Use of follow-on disease-modifying treatments for multiple sclerosis: Consensus recommendations.

BACKGROUND: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. OBJECTIVES: To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. METHODS: Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. RESULTS: All principles and statements were endorsed by >80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. CONCLUSION: Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere.

Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management.

Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

Glatiramer Acetate Treatment in Multiple Sclerosis-Associated Fatigue-Beneficial Effects on Self-Assessment Scales But Not on Molecular Markers.

Although fatigue is a common symptom in multiple sclerosis (MS), its pathomechanisms are incompletely understood. Glatiramer acetate (GA), an immunomodulatory agent approved for treatment of relapsing-remitting MS (RRMS), possesses unique mechanisms of action and has been shown to exhibit beneficial effects on MS fatigue. The objective of this study was to correlate clinical, neuropsychological, and immunological parameters in RRMS patients with fatigue before and during treatment with GA. In a prospective, open-label, multicenter trial, 30 patients with RRMS and fatigue were treated with GA for 12 months. Inclusion criterion was the presence of fatigue as one of the most frequent and disabling symptoms. Before and during treatment, fatigue was assessed using the Fatigue Severity Scale (FSS), the MS-FSS, and the Modified Fatigue Impact Scale (MFIS). In addition, fatigue and quality of life were assessed using the Visual Analog Scales (VAS). Laboratory assessments included screening of 188 parameters using real-time PCR microarrays followed by further analysis of several cytokines, chemokines, and neurotrophic factors. Fatigue self-assessments were completed in 25 patients. After 12 months of treatment with GA, 13 of these patients improved in all three scales (with the most prominent effects on the MFIS), whereas 5 patients had deteriorated. The remaining 7 patients exhibited inconsistent effects within the three scales. Fatigue and overall quality of life had improved, as assessed via VAS. Laboratory assessments revealed heterogeneous mRNA levels of cytokines, chemokines, and neurotrophic factors. In conclusion, we were not able to correlate clinical and molecular effects of GA in patients with RRMS and fatigue.

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

Interdisciplinary Risk Management in the Treatment of Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system. There are at least 150 000 persons with MS in Germany. Recent years have seen the approval of new drugs against. METHODS: This article is based on pertinent literature retrieved by a selective search in PubMed as well as on documentation of relevant risks and adverse effects in "red hand letters" (information bulletins from pharmaceutical companies to physicians about adverse drug effects) and elsewhere, along with data provided by the German Multiple Sclerosis Competence Network. RESULTS: In recent years, there have been major advances enabling better, more individualized treatment of patients with MS. Physicians must, however, give due consideration to potentially severe or even life-threatening adverse drug effects. These can include, for example, transaminase elevation (hepatotoxicity), cardio- and nephrotoxicity, or lympho- and leukopenia with a variable risk of infection. Among patients taking natalizumab, the cumulative risk of developing progressive multifocal leukencephalopathy (PML) may be 1:100 or higher, depending on the individual risk profile. Rare cases of PML have also been seen under treatment with fingolimod and dimethyl fumarate. Moreover, any type of immunosuppressive treatment can, at least theoretically, increase the risk of malignant disease. Secondary autoimmune diseases can arise as well: approximately 35% of patients treated with alemtuzumab develop autoimmune thyroid disease within two years, and 2% of patients who take daclizumab have severe autoimmune dermatological side effects. Teriflunomide, fingolimod, natalizumab, mitoxantrone, interferon ß1-a/b, and daclizumab can all damage the liver. There are also psychiatric, reproductive, and vaccineassociated risks and side effects that must be considered. CONCLUSION: Newer drugs for MS have enabled more effective treatment, but are also associated with a higher risk of side effects. Interdisciplinary risk management is needed.

Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis.

Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2) = 0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio = 1.15, P = 3.48 × 10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.

Peripheral neuropathy: assessment of proximal nerve integrity by diffusion tensor imaging.

INTRODUCTION: We investigated the utility of diffusion tensor imaging (DTI) for detecting neuropathic changes in proximal nerve segments in patients with peripheral neuropathy. METHODS: Twenty-one individuals with (n = 11) and without (n = 10) peripheral neuropathy underwent DTI of a defined sciatic nerve segment. Patients and controls were evaluated by clinical examination and nerve conduction studies at baseline and 6 months after the initial DTI scan. RESULTS: The mean fractional anisotropy (FA) value was significantly lower in sciatic nerves from patients with peripheral neuropathy as compared with controls. Sciatic nerve FA values correlated with clinical disability scores and electrophysiological parameters of axonal damage at baseline and 6 months after MRI scan. CONCLUSIONS: DTI-derived FA values are a sensitive measure to discriminate healthy from functionally impaired human sciatic nerve segments. DTI of proximal nerve segments may be useful for estimating the proximal axonal degeneration burden in patients with peripheral neuropathies.

Cost-effectiveness analysis of interferon beta-1b for the treatment of patients with a first clinical event suggestive of multiple sclerosis.

OBJECTIVES: To assess, from a Swedish societal perspective, the cost effectiveness of interferon ß-1b (IFNB-1b) after an initial clinical event suggestive of multiple sclerosis (MS) (ie, early treatment) compared with treatment after onset of clinically definite MS (CDMS) (ie, delayed treatment). METHODS: A Markov model was developed, using patient level data from the BENEFIT trial and published literature, to estimate health outcomes and costs associated with IFNB-1b for hypothetical cohorts of patients after an initial clinical event suggestive of MS. Health states were defined by Kurtzke Expanded Disability Status Scale (EDSS) scores. Model outcomes included quality-adjusted life years (QALYs), total costs (including both direct and indirect costs), and incremental cost-effectiveness ratios. Sensitivity analyses were performed on key model parameters to assess the robustness of model results. RESULTS: In the base case scenario, early IFNB-1b treatment was economically dominant (ie, less costly and more effective) versus delayed IFNB-1b treatment when QALYs were used as the effectiveness metric. Sensitivity analyses showed that the cost-effectiveness results were sensitive to model time horizon. Compared with the delayed treatment strategy, early treatment of MS was also associated with delayed EDSS progressions, prolonged time to CDMS diagnosis, and a reduction in frequency of relapse. CONCLUSION: Early treatment with IFNB-1b for a first clinical event suggestive of MS was found to improve patient outcomes while controlling costs.

Managing the risks of immunosuppression.

PURPOSE OF REVIEW: New immunomodulating approaches to neuroinflammatory diseases present new challenges in clinical risk management. We review recent data on immunosuppression in diverse settings to guide the assessment and prevention of adverse effects from these therapies with the aim of improving the benefit to risk equation. RECENT FINDINGS: Although individual immunomodulatory agents affect the immune system in different ways, there are common themes in patient risk. Impairment of immunity is primarily responsible for an increased risk of a characteristic spectrum of infection-related cancers in immunocompromised patients. Additional themes include the reactivation of existing infections such as herpes viruses, mycobacterial and JC virus infections, vaccine preventable disease, cardiovascular and metabolic risk and immune dysregulation resulting in autoimmune and immune reconstitution inflammatory syndromes. An online immunosuppression screening tool may help reduce omissions in individual patient-specific risk assessment. SUMMARY: Systematic patient-tailored risk management protocols will be required to ensure reduction in preventable adverse outcomes with new immunomodifying approaches to neuroinflammatory disease and thereby optimize the benefits to patients from these treatments.

Risks and benefits of multiple sclerosis therapies: need for continual assessment?

PURPOSE OF REVIEW: The aim is to describe and discuss the ongoing debate on how to balance an increase in clinical efficacy against a heightened risk of developing serious side-effects, as has surfaced recently with some novel therapies for relapsing forms of multiple sclerosis. RECENT FINDINGS: New therapies are emerging that differ with regard to their mechanism of action, their mode of administration, their side-effect profile and the clinical benefits that they offer to patients in comparison with established therapeutic modalities in multiple sclerosis. Treating physicians will need to make choices on the best treatments for their patients on the basis of limited experience. This process requires optimal assessment of risks and benefits. SUMMARY: Careful assessment of the risk-benefit profile of the various options may allow treatment choices and perhaps ensure that patients obtain the most benefit from treatment without being exposed to unnecessary risk.

Plasma exchange in immune-mediated neuropathies.

PURPOSE OF REVIEW: Plasma exchange is frequently used for treatment of immune-mediated neuropathies. Here, we review the current value of plasma exchange in the treatment of different forms of immune-mediated neuropathies and discuss latest developments. RECENT FINDINGS: Plasma exchange is used in various disease conditions; however, of all immune-mediated disorders of the peripheral nerve, Guillain-Barré syndrome represents the disease entity in which short and long-term efficacy, optimal frequency, side effects and cost effectiveness of plasma exchange are best documented. Although randomized trials evaluated the value of plasma exchange in chronic forms of immune-neuropathies, its long-term efficacy and its optimal frequency still remain unclear. SUMMARY: Especially in chronic forms of immune-mediated neuropathies, plasma exchange needs to be further evaluated in clinical trials to assess long-term efficacy and its potential as adjuvant treatment option.

Assessment and management of neutralizing antibodies in patients with multiple sclerosis.

The development of neutralizing antibodies (NAbs) to interferon beta (IFNbeta) products during treatment of MS poses a challenge for clinicians. Given the impact of NAbs on the clinical efficacy of IFNbetas, the immunogenicity of different IFNbeta products should be one of the factors that neurologists consider in the treatment of patients with MS. However, no clear guidelines are available for the practicing neurologist concerning which patients should be tested for NAbs and how to clinically manage patients who develop NAbs. This article summarizes the content of this supplement, discusses issues related to measuring NAbs in clinical practice, and gives practical alternatives for managing MS in patients who develop NAbs during IFNbeta therapy.