Primary Progressive Multiple Sclerosis Research Articles

Differences in correlates of fatigue between relapsing and progressive forms of multiple sclerosis

BackgroundFatigue is one of the most prevalent and impactful symptoms for people with multiple sclerosis (MS). Yet, fatigue is less understood in progressive forms of MS, and few studies have explored the extent to which MS disease course is associated with fatigue. The current study aimed to (1) describe fatigue severity and fatigue interference (the extent to which fatigue interferes with individuals’ physical, mental, and social activities) in people with progressive MS (primary progressive MS and secondary progressive MS); (2) compare fatigue severity and fatigue interference in people with progressive forms of MS to people with relapsing-remitting MS (RRMS); and (3) identify factors associated with fatigue severity and fatigue interference in people with progressive forms of MS and RRMS. MethodsSecondary analysis of baseline data from participants with MS (N = 573; progressive forms of MS n = 142; RRMS n = 431) in a survey-based longitudinal study on healthy aging in people with a physical disability. Primary outcomes were average fatigue severity (0–10 Numerical Rating Scale), and fatigue interference (PROMIS Fatigue Short Form). Correlates were variables across the demographic and biopsychosocial domains, collected with validated self-reported measures. Statistical methods included t-test and chi-square analyses to compare fatigue severity and fatigue interference in people with progressive MS to those with RRMS, and multiple regression analyses to examine the association of variables with fatigue severity and fatigue interference. ResultsParticipants with progressive forms of MS reported moderate to severe levels of average fatigue severity (5.9 ± 2.8) and elevated levels of fatigue interference (T-Score of 58.2 ± 7.9). There were no group differences between people with progressive MS and RRMS in average fatigue severity or fatigue interference. Common factors associated with greater fatigue severity were lower income, being unemployed, shorter disease duration, greater disability, and greater sleep disturbance. Common factors associated with fatigue interference were younger age, lower income, being unemployed, greater disability, lower alcohol consumption, being a smoker, and greater sleep disturbance. For those with progressive forms of MS, longer MS disease duration was associated with lower average fatigue severity (b = -0.08, t(532) = -3.69, p < .001) and having a college degree or higher was associated with higher fatigue interference (b = 2.84, t(520) = 2.23, p = .026). ConclusionIn this sample, fatigue severity and fatigue interference were similar for progressive forms of MS and RRMS. Future research should consider if interventions that work for fatigue management in people with relapsing forms of MS work similarly for people with progressive forms of MS.

Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.

Memory B Cells in Multiple Sclerosis: Emerging Players in Disease Pathogenesis.

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Once thought to be primarily driven by T cells, B cells are emerging as central players in MS immunopathogenesis. Interest in multiple B cell phenotypes in MS expanded following the efficacy of B cell-depleting agents targeting CD20 in relapsing-remitting MS and inflammatory primary progressive MS patients. Interestingly, these therapies primarily target non-antibody secreting cells. Emerging studies seek to explore B cell functions beyond antibody-mediated roles, including cytokine production, antigen presentation, and ectopic follicle-like aggregate formation. Importantly, memory B cells (Bmem) are rising as a key B cell phenotype to investigate in MS due to their antigen-experience, increased lifespan, and rapid response to stimulation. Bmem display diverse effector functions including cytokine production, antigen presentation, and serving as antigen-experienced precursors to antibody-secreting cells. In this review, we explore the cellular and molecular processes involved in Bmem development, Bmem phenotypes, and effector functions. We then examine how these concepts may be applied to the potential role(s) of Bmem in MS pathogenesis. We investigate Bmem both within the periphery and inside the CNS compartment, focusing on Bmem phenotypes and proposed functions in MS and its animal models. Finally, we review how current immunomodulatory therapies, including B cell-directed therapies and other immunomodulatory therapies, modify Bmem and how this knowledge may be harnessed to direct therapeutic strategies in MS.

The Role of B Cells in Primary Progressive Multiple Sclerosis.

The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it's unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS.

Serum neurofilament light is a sensitive biomarker that reflects grey matter volume in Japanese patients with multiple sclerosis

ObjectiveTo evaluate the degree of neuroaxonal injury in Japanese multiple sclerosis (MS) patients using serum neurofilament light (sNfL) and to investigate the relationship of sNFL with the degree of brain volume. MethodssNfL levels in 82 consecutive Japanese MS patients in remission were cross-sectionally evaluated using a single molecule array assay. Within this sample, cross-sectional volumetric brain MRI data was evaluated in 80 patients, and longitudinal data was evaluated in 63 patients. ResultsMS patients (female/male = 61/21), including those with relapsing-remitting MS (82%), secondary progressive MS (17%), and primary progressive MS (1%), were studied. The mean age of the patients was 41.2 ± 8.7 years, and 77 of the MS patients (94%) were treated with disease-modifying therapy (DMT). Their median sNfL level was 7.985 (IQR, 5.959–10.9), and their sNfL levels were significantly correlated with their grey matter volume and their age. A standard least squares regression model revealed that approximately 57% of the variation in grey matter volume could be explained by a regression equation using three explanatory variables: sNfL concentration, age, and sex. Moreover, the sNfL level multiplied by disease duration was significantly correlated with the Expanded Disability Status Scale (EDSS) scores and whole and grey matter volumes. ConclusionAlthough neuroaxonal injury appeared to be mild in our Japanese MS patients, their sNfL levels significantly reflected grey matter volume. Moreover, when multiplied by the disease duration, sNfL can reflect disability and brain volume.

PND16 Socioeconomic Value of Ocrelizumab in the Treatment of Patients with Primary Progressive Multiple Sclerosis

Ocrelizumab is the first and only disease-modifying therapy (DMT) approved by Health Canada for patients with primary progressive multiple sclerosis (PPMS). In this study, we assess the socioeconomic benefits derived from using ocrelizumab in PPMS compared with best supportive care (BSC) in Canada. A Markov-state model based on one-point spaced Expanded Disability Status Scale (EDSS) states (0–9) was used to estimate costs associated with disease progression. EDSS at baseline and transition probabilities were derived from the ORATORIO trial and MSBase natural history study, respectively. Treatment effect on delaying disability progression was modeled through the hazard ratio for time to 24-week confirmed disability progression, which was derived from a counterfactual analysis of the ORATORIO double-blind and open-label extension phases. Societal benefits included savings in direct healthcare and non-healthcare costs, and indirect costs (including informal care and productivity loss, among others). Drug costs were excluded to focus on treatment benefits. Resource use and cost inputs at 2019 prices were derived from published studies in the multiple sclerosis space or from national statistics databases. Data on PPMS prevalence and proportion of patients receiving BSC in Canada were obtained by triangulating Canadian epidemiologic data, Roche PPMS market share forecast, and real world data from the Ocrevus patient support program. The socioeconomic value of ocrelizumab compared with BSC in Canada is estimated to be CAD$61.3 million over 5 years. These cost savings are driven by reduction in the utilization of healthcare resources and community services ($33.1 million), productivity loss ($13.8 million), and informal care ($10.8 million). Ocrelizumab for PPMS offers substantial socioeconomic benefits compared with BSC in Canada.

TCR repertoire diversity in Multiple Sclerosis: High-dimensional bioinformatics analysis of sequences from brain, cerebrospinal fluid and peripheral blood.

BackgroundT cells play a key role in the pathogenesis of multiple sclerosis (MS), a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Although several studies recently investigated the T-cell receptor (TCR) repertoire in cerebrospinal fluid (CSF) of MS patients by high-throughput sequencing (HTS), a deep analysis on repertoire similarities and differences among compartments is still missing.MethodsWe performed comprehensive bioinformatics on high-dimensional TCR Vβ sequencing data from published and unpublished MS and healthy donors (HD) studies. We evaluated repertoire polarization, clone distribution, shared CDR3 amino acid sequences (CDR3s-a.a.) across repertoires, clone overlap with public databases, and TCR similarity architecture.FindingsCSF repertoires showed a significantly higher public clones percentage and sequence similarity compared to peripheral blood (PB). On the other hand, we failed to reject the null hypothesis that the repertoire polarization is the same between CSF and PB. One Primary-Progressive MS (PPMS) CSF repertoire differed from the others in terms of TCR similarity architecture. Cluster analysis splits MS from HD.InterpretationIn MS patients, the presence of a physiological barrier, the blood-brain barrier, does not impact clone prevalence and distribution, but impacts public clones, indicating CSF as a more private site. We reported a high Vβ sequence similarity in the CSF-TCR architecture in one PPMS. If confirmed it may be an interesting insight into MS progressive inflammatory mechanisms. The clustering of MS repertoires from HD suggests that disease shapes the TCR Vβ clonal profile.FundingThis study was partly financially supported by the Italian Multiple Sclerosis Foundation (FISM), that contributed to Ballerini-DB data collection (grant #2015 R02).

PND57 Examining Fatigue in Progressive MS: Results from a Qualitative Study and Review of PRO Measures

Although fatigue is one of the most common symptoms of multiple sclerosis (MS) and several patient-reported outcome (PRO) instruments assess MS-related fatigue, few PROs include the perspective of progressive MS (PMS) patients in their development. This qualitative study was conducted to understand fatigue in a PMS population and evaluate the conceptual frameworks of existing MS-specific PROs for use in this population. A previous targeted literature review identified MS-specific fatigue PROs. A discussion guide was developed with the concepts from these PROs. Following IRB approval and consent, adult PMS subjects who reported MS-related fatigue in the last 6 months were individually interviewed to elicit MS-related fatigue concepts. Data were analyzed and compared to concepts in existing PRO instruments to evaluate their relevance in a PMS population. Of the 30 PMS subjects that participated, 70% were female, mean age was 51 years [range 32–75 years] and 47% were primary PMS, 33% were active secondary PMS, and 20% were non-active secondary PMS. All participants reported fatigue had physical components, described commonly as feeling “tired”, “weak”, “exhausted”, or having “low energy”. Most participants (80%) noted fatigue had mental components including difficulty communicating, concentrating, or focusing. When comparing the qualitative interview findings to the concepts in the identified MS-specific fatigue PROs, the fatigue symptoms and impacts questionnaire (FSIQ-RMS) was the most suitable to PMS individuals as concepts in the qualitative research aligned with the FSIQ-RMS items. The modified fatigue impact scale (MFIS) was deemed suitable contingent on modifications. Other identified PRO instruments have low suitability as they omit key concepts and/or do not distinguish between mental and physical aspects of fatigue. This qualitative study provides meaningful physical and mental concepts of fatigue in a PMS population and preliminary support of the appropriateness of the FSIQ-RMS in assessing fatigue in PMS patients.

Aggressive multiple sclerosis in Argentina: Data from the nationwide registry RelevarEM

The objectives of the present study were to describe the frequency of aggressive multiple sclerosis (aMS) as well as to compare clinical and radiological characteristics in aMS and non-aMS patients included in RelevarEM (NCT 03375177). MethodsThe eligible study population and cohort selection included adult-onset patients (≥18 years) with definite MS. AMS were defined as those reaching confirmed EDSS ≥ 6 within 5 years from symptom onset. Confirmation was achieved when a subsequent EDSS ≥ 6 was recorded at least six months later but within 5 years of the first clinical presentation. AMS and non-aMS were compared using the χ2 test for categorical and the Mann-Whitney for continuous variables at MS onset and multivariable analysis was performed using forward stepwise logistic regression with baseline characteristics at disease onset. ResultsA total of 2158 patients with MS were included: 74 aMS and 2084 non-aMS. The prevalence of aMS in our cohort was 3.4% (95%CI 2.7–4.2). AMS were more likely to be male (p = 0.003), older at MS onset (p < 0.001), have primary progressive MS (PPMS) phenotype (p = 0.03), multifocal presentation (p < 0.001), and spinal cord as well as infratentorial lesions at MRI during disease onset (p = 0.004 and p = 0.002, respectively). Conclusion3.4% of our patient population could be considered aMS. Men, patients older at symptom onset, multifocal presentation, PPMS phenotype, and spinal cord as well as brainstem lesions on MRI at clinical presentation all had higher odds of having aMS.

Multiple Sclerosis.

Many groundbreaking advances have occurred in the field of multiple sclerosis since this series last reviewed the disorder in 2014. The U.S. Food and Drug Administration has approved 7 new medications for relapsing-remitting multiple sclerosis and approved the first medication for primary progressive multiple sclerosis. The McDonald criteria for diagnosing multiple sclerosis were updated in 2017. New blood tests can now differentiate patients with multiple sclerosis from those with neuromyelitis optica spectrum disorder, and 3 new medications have been approved specifically for the latter disorder. Also, new medications for treating the symptoms of multiple sclerosis have been introduced.

New strategy for MS treatment with autoantigen-modified liposomes and their therapeutic effect

As current treatments for multiple sclerosis (MS) remain chemotherapeutic ones directed toward symptoms, the development of a curative treatment is urgently required. Herein, we show an autoreactive immune cell-targetable approach using autoantigen-modified liposomes for the curative treatment of MS. In these experiments, experimental autoimmune encephalomyelitis (EAE) induced by autoantigenic myelin oligodendrocyte glycoprotein (MOG) peptide was used as a model of primary progressive MS, and MOG-modified liposomes encapsulating doxorubicin (MOG-LipDOX) were used as a therapeutic drug. The results showed that the progression of encephalomyelitis symptoms was significantly suppressed by MOG-LipDOX injection, whereas the other samples failed to show any effect. Additionally, invasion of inflammatory immune cells into the spinal cord and demyelination of neurons were clearly suppressed in the MOG-LipDOX-treated mice. FACS analysis revealed that the number of both MOG-recognizable CD4+ T cells in the spleen was obviously decreased after MOG-LipDOX treatment. Furthermore, the number of effector Th17 cells in the spleen was significantly decreased and that of regulatory Treg cells was concomitantly increased. Finally, we demonstrated that myelin proteolipid protein (PLP)-modified liposomes encapsulating DOX (PLP-LipDOX) also showed the therapeutic effect on relapsing-remitting EAE. These findings indicate that autoantigen-modified liposomal drug produced a highly therapeutic effect on EAE by delivering the encapsulated drug to autoantigen-recognizable CD4+ T cells and thus suppressing autoreactive immune responses. The present study suggests that the use of these autoantigen-modified liposomes promises to be a suitable therapeutic approach for the cure of MS.

Peculiarities of primary-progressive multiple sclerosis in the residents of volyn region

The course of primary progressive multiple sclerosis (PPMS) among the residents of Volyn region was studied. It was established that the proportion of patients with PPRS is 7.95%. The typical characteristics of the cohort of the patients are polysymptomatic debut, in early thirties, with primarily involving the cerebellum and pyramidal systems, with a significant degree of disability and rapid progression of the disease. The data can be used in the planning of health andsocial care on the patients with PPMS.

Real-world experience of ocrelizumab initiation in a diverse multiple sclerosis population

BackgroundOcrelizumab (OCR) is a humanized monoclonal antibody directed against CD20 positive B-lymphocytes. It was approved for use in 2017 by the U.S. Food and Drug Administration (FDA) for both the relapsing-remitting and primary progressive forms of multiple sclerosis (MS). ObjectiveTo provide real-world data for patients with MS treated with OCR in our center and evaluate both the safety and efficacy across different ethnic groups not studied in previous clinical trials. MethodsWe performed a retrospective observational analysis of MS patients who were treated with OCR from March 31, 2017 to April 30, 2020. We collected data on patients who had received at least a one dose infusion of OCR at our MS center. Patient characteristics, including demographics, clinical disease course, and documented side effects, were collected and analyzed. ResultsA total of 82 patients were eligible for this study, of which 72% had relapsing-remitting MS (RRMS), 14% had primary progressive MS (PPMS), and 11% active/relapsing secondary progressive MS (SPMS). 22% of our patients were of African American descent, 61% Caucasian, and 17% of Hispanic descent. The mean age of starting OCR was 41 ± 11 years. 47% were treatment naïve when started on OCR, 24% were previously treated with one disease-modifying therapy (DMT), 14% were treated with two DMTs, and 15% were treated with more than two DMTs prior to OCR. 50% of patients had at least one adverse event while on OCR; 4.8% had adverse events requiring to OCR discontinuation, 36% had infusion-related reactions, and 7.3% had viral infections. We found two cases of severe babesiosis along with index cases of re-activation of lichen planus, agranulocytosis, severe lymphopenia, and ectopic pregnancy. There were no cases of malignancy, progressive multifocal leukoencephalopathy, or death within our cohort. The mean time after OCR initiation was 17.3 months in the RRMS group, 22.2 months in the PPMS group, and 28.2 months in SPMS group. The annualized relapse rate reduced from 1.33 to 0.15 in the RRMS group. The mean extended disability status scale (EDSS) scores did not worsen across MS phenotypes and ethnic groups while being treated with OCR. ConclusionsIn a diverse patient population, OCR was well-tolerated without significant adverse events. There were novel cases of severe babesiosis, re-activation of lichen planus, lymphopenia, agranulocytosis, and ectopic pregnancy. It is vital to consider geographic risk factors that may expose patients to Babesia microti (B. microti) when either considering or initiating OCR therapy. There were an additional six cases of severe B. microti cases associated with OCR that were reported to the FDA adverse event reporting system (FAERS) along with multiple babesiosis cases associated with other DMTs, including rituximab. OCR was found in our cohort to be effective by decreasing relapse rates and maintaining EDSS scores. Our study extends the generalizability of OCR from clinical trials to a real-world setting consisting of a diverse population.

Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry.

Background and purposeReaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double‐blind and extended controlled periods (DBP+ECP), (ii) quantify likely long‐term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real‐world cohort (MSBase registry; ACTRN12605000455662).MethodsPost hoc analyses assessing time to 24‐week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–6.5) were investigated in ORATORIO and MSBase.ResultsIn the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24‐week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31–0.92; p = 0.022). Extrapolated median time to 24‐week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1‐year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24‐week confirmed EDSS ≥7.0 was 12.4 years.ConclusionsCompared with placebo, ocrelizumab significantly delayed time to 24‐week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real‐world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.

Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis

Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging. To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards. Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506. We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management. Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit. We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time. In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

Primary Progressive Multiple Sclerosis

Primary progressive multiple sclerosis (PPMS) is a chronic inflammatory disease of the central nervous system that leads to demyelination and neurodegeneration. PPMS is characterized by a gradual accumulation of disabilities that may occur from the initial disease onset. The pathological processes underlying PPMS are complex and include a variety of different mechanisms and pathways, including inflammation, axonal degeneration, microglial activation/oxidation byproducts, mitochondrial injury, and glutamate excitotoxicity. There is currently no disease-modifying drug approved for PPMS in Japan. However, ocrelizumab, a humanized anti-CD20 monoclonal antibody, has been approved for PPMS by the Food and Drug Administration. In addition, some disease-modifying drugs have demonstrated significant efficacy in the treatment of PPMS in clinical trials.

Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis.

ObjectiveThe clinical course of multiple sclerosis (MS) is variable and largely unpredictable pointing to an urgent need for markers to monitor disease activity and progression. Recent evidence revealed that tissue transglutaminase (TG2) is altered in patient-derived monocytes. We hypothesize that blood cell–derived TG2 messenger RNA (mRNA) can potentially be used as biomarker in patients with MS.MethodsIn peripheral blood mononuclear cells (PBMCs) from 151 healthy controls and 161 patients with MS, TG2 mRNA was measured and correlated with clinical and MRI parameters of disease activity (annualized relapse rate, gadolinium-enhanced lesions, and T2 lesion volume) and disease progression (Expanded Disability Status Scale [EDSS], normalized brain volume, and hypointense T1 lesion volume).ResultsPBMC-derived TG2 mRNA levels were significantly associated with disease progression, i.e., worsening of the EDSS over 2 years of follow-up, normalized brain volume, and normalized gray and white matter volume in the total MS patient group at baseline. Of these, in patients with relapsing-remitting MS, TG2 expression was significantly associated with worsening of the EDSS scores over 2 years of follow-up. In the patients with primary progressive (PP) MS, TG2 mRNA levels were significantly associated with EDSS, normalized brain volume, and normalized gray and white matter volume at baseline. In addition, TG2 mRNA associated with T1 hypointense lesion volume in the patients with PP MS at baseline.ConclusionPBMC-derived TG2 mRNA levels hold promise as biomarker for disease progression in patients with MS.Classification of EvidenceThis study provides Class II evidence that in patients with MS, PBMC-derived TG2 mRNA levels are associated with disease progression.

A Clinical Perspective: Somatosensory Evoked Potentials May Suggest MS Type and Care Management

Background: This Multiple Sclerosis (MS) is a Central Nervous System (CNS) disease characterized by demyelination or axonal loss encompassing several clinical subtypes—Relapsing-Remitting MS (RRMS), Secondary-Progressive MS (SPMS), and Primary-Progressive MS (PPMS). Strategies for treating progressive forms are limited, and better understanding of underlying pathophysiology is essential. Method: Somatosensory Evoked Potentials (SEP) were analyzed for CNS conduction slowing caused by myelin impairment defined as 3 or more standard deviations, in 109 people with MS (16 with PPMS compared to 93 with RRMS and/or SPMS). Results: People with RRMS and SPMS have a higher prevalence of CNS conduction slowing compared to PPMS (83.9% compared to 12.5% respectively, P<.001). Subgroup analysis suggests this is not due to differences in age at SEP, timing of SEP in disease course, or differences in disease severity at time of SEP. Conclusion: CNS demyelination can be assessed by SEP and tends to be significantly less in patients with PPMS compared to RRMS or SPMS, despite similar levels of disability. This has important implications for underlying pathophysiology, suggesting that demyelination and axonal degeneration may independently contribute to disease progression.

Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) (p = 0.017) for progression during follow-up. Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20\u2014Yet Progress Continues

Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies.