Leveraging real-world data to investigate multiple sclerosis disease behavior, prognosis, and treatment.

Randomized controlled clinical trials and real-world observational studies provide complementary information but with different validity. Some clinical questions (disease behavior, prognosis, validation of outcome measures, comparative effectiveness, and long-term safety of therapies) are often better addressed using real-world data reflecting larger, more representative populations. Integration of disease history, clinician-reported outcomes, performance tests, and patient-reported outcome measures during patient encounters; imaging and biospecimen analyses; and data from wearable devices increase dataset utility. However, observational studies utilizing these data are susceptible to many potential sources of bias, creating barriers to acceptance by regulatory agencies and the medical community. Therefore, data standardization and validation within datasets, harmonization across datasets, and application of appropriate analysis methods are important considerations. We review approaches to improve the scope, quality, and analyses of real-world data to advance understanding of multiple sclerosis and its treatment, as an example of opportunities to better support patient care and research.

Spinal cord involvement in multiple sclerosis and neuromyelitis optica spectrum disorders.

Spinal cord involvement is an important cause of disability in patients with multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSDs). Multiple sclerosis and NMOSDs can be distinguished from other disorders that cause myelopathy by results from laboratory and radiological investigations. However, limitations in the sensitivity and specificity of spinal cord imaging and poor correlation with disability megasures have impeded the understanding of the relationship between spinal cord involvement and clinical manifestations. Nevertheless, studies of the pathological features of multiple sclerosis and NMOSDs have shown that quantitatively different mechanisms lead to differences in clinical course and pattern of accrual of permanent disability in the two disorders. Better understanding of these mechanisms is necessary to develop more informative clinical measures, electrophysiological methods, fluid biomarkers, and imaging techniques to detect and monitor spinal cord involvement in the diagnosis and management of patients with multiple sclerosis or NMOSDs, and as outcome measures in clinical trials.

Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Cell-based therapeutic strategies for multiple sclerosis.

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.

Vision and vision-related outcome measures in multiple sclerosis.

Visual impairment is a key manifestation of multiple sclerosis. Acute optic neuritis is a common, often presenting manifestation, but visual deficits and structural loss of retinal axonal and neuronal integrity can occur even without a history of optic neuritis. Interest in vision in multiple sclerosis is growing, partially in response to the development of sensitive visual function tests, structural markers such as optical coherence tomography and magnetic resonance imaging, and quality of life measures that give clinical meaning to the structure-function correlations that are unique to the afferent visual pathway. Abnormal eye movements also are common in multiple sclerosis, but quantitative assessment methods that can be applied in practice and clinical trials are not readily available. We summarize here a comprehensive literature search and the discussion at a recent international meeting of investigators involved in the development and study of visual outcomes in multiple sclerosis, which had, as its overriding goals, to review the state of the field and identify areas for future research. We review data and principles to help us understand the importance of vision as a model for outcomes assessment in clinical practice and therapeutic trials in multiple sclerosis.

A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis.

BACKGROUND: As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS). OBJECTIVE: The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS. METHODS: The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies. RESULTS: Sixty-one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid. CONCLUSION: Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide.

A systematic review of the incidence and prevalence of cancer in multiple sclerosis.

BACKGROUND: Studies of cancer incidence and prevalence in multiple sclerosis (MS) have produced conflicting results. OBJECTIVE: To estimate the incidence and prevalence of cancer in persons with MS and review the quality of included studies. METHODS: We searched the PUBMED, SCOPUS, Web of Knowledge, and EMBASE databases, conference proceedings, and reference lists of all articles retrieved. Abstracts were screened for relevance by two reviewers. Data from included articles were captured using a standardized form, and the abstraction was verified by a second reviewer. We assessed quality of the included studies. We quantitatively assessed studies using the I (2) statistic, and conducted meta-analyses for population-based studies. RESULTS: We identified 38 studies. Estimates for incidence and prevalence varied substantially for most cancers. In population-based studies, cervical, breast, and digestive cancers had the highest incidence. The risk of meningiomas and urinary system cancers appeared higher than expected, while the risks of pancreatic, ovarian, prostate and testicular cancer were lower than expected. CONCLUSION: The complexity of understanding cancer risk in MS is augmented by inconsistencies in study design, and the relative paucity of age, sex and ethnicity-specific risk estimates from which the strong impact of age on the incidence of cancers can be assessed.

The incidence and prevalence of comorbid gastrointestinal, musculoskeletal, ocular, pulmonary, and renal disorders in multiple sclerosis: a systematic review.

BACKGROUND: As new disease-modifying therapies emerge a better knowledge of the risk of comorbid disease in multiple sclerosis (MS) is needed. OBJECTIVE: To estimate the incidence and prevalence of comorbid gastrointestinal, musculoskeletal, ocular, pulmonary, and renal disorders in MS. METHODS: We systematically reviewed the world literature by searching PUBMED, EMBASE, SCOPUS, the Web of Knowledge, and reference lists of retrieved articles. For selected articles, one reviewer abstracted data using a standardized form. The abstraction was verified by a second reviewer. The quality of all selected studies was assessed. For population-based studies we quantitatively assessed studies using the I² statistic, and conducted random effects meta-analyses. RESULTS: Study designs were heterogeneous with respect to populations, case definitions, and methods of ascertainment. Incidence of the studied comorbidities was rarely reported. Irritable bowel syndrome and chronic lung disease had a prevalence of more than 10% in the MS population. Irritable bowel syndrome, fibromyalgia, cataracts and glaucoma were more common than expected in the MS population. CONCLUSION: Although they have been the subject of less study than other comorbidities, irritable bowel syndrome, arthritis, and chronic lung disease are common in the MS population and occur more often than expected when compared to the general population.

Defining the clinical course of multiple sclerosis: the 2013 revisions.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Pregnancy, sex and hormonal factors in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is influenced by pregnancy, sex and hormonal factors. OBJECTIVES: A comprehensive understanding of the role of pregnancy, sex and hormonal factors can provide insights into disease mechanisms, and new therapeutic developments and can provide improved patient care and treatment. METHODS: Based on an international conference of experts and a comprehensive PubMed search for publications on these areas in MS, we provide a review of what is known about the impact of these factors on disease demographics, etiology, pathophysiology and clinical course and outcomes. RESULTS AND CONCLUSIONS: Recommendations are provided for counseling and management of people with MS before conception, during pregnancy and after delivery. The use of disease-modifying and symptomatic therapies in pregnancy is problematic and such treatments are normally discontinued. Available knowledge about the impact of treatment on the mother, fetus and newborn is discussed. Recommendations for future research to fill knowledge gaps and clarify inconsistencies in available data are made.

Risk evaluation and monitoring in multiple sclerosis therapeutics.

BACKGROUND: Risk for multiple sclerosis (MS) disease-modifying therapies (DMT) must be assessed on an ongoing basis. Early concerns regarding the first-approved DMTs for MS have been mitigated, but recently licensed therapies have been linked to possibly greater risks. OBJECTIVES: The objective of this review is to discuss risk assessment in MS therapeutics based on an international workshop and comprehensive literature search and recommend strategies for risk assessment/monitoring. RESULTS: Assessment and perception of therapeutic risks vary between patients, doctors and regulators. Acceptability of risk depends on the magnitude of risk and the demonstrated clinical benefits of any agent. Safety signals must be distinguishable from chance occurrences in a clinical trial and in long-term use of medications. Post-marketing research is crucial for assessing longer-term safety in large patient cohorts. Reporting of adverse events is becoming more proactive, allowing more rapid identification of risks. Communication about therapeutic risks and their relationship to clinical benefit must involve patients in shared decision making. CONCLUSIONS: It is difficult to produce a general risk-assessment algorithm for all MS therapies. Specific algorithms are required for each DMT in every treated-patient population. New and evolving risks must be evaluated and communicated rapidly to allow patients and physicians to be well informed and able to share treatment decisions.

Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects.

Many of the available disability outcome measures used in clinical trials of multiple sclerosis are insensitive to change over time, inadequately validated, or insensitive to patient-perceived health status or quality of life. Increasing focus on therapies that slow or reverse disability progression makes it essential to refine existing measures or to develop new tools. Major changes to the expanded disability status scale should be avoided to prevent the loss of acceptance by regulators as a measure for primary outcomes in trials that provide substantial evidence of effectiveness. Rather, we recommend practical refinements. Conversely, although substantial data support the multiple sclerosis functional composite as an alternative measure, changes to its component tests and scoring method are needed. Novel approaches, including the use of composite endpoints, patient-reported outcomes, and measurement of biomarkers, show promise as adjuncts to the current disability measures, but are insufficiently validated to serve as substitutes. A collaborative approach that involves academic experts, regulators, industry representitives, and funding agencies is needed to most effectively develop disability outcome measures.

Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis.

The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity.

Imaging outcomes for neuroprotection and repair in multiple sclerosis trials.

Multiple sclerosis (MS) is commonly regarded as an inflammatory disease, but it also has a neurodegenerative component, which represents an additional target for treatment. The use of MRI to evaluate the inflammatory disease component in 'proof-of concept' clinical trials is well established, but no systematic assessment of imaging outcomes to evaluate neuroprotection or repair in MS has been performed. In this Review, we examine the potential of traditional and novel imaging parameters to serve as primary outcomes in phase II clinical trials of neuroprotective and reparative strategies in MS. We present the conclusions of an international meeting of imaging, clinical and statistical experts, as well as a review of relevant literature. The available imaging techniques are appraised in five categories of performance: pathological specificity, reproducibility, sensitivity to change, clinical relevance, and response to treatment. At present, the three most promising primary outcomes in phase II trials of neuroprotective and/or reparative strategies in MS are: changes in whole-brain volume to gauge general cerebral atrophy; T1 hypointensity and magnetization transfer ratio to monitor the evolution of lesion damage; and optical coherence tomography findings to evaluate the anterior visual pathway. Power calculations show that these outcome measures can be applied with attainable sample sizes.

Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria".

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Multiple sclerosis diagnostic criteria: three years later.

New diagnostic criteria for multiple sclerosis (MS) were developed by an International Panel in 2001 and have had wide distribution and discussion since publication. These provided the first formal incorporation of magnetic resonance imaging (MRI) in a diagnosis work-up for patients suspected of having MS. The so-called McDonald criteria have been studied in retrospective and prospective analyses for sensitivity, specificity and utility, and have been proven to compare favourably or to be an improvement upon prior MS diagnostic criteria. The purpose of the current review is to present and evaluate the key studies that have been performed using the McDonald criteria since 2001 and to set the stage for an upcoming re-evaluation of the new criteria based on data-driven information gathered since their development.