaria et al (5) (1987) -- ([double dagger] [double dagger]) Munch et al (6) (1998) 0.0004 ([dagger]) Myhr et al (7) (1998) * 0.008 Wagner et al (8) (2000) 0.01 ([dagger]) Ascherio et al (9) (2001) 0.008 ([dagger][dagger]) Sundstrom et al (10) (2004) ns Haahr et al (11) (2004) ([dagger]) 0.05 Ponsonby et al (12) (2005) ([double 0.05 dagger][double dagger]) Total P<[10.sup.-23] * Study measured antibodies against the Epstein-Barr nuclear antigens (EBNA), the viral capsid antigen (VCA), and the early antigens (EA) ([double dagger]) Study measured antibodies only against VCA ([dagger]) Study measured antibodies only against EBNA and EA ([dagger][dagger]) Study measured antibodies only against EBNA and VCA. One person was antibody-negative to each antigen but it is unclear from the text whether they were the same person. The review by Haahr et al. (2006) suggests they were not ([double dagger][double dagger]) Study measured antibodies only against EBNA and VCA
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