Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet?

Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing–remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS.     

Cost-Effectiveness of Disease-Modifying Therapies in Multiple Sclerosis

Multiple sclerosis (MS) is a leading cause of disability among young adults and has a significant economic impact on society. Although MS is not currently a curable disease, costly treatments known as disease-modifying therapies (DMTs) are available to reduce the disease impact in certain types of MS. In the current economic downturn, cost-effectiveness analysis (CEA) of therapies in MS has become an important part of the decision-making process in order to use resources efficiently in the face of the rapidly escalating costs of MS. While some studies have reported costs of DMTs at the level of cost-effectiveness thresholds, some have estimated their costs beyond the tolerance level of health care systems. On the basis of the current literature and given the difficulties in accurately assessing cost-effectiveness in diseases like MS, it is challenging to determine whether DMTs are cost-effective. Further population-based studies are required regarding the cost-effectiveness of therapies in MS.     

Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics

The remarkable global development of disease-modifying therapies(DMTs) specific for multiple sclerosis(MS) has signifi cantly reduced the frequency of relapse,slowed the progression of disability,and improved the quality of life in patients with MS. With increasing numbers of approved DMTs,neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome,and in many cases,no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defi ned by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical signifi cance,thus further increasing the diffi culty of completing randomized controlled trials(RCTs) for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types,and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently,data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the Mc Donald MS diagnostic criteria carefully excluded patients with neuromyelitis optica(NMO) and NMO spectrum disorder,and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries.     

Immunogenicity and safety of mRNA COVID-19 vaccines in people with multiple sclerosis treated with different disease-modifying therapies

The potential impact of disease-modifying therapies (DMTs) for multiple sclerosis (MS) on COVID-19 vaccination is poorly understood. According to recent observations, the humoral immune response could be impaired in patients treated with ocrelizumab or fingolimod. Our study evaluated the immunogenicity and safety of mRNA COVID-19 vaccines in a convenience sample of 140 MS patients treated with different DMTs, undergoing vaccination between April and June 2021. Humoral immune response was tested 1 month after the second dose, using a chemiluminescent microparticle immunoassay to detect IgG against SARS-CoV-2 nucleoprotein. We explored the potential correlation between the IgG titer and DMTs. All patients in treatment with first-line DMTs, natalizumab, cladribine, and alemtuzumab, developed a measurable humoral response. In patients treated with ocrelizumab and fingolimod, the IgG level was significantly lower, but only some patients (22.2% for fingolimod and 66% for ocrelizumab) failed to develop a measurable humoral response. In the ocrelizumab group, the IgG level was positively correlated with the time from last infusion. No SARS-CoV-2 infections were reported after vaccination. The most reported side effects were pain at the injection site (57.1%) and fatigue (37.9%). No patient experienced severe side effects requiring hospitalization. Our study confirms that COVID-19 vaccination is safe and well-tolerated in MS patients and should be recommended to all patients regardless of their current DMTs. Since fingolimod and ocrelizumab could reduce the humoral immune response, in patients treated with these drugs, detecting SARS-CoV-2 antibodies could be helpful to monitor the immune response after vaccination.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01165-9.     

L’IRM est-elle utile dans le suivi des patients atteints de sclérose en plaques ? Oui

The place of magnetic resonance imaging (MRI) in the monitoring of patients with multiple sclerosis (MS) is not codified except during the diagnostic phase. Several studies in the literature have shown that lesion load measured on an MRI done at the beginning of the disease or its increase during the first years had a predictive value, although moderate, on the occurrence of long-term disability as measured by the EDSS. Early worsening of brain atrophy during the early stages of the disease is predictive of worsening cognitive impairment in the following years. Perform an MRI is not required when setting up a first-line disease-modifying therapy (DMT) such as an immunomodulatory treatment but it is useful because it can be used as a reference scan in case of treatment failure. The indications of second-line DMTs, whether prescribed in naive patients with an active disease or after failure of a first-line DMT, are based on combined criteria incorporating MRI data acquired in the previous 3 months compared with a recent MRI. Thus the practical criteria for failure of first-line DMTs are partly based on MRI. During interferon therapy, identification of disease activity on an MRI conducted 1 year after the start of the treatment can predict treatment failure in combination with clinical criteria, such as relapses occurring during the first year. Finally, MRI is essential to the safety monitoring of patients on natalizumab to detect progressive multifocal leukoencephalopathies (PML). In patients at high risk for PML, tested positive for JC virus antibodies and having received natalizumab for more than 2 years, it could be proposed to do a short MRI with FLAIR and diffusion weighted imaging sequences every 3 months to detect preclinical PML.     

New OFSEP recommendations for MRI assessment of multiple sclerosis patients: Special consideration for gadolinium deposition and frequent acquisitions

PurposeNew multiple sclerosis (MS) disease-modifying therapies (DMTs), which exert beneficial effects through prevention of relapse, limitation of disability progression, and improvement of patients’ quality of life, have recently emerged. Nonetheless, these DMTs are not without associated complications (severe adverse events like. progressive multifocal leukoencephalopathy). Patient follow-up requires regular clinical evaluations and close monitoring with magnetic resonance imaging (MRI). Detection of new T2 lesions and potential brain atrophy measurements contribute to the evaluation of treatment effectiveness. Current MRI protocols for MS recommend the acquisition of an annual gadolinium (Gd) enhanced MRI, resulting in administration of high volume of contrast agents over time and Gd accumulation in the brain.MethodsA consensus report was established by neuroradiologists and neurologists from the French Observatory of MS, which aimed at reducing the number of Gd injections required during MS patient follow-up.RecommendationsThe French Observatory of MS recommends the use of macrocyclic Gd enhancement at time of diagnosis, when a new DMT is introduced, at 6-month re-baseline, and when previous scans are unavailable for comparison. Gd administration can be performed as an option in case of relapse or suspicion of intercurrent disease such as progressive multifocal leukoencephalopathy. Other follow-up MRIs do not require contrast enhancement, provided current and previous MRI acquisitions follow the same standardized protocol including 3D FLAIR sequences.     

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches

Multiple sclerosis(MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies(DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.     

Association Between Disease-Modifying Therapies Prescribed to Persons with Multiple Sclerosis and Cancer: a WHO Pharmacovigilance Database Analysis

The risk of cancer associated with persons with multiple sclerosis (pwMS) prescribed with disease modifying therapies (DMTs) is not well established. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database: VigiBase®. All consecutive reports of DMTs prescribed to pwMS (alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-β, natalizumab, ocrelizumab, and teriflunomide), and their serious adverse event cases were eligible, excluding those reporting immunosuppressant DMTs used as anticancer therapies. The primary outcome was the multivariate odds ratio of cancer reporting (r-OR) for DMTs prescribed to pwMS after imputation of missing data. There were 5966 cancer cases from 240,993 reports of DMTs prescribed to pwMS. After adjustments on age, sex, and geographical region, natalizumab (r-OR 1.74, 95% CI 1.63–1.87), interferon-β (r-OR 1.39, 95% CI 1.30–1.49), dimethyl fumarate (r-OR 1.35, 95% CI 1.25–1.46), and fingolimod (r-OR 1.15, 95% CI 1.06–1.24) were significantly associated with a greater cancer reporting, whereas alemtuzumab, glatiramer acetate, ocrelizumab, and teriflunomide were not, in the disproportionality analysis. As exploratory analyses, upper aerodigestive tract, breast, urinary including the male genitourinary tract, and nervous system cancers were associated with natalizumab, interferon-β, and dimethyl fumarate. Fingolimod was only associated with skin cancer types. Cancer cases reporting these four DMTs prescribed to pwMS were younger in age than for non-pwMS drugs in the VigiBase® (p < 0.0001). A close and regular cancer screening in pwMS treated with natalizumab, interferon-β, dimethyl fumarate, and fingolimod may be warranted, even for persons at a younger age. Trial Registration {"type":"clinical-trial","attrs":{"text":"NCT04237337","term_id":"NCT04237337"}}NCT04237337Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01073-y.     

Natalizumab in aggressive multiple sclerosis after haematopoietic stem cell transplantation

High-dose cyclophosphamide followed by autologous haematopoietic stem cell transplantation (HDC-AHSCT) is a treatment option for aggressive and refractory multiple sclerosis (MS). Natalizumab is a monoclonal antibody approved for relapsing-remitting (RR) MS unresponsive to immunomodulating drugs. Nothing is known about the use of natalizumab in patients after HDC-AHSCT. We describe five female RR-MS patients with incomplete response to HDC-AHSCT. Natalizumab was then administered with abolition of both MRI and clinical activity. No severe adverse events, in particular opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML), were observed. Our results suggest that the use of natalizumab in aggressive RR-MS after HDC-AHSCT could be effective and safe. The very long-term risk of adverse events due to sequential aggressive immunosuppression has to be established.     

New Disease-Modifying Therapies and New Challenges for MS

The availability of the second-generation therapies for relapsing multiple sclerosis (MS), natalizumab and fingolimod, provides new treatment options for MS but also presents new challenges. Both natalizumab and fingolimod appear to be more effective than the interferon beta products and glatiramer acetate, but both have more safety problems than do the first-generation therapies. Treatment with natalizumab is associated with a significant risk of patients developing progressive multifocal leukoencephalopathy (PML), which the JC virus causes. We now are able to risk stratify MS patients into high- and low-risk groups for developing PML on the basis of the presence or absence of antibodies to the JC virus, history of prior use of immunosuppressants, and duration of therapy with natalizumab. Fingolimod appears to be associated with a risk of asystole and sudden death. It may also increase the risk of serious herpes infections and paradoxical activation of MS. More information is needed about these serious side effects from fingolimod to allow us to use it safely in patients.     

Multiple sclerosis disease-modifying therapies: adverse effect surveillance and management

There are five approved, partially effective, parenteral disease-modifying therapies for multiple sclerosis (MS), including three interferon-beta preparations, glatiramer acetate and the antineoplastic agent mitoxantrone. A sixth drug, natalizumab, was withdrawn from the market in 2005 but could return with increased safety measures. Careful surveillance for, and management of, the minor and serious adverse effects associated with these therapies in routine practice provides the best opportunity for maintaining compliance and achieving maximal therapeutic efficacy. This review outlines the strategies for the prevention, identification and management of the complications associated with administration and ongoing use of current MS therapies. These skills will become increasingly important to those caring for MS patients as contemporary treatment regimens become increasingly complex.     

Disease modifying drugs in multiple sclerosis: mechanisms of action and new drugs in the horizon

The term "disease modifying drugs" (DMD) is taken from rheumatologists who coined it after the use of immunosuppressive drugs and, more recently, the association of "biological drugs" that changed the degenerative course of rheumatic disease. In the treatment of multiple sclerosis (MS), the advent of interferon (IFN)-β, which caused a reduction in the number of relapses and possibly improvement in disability outcomes, was the first strategy to prevent inflammatory damage in the central nervous system (CNS). Soon after, glatiramer acetate showed similar results. It would be more than a decade before natalizumab was licensed, showing a much better efficiency in relapse reduction than was seen after first-line therapies failed. The pipeline is now much larger with several drugs on the horizon. Overall, the anti-inflammatory strategy has been mostly successful but drugs that have protection and repair mechanisms are still missing.     

Natalizumab is effective in multiple sclerosis patients switching from other disease modifying therapies in clinical practice

Natalizumab is one option for multiple sclerosis patients responding poorly to classical immunomodulators, but pilot studies did not point to its effectiveness as a second-line therapy. Aim of this study was to assess the efficacy of natalizumab as second-line therapy in patients switching from disease modifying therapies (DMTs) in a clinical setting. We retrospectively selected patients who had been treated with natalizumab for at least 12 months after switching from one or more DMTs. We collected clinical and neuroradiological data and we analysed the reduction in annualised relapse rate (ARR), the change of Expanded Disability Status Scale (EDSS) and the reduction of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI) of the brain at 12 months of natalizumab and of previous DMT therapy. Fifty patients were included in the analysis (11 males, 39 females).We observed a reduction of ARR on natalizumab (p = 0.000) and a statistically significant different trend of relapse event between the two treatments (p = 0.0149). EDSS was stable during natalizumab therapy whilst it showed an increase on DMTs (p = 0.0244). The number of CELs decreased significantly (p = 0.006) during the 12 months of treatment with natalizumab, whilst it was stable on DMTs. Natalizumab showed to decrease ARR, stabilize EDSS, increase the percentage of CELs free patients and decrease the number of CELs in a group of 50 poor responders to classical DMT, after the first 12 months of therapy.     

Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence

Reviews of therapeutic drugs usually focus on the highly selected and closely monitored patient populations from randomized controlled trials. The objective of this study was to review systematically the tolerability and adherence of multiple sclerosis disease-modifying therapies, using data from both randomized controlled trials and observational settings. Relevant literature was identified using predefined search terms, and adverse event and study discontinuation data were extracted and categorized according to study type (randomized controlled trial or observational) and study duration. A total of 151 papers were selected for analysis; 33% were classified as randomized controlled trials and 62% as observational studies. Most of the papers concerned interferon preparations and glatiramer acetate; the limited available information on mitoxantrone and natalizumab precluded extensive examination of these. The most common adverse events were flu-like symptoms (interferon therapies only) and injection-site reactions. Mean discontinuation rates ranged from 16% to 27%. There were no marked differences in tolerability or adherence data from randomized controlled trials and observational studies, but the incidence of adverse events remained high in lengthy studies and discontinuations accumulated with time. The present systematic review of randomized clinical trial and observational data highlights the tolerability and adherence issues associated with commonly used first-line multiple sclerosis treatments.     

Comparative studies of glatiramer acetate and interferon beta

Over the last decade and a half, several disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) including glatiramer actetate (GA; Copaxone), interferon beta (IFNB)-1a (Avonex, Rebif), IFNB-1b (Betaferon/Betaseron), mitoxantrone (Novantrone), and natalizumab (Tysabri). Randomized controlled trials (RCTs) of each of these DMTs have demonstrated that treatment has a favourable impact on at least one (often several) of the short-term outcome measures typically used to assess efficacy in MS clinical trials. These outcomes include clinical measures of disease activity such as the number or frequency of relapses, the time to first relapse, etc. They also include clinical measures of disease severity such as disease progression on the Expanded Disability Status Scale (EDSS) or the MS Functional Composite score (MSFC), determined either as a confirmed change over a 3 to 6 month interval or as a total change over the entire duration of the trial, in addition to various magnetic resonance imaging (MRI) measures such as the number and volume of T2 lesions, the number and volume of new or gadolinium (Gd)-enhancing lesions, or the number and volume of T1 dark lesions.     

Treating multiple sclerosis with natalizumab

Natalizumab is the first monoclonal antibody approved for the treatment of relapsing multiple sclerosis. Pivotal trials demonstrated the efficacy of natalizumab on clinical and paraclinical measures of disease activity and disability progression. Although a direct comparison has not been performed yet, natalizumab seems to be more efficacious than the currently available immunomodulant drugs, such as IFN-β and glatiramer acetate. Despite its efficacy, the occurrence of an increased risk of progressive multifocal leukoencephalopathy with the treatment, raises concerns about its widespread use in multiple sclerosis patients. This paper provides an overview of the most relevant results from the Phase I-IV studies on natalizumab and highlights the challenges addressed to minimize and manage its adverse events in clinical practice.     

Injectable Versus Oral First-Line Disease-Modifying Therapies: Results from the Italian MS Register

The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48–0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76–1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58–0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-01001-6.Key Words: Multiple sclerosis, injectable DMTs, oral DMTs, real-world setting, EDSS score     

Comparative safety of high-efficacy disease-modifying therapies in relapsing–remitting multiple sclerosis: a systematic review and network meta-analysis

Neurological Sciences - This study aimed to compare the safety profile of high-efficacy disease-modifying therapies (DMTs) natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab,...     

Potential Risks and Benefits of Multiple Sclerosis Immune Therapies in the COVID-19 Era: Clinical and Immunological Perspectives

Coronavirus SARS-CoV2 has emerged as one of the greatest infectious disease health challenges in a century. Patients with multiple sclerosis (MS) have a particular vulnerability to infections through their use of immunosuppressive disease-modifying therapies (DMTs). Specific DMTs pose particular risk based on their mechanisms of action (MOA). As a result, patients require individualized approaches to starting new treatments and continuation of therapy. Additionally, vaccinations must be considered carefully, and individuals on long-term B cell–depleting therapies may have diminished immune responses to vaccination, based on preserved T cells and diminished but present antibody titers to influenza vaccines. We review the immunology behind these treatments and their impact on COVID-19, as well as the current recommendations for best practices for use of DMTs in patients with MS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01008-7.Key Words: Multiple sclerosis, SARS-CoV2, disease-modifying therapy, vaccination, COVID-19, immunology