This issue of the Journal of Internal Medicine features two comprehensive reviews [1, 2] on the dramatic evolution, current status and future challenges in the field of multiple sclerosis (MS) therapy. Both reviews are very timely and encouraging in terms of the ultimate goal of curative treatments. Here, I will also discuss selected personal views on these issues.
From a clinical perspective, and having seen patients with MS for more than 30 years, the advances in both drugs that affect the natural course of the disease (see Fig. 1) and MS care have been beyond all expectations. Decades ago, individuals diagnosed with MS were not often offered scheduled medical follow-up and were merely asked to ‘come back if feeling worse'. This had negative consequences for the general care of the patient even in the absence of disease-modifying drugs (DMDs). There are general symptoms and signs common to MS such as pain, depression, urogenital problems, spasticity, fatigue and cognitive impairment. The perception and treatment of these complications require an experienced physician and cannot be achieved by the general practitioner who, in view of the prevalence of the disease (around 2/1000 individuals in Scandinavian countries, which are particularly high-risk areas for the disease), may see on average only a very few persons with MS.
With the introduction of DMDs, it became necessary to include a scheduled follow-up of patients, which consequently resulted in better symptomatic treatments. In addition, it stimulated the development of team-based care, where specialized MS nurses have a key role. Furthermore, before the introduction of DMDs, there was a tendency amongst neurologist to withhold the diagnosis, telling patients indirectly about inflammation in the central nervous system. Lack of awareness of a specific diagnosis complicated life of the patient with respect to contacts with other healthcare providers (who were not aware of MS symptoms), and with respect to insurance. It should be noted that the complications of MS have a striking effect on the affected person's global health, as reflected in the fact that 62% of individuals with MS received partial or full pension during 2005, compared with 14% amongst population-based controls, selected randomly in the population, but matched for sex, age and area of living, during the same year . The introduction of DMDs has also increased pressure on physicians to make an early MS diagnosis, as there is increasing evidence to suggest that treatment should be introduced as early as possible during the disease course. Criteria for MS now allow diagnosis after a first neuroinflammatory episode, with additional magnetic resonance imaging (MRI) data to support the diagnosis . Many physicians and neurologists, especially in Scandinavia, strongly advocate the use of (CSF) markers as part of the laboratory tests to support diagnosis . In particular, the presence of oligoclonal IgG bands in the CSF gives strong support for the diagnosis.
As a consequence, individuals with MS are now diagnosed early, which is not only important for treatment with DMDs, but also for their care in general.
What has led to the current development of new drugs for a disease for which the neurologist previously only had diagnostic options? MS is often presented as an enigmatic disorder. However, through numerous studies in experimental models and translational research in humans, a considerable amount is known about the cornerstones of the pathogenesis, which in turn has provided suitable targets for immune intervention (see Fig. 2 in review by Piehl ). It has been debated whether MS is primarily a neurodegenerative disease with secondary recruitment of an inflammatory response [6, 7], or vice versa. As discussed in both reviews [1, 2], there is strong evidence to suggest that, at least during the relapsing–remitting stage of MS (RRMS), the disease is driven by a systemic immune response, probably autoimmune, targeted against central nervous system (CNS) components. The evidence for this comes from the following observations: (i) several rodent experimental models of MS induced by provoking an autoimmune response against the CNS strongly mimic the disease course and histopathology of MS , (ii) selective inflammatory attack on the CNS – that is, only the specific T- and B-cell receptors of the immune system would be able to discriminate so precisely between targets, (iii) a genetic component of MS, in particular the HLA class II genes, where the expressed molecules present peptide antigens to CD4+ T cells, and nearly, all 110 non-HLA MS risk single-nucleotide polymorphisms are located on immune-related genes [9, 10]; and finally, (iv) treatments targeting the systemic immune compartment, including lymphocyte trafficking, can dramatically alter the clinical course of MS (for further discussion see [1, 2]).
Thus, all current treatments and those that are about to enter the market act on systemic immunity [1, 2]. Interferon-β preparations may also have a similar mechanism of action, although initial testing of these agents was based on the notion that MS was caused by a virus. Success in the treatment of MS has not decreased activity in the area; on the contrary, it has become clear to the pharmaceutical industry that MS drugs are lucrative (these drugs are expensive), and thus, efforts in this area have increased. Knowing that the natural course of MS can be altered has also stimulated academic research, leading to further targets for more effective treatments. It is interesting to note that there were 50–200 attendants at the annual meetings of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) during the 1980s, compared with 8000 participants at the recent ECTRIMS meeting in Copenhagen in 2013.
The disadvantages of the current therapeutic arsenal are discussed in detail in the two reviews [1, 2]. Briefly, most MS treatments, especially those that have been available for many years, are only partially effective in reducing annualized relapse rates (i.e. by around 30–40%). On the other hand, they have now been used for close to 20 years with no major long-term safety concerns, despite the disturbing flu-like side effects upon injections and skin reactions with glatiramer acetate. Current second-line therapies are much more effective, but interfere more broadly with the immune system, posing potential long-term risks. For example, by targeting the VLA4, natalizumab blocks entry of inflammatory cells into the CNS, which is essential for elimination of JC virus, the opportunistic pathogen that causes progressive multifocal encephalopathy (PML). Indeed, the first postmarketing case of PML was diagnosed in Stockholm . Now more than 300 cases have been reported worldwide. However, postmarketing surveillance and biobanking may help to develop risk stratification. In essence, there seems to be a ‘trade off’ between efficacy and long-term risk of serious adverse events.
Clinical trials in MS are typically conducted over 2 years, whereas patients have MS disease over several decades. Thus, the only way to obtain long-term information is through observational postmarketing studies, because it is clearly unethical to carry out trials over decades. In particular, it will be important to determine whether the more effective MS drugs prolong the period before (or even eliminate) progression to secondary progressive disease (SPMS) in a relevant way. Intuitively, this would be the case if the drugs dramatically reduce the T- and B-cell-mediated inflammation in the CNS for very long periods, but the issue remains to be proven. This is important with regard to both health economics and the expectations of individual patients in terms of their life plans. Such surveillance systems have been established , and the biobanking of material, DNA and plasma may be utilized to develop methods to manage adverse events. For example, in the case of natalizumab treatment, carriage of JC virus can be detected serologically so that seronegative individuals can be treated without risk of PML, and those at high risk can be referred to other options .
A general conclusion is that there is still an unmet need for more effective drugs and drugs more selective for the MS unique pathogenesis [1, 2]. For this purpose, a better understanding is needed of the factors that cause inflammation in the CNS and in individuals with MS, but not in those getting MS. Such knowledge may pave the way for immunospecific/tolerogenic treatments such as in experimental models of MS, in which the major histocompatibility complex (MHC)-restricted autoimmune response is precisely defined with regard to auto-antigenic peptides, MHC molecules and auto-aggressive T cells. The immunospecific/tolerogenic treatment should be possible in MS, leaving the rest of the immune system intact. A way forward in human disease is to better define the risk genes, their functions, the lifestyle/environmental risk factors and the gene–lifestyle/environment interactions. For example, both active and passive smoking increase the risk of MS [14, 15], and smoking interacts strongly with MS HLA risk genes , and thus, the hypothesis that smoking increase the risk of MS through interaction with HLA risk genes can be studied. Irritation in the airways could lead to a proinflammatory environment, with post-translational modification of peptides, which may overcome immune tolerance leading to activation of CNS-specific auto-aggressive T cells.
Another consideration is that MS probably starts many years before it is clinically apparent, but ideally, therapy should be initiated at the start of the disease process. There is circumstantial evidence to suggest the existence of a form of ‘subclinical debut’ many years before a clear diagnosis has been made. At diagnosis, MRI scans in many patients display lesions implying previous inflammatory events in parts of the CNS with no recognizable deficits. Individuals who develop MS frequently seek help frequently for at least 5 years before clinical onset . Reduced fertility, affecting both men and women, is observed at least 5 years before clinical onset . Furthermore, many lifestyle/environmental factors that increase the risk of MS, such as obesity , night shift work  and infectious mononucleosis , may do so during adolescence or early adulthood many years before the onset of clinical disease. However, at present, it is not possible to identify systematically individuals with ‘preclinical MS’.
Use of the more recently introduced semiselective MS drugs with highly defined targets could be considered as a form of experimental ‘manipulation’ in humans. As pointed out [1, 2], the aim of this should be to learn more about MS pathogenesis, including the development of biomarkers for assessing therapeutic efficacy, leading to the potential future use in proof of concept Phase I and II clinical trials. A similar issue relates to prognostic markers. The instruments to predict future disease severity are inadequate at present. It would be of great value to be able to suggest a more risky treatment in cases with a poor prognosis based on a prognostic biomarker. Currently, the armamentarium for this is largely restricted to quite insensitive clinical measures or MRI, a technique where changes in some instances are not closely correlated with ‘biological’ therapeutic efficacy. CSF levels of CXCL13  and neurofilament light , which reflect inflammation and axonal damage, respectively, are promising MS biomarker candidates. In the near future, I expect that a broad spectrum of CSF biomarkers will be validated. However, the availability of reliable blood markers will still be lacking. Hopefully, the explosion in all types of ‘omics’ techniques will provide such markers in the coming years.
Finally, the issue of progressive MS represents a great challenge [1, 2]. It remains unclear for how long or how effectively the new MS drugs may delay the beginning of the SPMS stage of disease. It is possible that inflammatory events in the CNS, occurring before therapy is initiated decades later, may manifest as a form of CNS-compartmentalized, innate, destructive immune activation in the areas of incomplete structural recovery. Histopathological observations on autopsy or biopsy have mainly supported a hypothesis of microglial oxidative damage during late-phase disease . On the other hand, recent data have also demonstrated an altered systemic immune response involving follicular T helper, Th17 and activated B cells during progression . In any case, the mechanisms driving progressive disease are highly likely to be different from those responsible for RRMS. This is highlighted by the lack of effect of current MS drugs during progression, as described in the reviews. Thus, greater understanding of these mechanisms is needed to provide efficient therapy for this frustrating aspect of MS.