Management and Care – The Changing Landscape of Multiple Sclerosis
Management and Care – The Changing Landscape of Multiple Sclerosis
In early June 2008, the 18th meeting of the European Neurological Society (ENS) welcomed over 3,000 neurologists and physicians from all over the world to Nice, France. Among the multitude of symposia, oral sessions and scientific programmes on the latest in the progress made in neurodegenerative diseases were presentations by leaders in the field of multiple sclerosis (MS). Noted key points discussed included new developments in research, and the concept that drug efficacy varies depending on the treatment stage: beginning treatment earlier in the course of the disease may be more beneficial. With strong evidence presented in support of initiating treatment earlier, neurologists have been offered the opportunity to protect patients against disease progression. By implementing early intervention it may be possible to improve the prognosis of this debilitating neurodegenerative disease.
Latest Developments in Multiple Sclerosis
In a symposium discussing autoimmune disorders of the nervous system, Professor Giancarlo Comi (Italy) addressed important new issues arising from recent MS research on disease prevalence, causal factors, disease evolution and MS therapy. Recent epidemiological studies have suggested an increase in the prevalence of MS in a number of European nations – Spain,1 France,2 Greece,3 Germany4 and Italy5,6 – particularly in the last five years. There is a trend for a nearly exclusive increase of the disease in women compared with men, says Professor Comi, attributed to lifestyle changes in women or improvements in hygiene and control of early childhood infections.7
The role of genetics and environment as causal factors of MS continues to be debated. The genome-wide approach has identified interleukin-7 receptor alpha (IL-7 rα) and interleukin-2 receptor alpha (IL-2 rα) alleles as risk factors for developing MS.8 There is also evidence of an association between developing MS and low exposure to sunlight and vitamin D,9,10 and much research is being conducted on the relationship between MS and Epstein-Barr virus (EBV) and, more recently, varicella zoster virus (VZV). EBV RNA11 and EBV antigens12 have been detected in a high proportion of brain tissue samples from MS patients, indicative of a role for EBV in MS immunopathology. There is also evidence of a very strong correlation between the viral load of VZV in cerebrospinal fluid (CSF) and blood samples and the appearance of an MS attack.13
Other research has focused on the mechanisms concerning the irreversible damage to the central nervous system (CNS) during disease progression. Not only can axonal damage and inflammation in early phases of the disease produce acute lesions,14 but it appears that initial damage can also increase damage in positive feedback loops through the overexpression of glutamate receptors,15 voltage-gated sodium channel (Nav)1.616 and calcium channels.17 The extent of focal atrophy around a lesion has been associated with brain atrophy and loss of volume.18 Other factors such as the duration of the inflammation, the size of the lesion and the location of the lesion have been linked to predicting the degree of persistent damage.19 Furthermore, lesion damage has been found to evolve continuously in all phases of the disease in as little as a 12-month follow-up.20 With such detrimental effects on the brains of MS patients, Professor Comi concluded this presentation with a call to improve treatment by increasing accessibility to new treatments and improving the ability to better apply existing therapies.
Optimising Therapy Through Earlier Treatment and Drug Selection in Different Phases of the Disease
A theme common to many of the MS presentations at the ENS was to initiate MS therapy at an earlier stage, not just when a clinically definitive diagnosis has been made. Many clinical trials have shown a dissociation between disease progression and inflammation, supporting the hypothesis that MS is primarily an inflammatory disorder and that inflammatory axonal injury underlies the formation of new lesions and axonal degeneration.21 By protecting against inflammation, it may then be possible to slow progression in MS, and in turn reduce the degree of tissue injury and degeneration of the nervous system. According to Professor Alistair Compston (UK) in his talk about the rationale for early treatment, offering immunological therapies early in the course of the disease – before the cascade of events leading to axonal degeneration is irreversibly established – may be most beneficial in preventing sustained disability and disease progression. Indeed, early treatment has been shown to limit axonal damage and protect against irreversible nervous damage and ensuing disability.22
Treatment After a Clinically Isolated Syndrome
Patients who have experienced a clinically isolated syndrome (CIS) are at high risk of developing clinically definite MS (CDMS). Epidemiological studies and clinical trials have shown that approximately 85% of CIS patients are diagnosed with MS within two years.23 It is at this early stage of the disease that treatment should be initiated, elaborated Professor Comi, with evidence from magnetic resonance imaging (MRI) studies showing brain atrophy and decreased brain volume in the very early stages of MS.24,25
All three clinical trials testing the use of interferon beta formulations in CIS patients – the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis For Initial Treatment (BENEFIT) study, the Controlled High-risk Avonex Multiple Sclerosis Prevention study (CHAMPS) study and the Early Treatment Of MS (ETOMS) study – have shown obvious advantages with early therapy, including a reduced rate of conversion to CDMS (see Table 1), prolonged time to a second attack and reduced brain MRI activity.26–28 Furthermore, extensions of these studies with at least three years of follow-up confirm that CIS patients who received early therapy continued to benefit significantly in terms of preventing a second attack.29,30 The BENEFIT trial revealed that even as little as three years of early treatment can significantly reduce the risk (by 40%) of confirmed expanded disability status scale (EDSS) progression compared with patients in whom treatment with interferon beta-1b (Betaferon, Bayer Schering Pharma) was delayed,.29 Furthermore, the prospectively planned follow-up study showed that after three years this early treatment conferred an advantage in cognitive function over patients who received delayed treatment (p=0.011), as scored by the Paced Auditory Serial Addition Test (PASAT), which measures intellectual function and cognition. A retrospective follow-up of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]) after five years found that early treatment with interferon beta-1a could significantly lower the cumulative probability of developing CDMS compared with delayed treatment.30 The results of the Study to Evaluate the Efficacy of Early Glatiramer Acetate in Delaying the Conversion to CDMS of Subjects Presenting With a Clinically Isolated Syndrome (PreCISe), presented in a separate session by Professors Comi and Massimo Filippi on behalf of the PreCISe study group, showed that compared with placebo, glatiramer acetate (Copaxone, Teva Pharmaceutical) reduced the risk of developing CDMS by 45%.31 Interferon beta-1a has also shown clinical and cognitive benefits for patients with early relapsing–remitting MS (RRMS) in the Cognition Impairment in Multiple Sclerosis (COGIMUS) study at two and three years, respectively.32 Furthermore, evidence from a Cochrane meta-analysis supports the idea of early treatment; interferon beta therapy applied early – at the time of the first episode suggestive of MS – showed significant ability in preventing the conversion from CIS to CDMS in all studies analysed, with benefits persisting through two years of treatment.33
So, should all patients with a CIS be treated immediately following the first neurological episode? Not necessarily, says Professor Comi, as it depends largely on the patient’s clinical presentation. Rather, the following prognostic factors – as determined from ETOMS, CHAMPS, BENEFIT and PreCISe – can help to predict which CIS patients are at increased risk of early conversion to CDMS:
• ≥9 T2 lesions;
• >1 gadolinium-enhancing (Gd+) lesion;
• multifocal presentation;
• higher clinically and MRI-measured disease severity at onset, with a longer pre-clinical phase and/or more aggressive disease course; and
• ongoing brain activity in the MRI indicative of inflammation.
According to Professor Comi’s personal recommendations for patients with a first attack and brain MRI suggestive of MS, early treatment should be initiated for those exhibiting one or more negative prognostic factor, whereas those lacking negative prognostic factors should be carefully monitored and given repeat MRIs, with therapy being initiated on evidence of temporal dissemination. Patients who have suffered an attack but retain otherwise normal brain MRI or an MRI scan atypical of MS are at low risk of conversion to CDMS or disability, and should undergo annual MRI scans.34 However, Professor Comi does stress that he disagrees with the generalisation that CIS patients should not be treated with immunomodulatory drugs because of the chance that a subgroup may have a benign disease course. The reason for this is that the purpose of treating CIS patients is to anticipate and prevent potential damage; this is significant as 85–94% of untreated CIS patients have new attacks or lesion formations within two years of the original clinical event.23,26,27 Unfortunately, there are still some European countries that do not reimburse treatment for CIS patients, and many of these affected patients are denied access to highly effective therapies.
Treatment of Clinically Definite Multiple Sclerosis
The past 15 years have seen an expansion in the therapeutic armamentarium against MS from just interferon beta-1b alone to a small group of immunosuppressants and immunomodulatory drugs, and although this continually growing collection provides treatment options for patients with MS, it has also greatly complicated the selection of any specific drug for treatment at a given disease stage. However, stresses Professor Christian Confavreux (France), initiating treatment as soon as possible is essential – and the earlier, the better.
Although it may prove useful to follow official guidelines such as those provided by the European Federation of Neurological Societies,35 the patient’s disease phase must also be assessed as the initial step in selecting a treatment, accounting primarily for the clinical activity, with MRI activity as secondary criterion. It is known that the currently available treatments of interferon beta and glatiramer acetate can improve patient outcome by reducing the rates of relapse frequency and MRI activity. However, long-term efficacy in delaying disability remains uncertain. Drawing on the data from the head-to-head comparisons Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND),36 Rebif vs Glatiramer Acetate in Relapsing MS Disease (REGARD)37 and Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME),38 Professor Confavreux concluded that the similarities in efficacy and long-term safety exhibited by the interferon betas and glatiramer acetate qualifies them as prime candidates in the first-line treatment of active forms of RRMS.
The efficacy of natalizumab is even greater, with a 68% reduction in relapse rate and 83% reduction of new or enlarging T2 lesions,39 but it is indicated as a second-line therapy for RRMS patients who have failed treatment with interferon beta or glatiramer acetate, or for treatment-naïve patients with rapidly evolving severe MS.40 However, the association with serious and fatal infection such as progressive multifocal leukoencephalopathy (PML) and possible neoplastic complications requires close monitoring upon prescribing natalizumab. Immunosuppressive third-line therapies such as mitoxantrone or cyclophosphamide are recommended for severe aggressive MS or disease breakthrough.
Deciding on a treatment is rarely as simple and clear-cut as following recommendations, however; MS is a long-term, chronic and very heterogeneous disease, with disease activation presenting differently between patients. Patient characteristics, such as age at onset and apparent disease severity, and clinical factors, such as drug efficacy, safety and tolerability, need to be considered together in assessing treatment options; ultimately, any chosen therapy should have an extremely important effect on the disease pattern and future prognosis of MS.
Induction Therapy in Multiple Sclerosis
There are cases where patients continue to experience frequent relapses and disease progression despite disease-modifying therapy. Combination therapy is typically designated for treatment failures, and the few studies available are limited in sample size, efficacy data or long-term safety data; a large-scale randomised, double-blind, placebo-controlled study sponsored by the National Institutes of Health (NIH) is currently enrolling to determine the effects of glatiramer acetate/interferon beta-1a (Avonex, Biogen Idec) combination therapy. Alternatively, induction therapy using immunosuppressants followed by immunomodulatory agents has been proposed to offer benefits to clinically active relapsing MS patients. Presenting on this topic, Dr Robert Lisak (US) debated the rationale behind induction therapy and for which patients it would be appropriate.
Small studies have shown that patients who received induction therapy had significantly lower MRI activity compared with those who did not,41,42 with the potential to reduce EDSS progression by 65%, sustained by a decrease of 61.5% in the annualised relapse rate and no significant adverse effects.43 Intense immunosuppression is often used as rescue or disease-stabilising therapy for actively relapsing MS patients with suboptimal response to immunomodulatory agents, but very little data are available regarding the use of intense immunosuppression as initial MS therapy. Patients who received monthly cyclophosphamide intravenously for six months before initiating disease-modifying therapy with interferons or glatiramer acetate showed significant reductions in mean EDSS, relapse rate and Gd+ lesions one year after immunosuppression was initiated, with good tolerance and no adverse events.44 Data from a one-year follow-up are expected. However, there is a caveat, warns Dr Lisak, because even short-term use of immunosuppressants may pose long-term risks, including oncogenesis,45 infertility and congestive heart failure, depending on the choice of antisuppressant.
Similar to the problem of identifying which patients qualify for early MS treatment, those with suboptimal responses also need to be identified for treatment, be it by switching between immunomodulatory agents or switching from immunomodulation to immunosuppression; so far, clinical criteria, MRI criteria and biomarkers have been the most help in selecting patients for induction therapy.46 Dr Lisak concluded that a composite using criteria indicative of highly active disease that clearly warrants induction with immunosuppressive therapy is necessary, and presented provisional recommendations put together by himself and his colleague Dr Omar Khan (US). These recommendations state that observing any three or more of the following criteria in a patient should compel the clinician to initiate immunosuppressive therapy:
• >2 relapses in the past 12 months requiring corticosteroid treatment;
• recurrent brain stem or spinal cord relapses;
• EDSS >3.0 within three to six months following the last relapse;
• ≥3 Gd+ lesions that are >3mm in size on a single scan;
• ≥3 new T2 lesions in the past 12 months; and
• any evidence of atrophy.
Diagnosing Benign Multiple Sclerosis
Designating a case of MS as benign confers a favourable course of MS in which such patients experience mild or no disability after the initial clinical onset. However, an increasing amount of emerging data has instigated great debate as to how benign MS can be diagnosed with absolute certainty, and whether or not such a condition actually exists. The problem with this label is that patients with benign MS are under the impression that their symptoms will not worsen, and as a result will be unlikely to seek out the same level of medical attention as patients who have been diagnosed with CDMS. Moreover, for benign patients who become non-benign over time, this poses a great loss in terms of health and protection against disability that could otherwise have been prolonged or delayed with early treatment.
Patients with benign MS experience fewer lesions than patients with early RRMS.47 However, lesion load has been found to be higher in benign patients than in those with early RRMS48 and those with non-disabling RRMS.49 Furthermore, no significant difference could be found in normal brain volume and, by association, neuroaxonal brain viability between benign and early RRMS patients.49 The researchers of these studies argue that patients with benign MS experience a relative sparing of cortical damage, which then bestows upon them favourable clinical disease courses, but the presence of lesions in benign patients and the fact that these patients have an increase in lesion loads cannot be ignored. Cognitive dysfunction in benign MS is also associated with significantly more severe damage to the corpus callosum, with significantly higher lesion load compared with benign patients without cognitive impairment.50
Updates on Efficacy in Recommended Multiple Sclerosis Therapies
Prior to prescribing any sort of treatment to a patient, drug efficacy, safety and tolerability are all factors that must be carefully considered. This section of the report will focus on the advances and recent research that have been made available in these areas, as discussed at the ENS, as well as a special focus on the up-and-coming drugs in development.
Conclusive comparisons between the various therapies available for MS have been rather difficult because to date there has been no single study that has directly compared them all together in terms of efficacy and safety in a head-to-head manner. However, direct comparisons have shown that interferon beta-1b administered every other day has greater efficacy than a once-weekly dose of interferon beta-1a, with significant differences in the number of patients who remained relapse-free or experienced a delay to CDMS.51 High-dose interferon beta-1a given three times a week has a greater advantage over weekly dosage in terms of the percentage of patients who are relapse- and T2-lesion-free and the number of active lesions.52 Other comparisons have shown a similar efficacy between interferon beta-1b and glatiramer acetate: the BECOME study showed that treatment with interferon beta-1b led to fewer permanent black holes developing from enhancing lesions than glatiramer acetate, although no significant difference was observed in terms of ability to reduce MS activity and the mean number of combined active lesions.38 Similarly, the REGARD study found no significant difference between the treatments in the number and change in volume of active lesions or the time to the first relapse.37
Data from the BEYOND study presented at the ENS comparing the efficacy, safety and tolerability of interferon beta-1b 250mcg, interferon beta-1b 500mcg and glatiramer acetate 20mg daily in RRMS patients over a period of 24 months showed no significant differences between any of the treatment arms in relapse risk, the number or volume of T1 Gd+ lesions or T1 black holes or brain volume.53 A similarly high proportion of patients in each arm were free from disease activity.54 However, T2 lesion volume change and cumulative volume were lower in groups using interferon beta-1b compared with glatiramer acetate, suggesting that there may be different effects on the overall disease burden depending on treatment.53
Natalizumab has been recommended as second-line therapy for patients who continue to progress while receiving the first-line disease-modifying therapies. Patients with relapsing MS in the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) or Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) trials were monitored for disease activity, and researchers found that natalizumab, whether as a monotherapy or in combination with interferon beta-1a, yielded a significantly higher proportion of disease-activity-free patients compared with placebo over two years based on both clinical and MRI data measures.55 Although approved for use as in RRMS, natalizumab is associated with fatigue and allergic reactions, as well as potentially fatal adverse events such as anaphylactic shock, progressive multifocal leukoencephalopathy, infections and clinically significant liver damage. These safety issues and the lack of information regarding long-term use has led to reservations over using the drug outside of clinical research.
Although mitoxantrone has been suggested for aggressive forms of MS, it has also been associated with a risk of oncogenesis. The prevalence of acute myeloid leukaemia (AML) is significantly increased in MS patients who receive mitoxantrone treatment, and appears to occur in younger patients. No apparent correlation was found between previous MS treatments and cumulative mitoxantrone dose with the risk of developing AML.45
The Effect of Tolerability on Adherence and Quality of Life
For a patient to maintain adherence and reap the complete benefits of their disease-modifying therapy, their treatment must be tolerable. MS patients often experience headaches, and headaches related to treatment with interferon beta that were independent of flu-like symptoms have recently been found to be more frequent than previously reported. Although not a contraindication to therapy with interferon beta, physicians are suggested to monitor patients for headaches and to adjust therapy if the frequency increases.56
The BENEFIT studies have demonstrated good tolerability to interferon beta-1b in patients with CIS, with a high adherence rate after three years (>73.3%) and a large proportion (>89.3%) of patients choosing to continue therapy in the follow-up study.57 A comparison of tolerability between interferon beta-1b 250mcg and glatiramer acetate in the BEYOND study showed that patients treated with interferon were more likely to experience flu-like symptoms, although the incidence of this adverse effect decreased with time. In contrast, injection-site reactions were commonly reported by patients receiving glatiramer acetate.58
The new formulation of interferon beta-1a (Rebif new formulation [RNF]), produced without foetal bovine serum and human serum albumin, has shown reduced immunogenicity compared with the current formulation in patients with relapsing MS.59,60 The incidence of serious adverse events was similar to that seen in data from the Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) and REGARD studies, although patients were more likely to have flu-like symptoms with RNF. However, RNF had fewer patient-reported injection-site reactions and feelings of depression. The overall safety and tolerability profile of RNF relative to the current formulation of interferon beta-1a is proposed to influence treatment adherence.60
As with any chronic life-long disease, adherence to drug therapy is a major determinant of the success of the disease-modifying therapy, and this concept is no different in MS. Adherence and relapse rate are closely associated: one study has shown that patients who refused to adhere to treatment for over 90 days face a significantly increased risk of severe MS relapse compared with patients with shorter or no gaps in drugmodifying treatment.61
Studies have also shown that adherence varies depending on the drug in question. Adherence in the BEYOND trial was high in all groups, but a slightly higher number of patients treated with interferon beta-1b 250mcg (82%) saw the study through to completion compared with those treated with high-dose interferon beta-1b 500mcg (73%) or glatiramer acetate (78%).36,58,br>
Certainly, the results from clinical trials with respect to adherence are an area to be considered by physicians when prescribing medications for patients, and the subject of adherence is an important one, as drug compliance is closely linked to the patient’s quality of life – the efficacy of a drug is irrelevant if patients exhibit poor compliance, for example, due to bad adverse effects or low tolerance, which ultimately leads to disease progression and poor patient outcome. However, quality of life is not solely dependent on drug use and compliance: one study assessed a cohort of Polish subjects with MS to determine the most important factors affecting quality of life and found depression, level of disability, fatigue and marital status to be the strongest predictors of quality of life.62 In the symposium proceedings, Dr Kieseier showed that disability – not just physical disability but cognition as well – impairs quality of life in the patient; a higher EDSS score can be argued to present with a lower quality of life.63 Many studies have shown that traditional disease-modifying treatment can have a positive effect on more than just disability and relapse rate, and can indeed improve patient quality of life compared with the baseline quality of life assessment over time as well.57,63–67
Drug Deliverance – Bringing New Developments to the Table
Given the various presentations on new drugs for treating MS at the ENS, many new therapies are anticipated for the future, some of which may be available as early as next year. Among these new developments is the recombinant T-cell receptor ligand RTL1000, which, according to the phase I safety study update, has so far completed two of five planned cohorts assessing safety in escalating intravenous doses, and enrolment for this study is continuing.68 The first human-dose study of PI-2301, a second-generation peptide co-polymer with a mechanism of action similar to that of glatiramer acetate, found the investigational drug to be generally well tolerated among the 56 healthy male volunteers enrolled; further data collection and analyses are under way and are expected to be available by the end of 2008.69
A retrospective double-blind analysis of the MRI data collected from the first year of the two-year phase II clinical trial of MN-166 (ibudilast, MediciNova Inc.) in relapsing MS patients has suggested the drug’s ability to protect neurons from persistent damage following the formation of acute lesions, preventing conversion to persistent black holes; the presenters noted that further studies regarding black hole formation and disease progression in patients with relapsing or progressive MS are warranted.70 The CD52-specific monoclonal antibody alemtuzumab (Bayer/Genzyme), which targets lymphocytes, has been compared with high-dose interferon beta-1a (Rebif) in the phase II CAMMS223 study treating patients with RRMS. The study showed that at the three-year follow-up the antibody was more effective at suppressing relapses and disability in patients than the interferon, with patients in the former group experiencing a 73% reduction in risk of relapse (p<0.0001) and a 70% reduction in risk of sustained accumulation of disability (p<0.0001).71 Subgroup analyses found the treatment effects of alemtuzumab to be consistent across sex, age, race and country, indicating that these findings were independent of patient baseline demographics.
Some of these drugs being developed and studied are oral compounds – a class of MS therapies that is amassing increasing interest from researchers and physicians alike. One example of these new oral drugs is laquinimod (Teva Pharmaceutical); MRI data from an extension of the double-blind, randomised, placebo-controlled phase IIb study have shown that patients benefited in terms of reductions in the mean number of T1 lesions when switching to laquinimod from placebo, although no significant difference in annualised relapse rate could be discerned.72
Summary
The revelations in MS at the 18th meeting of the ENS have shown a great deal of evidence arguing in support of early treatment, endeavouring to protect patients against disease progression and further deterioration of the CNS. Recent research suggests an increase in the prevalence of the disease, which makes it all the more important to establish an optimal therapy. Many recommendations and even more options exist as to selecting a drug for a patient, and many factors must be considered before choosing to start a patient on any given treatment. Experts in the field have placed heavy emphasis on the benefits of early treatment, when patients can experience greater drug efficacy than at any other phase of the disease course. Many recent drug trials have demonstrated a move towards greater safety and tolerability, while maintaining a high level of efficacy. Therapies are only as effective as the adherence, and programmes providing personal assistance and monitoring have proved successful in upholding a high level of adherence among patients. Many new drugs are in development as well; of these, there is great anticipation for the oral therapies being tested, where it is hoped that the advantage of convenience over the current parenteral options will also help to maintain good adherence levels. ■
