Personalized treatment is highly desirable in multiple sclerosis because it is an immensely heterogeneous disease. This heterogeneity is seen in both the disease course and the treatment responses. ...Currently, a combination of clinical features and imaging parameters in magnetic resonance imaging is used to classify active and non-active patients and treatment responders and non-responders. Although this classification works on a group level, individual patients often behave differently from the group. Therefore additional biomarkers are needed to provide better indicators for prognosis and treatment response. Basic and clinical research have discovered different promising targets. It is now essential to verify the utility and accuracy of these markers in large, prospectively sampled patient cohorts.
Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease. To a great extent, this may ...reflect that the group of inflammatory CNS demyelinating disorders likely contains multiple pathogenetically distinct disease entities. Indeed, the greatest success so far in deciphering the pathogenesis of a CNS demyelinating disorder resulted from the discovery of anti-aquaporin (AQP)-4 antibodies (ab), which allowed progressive delineation of neuromyelitis optica (NMO), formerly considered a variant of the most common CNS demyelinating disorder, multiple sclerosis (MS), as a distinct disease. Nowadays, AQP-4+ NMO is considered an autoimmune astrocytopathy, in which CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. Delineating these patients concomitantly revealed that not all patients presenting with clinically NMO-suggestive disease phenotype express AQP-4 ab, which created the pathogenetically undefined category of NMO spectrum disorders (NMOSD). Recent investigations discovered that a subgroup of these AQP-4– NMOSD patients produce an ab response against myelin oligodendrocyte glycoprotein (MOG), a molecule expressed on the outer lamella of the myelin sheath. Using pathophysiologically meaningful cell-based assays, this humoral response is extremely rare in adult MS and absent in classical AQP-4+ NMO, sharply differentiating the evolving group from both established disorders. In this review, we summarize available clinical, immunological and histopathological data on patients with MOG+ CNS demyelinating disease. By comparing this clearly distinct cohort to AQP-4+ NMO as well as MS, we propose that MOG+ CNS demyelinating disease represents a distinct novel disease entity. In addition to its diagnostic value, we furthermore provide mechanistic insight on how this peripheral anti-MOG ab response may be of pathogenetic relevance in triggering acute flares of inflammatory CNS demyelination.
Background:
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS). Despite improvements of immunomodulatory therapies in relapsing–remitting MS, the ...pathomechanisms of progressive disease are poorly understood and therapeutically addressed to date. A pathophysiological role for proteins encoded by human endogenous retroviruses (HERVs) has been proposed. GNbAC1 is a monoclonal antibody directed against the envelope protein of a HERV with postulated involvement in MS.
Methods:
This review addresses the treatment concept of GNbAC1, the design, preclinical and clinical development of the antibody, as published by November 2018. All four in-human trials (of which two addressed MS) are discussed.
Conclusion:
The treatment concept of GNbAC1 is appealing but remains controversial due to conflicting results regarding the hypothesized underlying pathomechanism. Anticipated immunomodulatory effects were not observed in clinical or pharmacodynamic analyses of the currently available data. However, a magnetic resonance imaging sign compatible with the remyelinating potential of GNbAC1 encouraged further development of this antibody in progressive MS. No relevant issues with tolerability or safety have been described to date.
B cells and antibodies account for the most prominent immunodiagnostic feature in patients with multiple sclerosis (MS), namely oligoclonal bands. Furthermore, evidence is accumulating that B cells ...and antibodies contribute to MS pathogenesis in at least a subset of patients. The CNS provides a B-cell-fostering environment that includes B-cell trophic factors such as BAFF (B-cell-activating factor of the TNF family), APRIL (a proliferation-inducing ligand), and the plasma-cell survival factor CXCL12. Owing to this environment, the CNS of patients with MS is not only the target of the immunopathological process, but also becomes the site of local antibody production. B cells can increase or dampen CNS inflammation, but their proinflammatory effects seem to be more prominent in most patients, as B-cell depletion is a promising therapeutic strategy. Other therapies not primarily designed to target B cells have numerous effects on the B-cell compartment. This Review summarizes key features of B-cell biology, the role of B cells and antibodies in CNS inflammation, and current attempts to identify the targets of pathogenic antibodies in MS. We also review the effects of approved and investigational interventions-including CD20-depleting antibodies, BAFF/APRIL-depleting agents, alemtuzumab, natalizumab, FTY720, IFN-β, glatiramer acetate, steroids and plasma exchange-on B-cell immunology.
Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are specific cytoskeletal proteins of neurons and their quantification has shown encouraging ...results as a biomarker for axonal injury.
We aimed at comparing a widely used conventional ELISA for Nf light chain (NfL) with an electrochemiluminescence-based method (ECL assay) and a newly developed single-molecule array (Simoa) method in clinically relevant cerebrospinal fluid (CSF) and serum samples.
Analytical sensitivity was 0.62 pg/mL for Simoa, 15.6 pg/mL for the ECL assay, and 78.0 pg/mL for the ELISA. Correlations between paired CSF and serum samples were strongest for Simoa (r=0.88, p<0.001) and the ECL assay (r=0.78, p<0.001) and weaker for ELISA measurements (r=0.38, p=0.030). CSF NfL measurements between the platforms were highly correlated (r=1.0, p<0.001). Serum NfL levels were highly related between ECL assay and Simoa (r=0.86, p<0.001), and this was less visible between ELISA-ECL assay (r=0.41, p=0.018) and ELISA-Simoa (r=0.43, p=0.013). Multiple sclerosis (MS) patients had significantly higher serum NfL levels than controls when measured with Simoa (p=0.001) but not with the other platforms.
We found Simoa to be more sensitive than ELISA or the ECL assay. Our results support the feasibility of quantifying NfL in serum; the results correlate with the more-established CSF NfL test. The highly sensitive Simoa technology deserves further studies in larger patient cohorts to clarify whether serum NfL could be used in the future to measure disease severity and determine prognosis or response to treatment interventions in neurological diseases.
Background:
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in ...treatment decisions.
Objectives:
To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS.
Methods:
This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients–Intervention–Comparator–Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results:
A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus.
Conclusion:
The present guideline will enable homogeneity of treatment decisions across Europe.
Background:
No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing–remitting multiple sclerosis (RRMS).
Objective:
...To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS.
Methods:
Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses.
Results:
Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9–2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95% confidence interval (CI) 0.3–0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95% CI 1.1–2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95% CI 0.5–1.5, p = 0.62).
Conclusion:
Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod.
Early intervention with high-efficacy disease-modifying therapy (HE DMT) may be the best strategy to delay irreversible neurological damage and progression of multiple sclerosis (MS). In European ...healthcare systems, however, patient access to HE DMTs in MS is often restricted to later stages of the disease due to restrictions in reimbursement despite broader regulatory labels. Although not every patient should be treated with HE DMTs at the initial stages of the disease, early and unrestricted access to HE DMTs with a positive benefit–risk profile and a reasonable value proposition will provide the freedom of choice for an appropriate treatment based on a shared decision between expert physicians and patients. This will further optimize outcomes and facilitate efficient resource allocation and sustainability in healthcare systems and society.
Background:
The spread of Coronavirus disease-19 (COVID-19) poses unique challenges in the management of people with multiple sclerosis (PwMS).
Objectives:
To collect data about the impact of ...COVID-19 emergency on access to care for PwMS and on MS treatment practices.
Methods:
Between March and July 2020, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) promoted an online survey covering patient access to care, management of relapses and visits, disease-modifying therapy (DMT) and experience with COVID-19.
Results:
Three-hundred and sixty neurologists from 52 countries (68% from Europe) completed the survey. 98% reported COVID-19-related restrictions. Telemedicine was adopted to overcome the limited access to care and was newly activated (73%) or widely implemented (17%). 70% reported changes in DMT management. Interferons and glatiramer were considered safe. Dimethyl fumarate, teriflunomide and fingolimod were considered safe except for patients developing lymphopenia. No modifications were considered for natalizumab in 64%, cladribine in 24%, anti-CD20 in 22% and alemtuzumab in 17%; 18% (for alemtuzumab and cladribine) and 43% (for anti-CD20) considered postponing treatment.
Conclusion:
The ECTRIMS survey highlighted the challenges in keeping standards of care in clinical practice. Telemedicine clearly needs to be implemented. Gathering data on DMT safety will remain crucial to inform treatment decisions.
PDF
