Biofiltration of gaseous mixtures of dimethyl sulfide, dimethyl disulfide and dimethyl trisulfide: Effect of operational conditions and microbial analysis.

The efficient removal of volatile sulfur compounds (VSCs), such as dimethyl sulfide (DMS), dimethyl disulfide (DMDS) and dimethyl trisulfide (DMTS), is crucial due to their foul odor and corrosive potential in sewer systems. Biofilters (BFs) offer promise for VSCs removal, but face challenges related to pH control and changing conditions at full scale. Two BFs, operated under acidophilic conditions for 78 days, were evaluated for their performance at varying inlet concentrations and empty bed residence times (EBRTs). BF1, incorporating 4-6 mm marble limestone for pH control, outperformed BF2, which used NaHCO3 in the nutrient solution. BF1 displayed better resilience, maintained a stable pH of 4.6 ± 0.6, and achieved higher maximum elimination capacities (ECmax, 41 mg DMS m-3 h-1 (RE 38.3%), 146 mg DMDS m-3 h-1 (RE 83.1%), 47 mg DMTS m-3 h-1 (RE 93.1%)) at an EBRT of 56 s compared to BF2 (9 mg DMS m-3 h-1 (RE 7.1%), 9 mg DMDS m-3 h-1 (RE 4.8%) and 11 mg DMTS m-3 h-1 (RE 26.6%)). BF2 exhibited pH stratification and decreased performance after feeding interruptions. The biodegradability of VSCs followed the order DMTS > DMDS > DMS, and several microorganisms were identified contributing to VSCs degradation in BF1, including Bacillus (14%), Mycobacterium (11%), Acidiphilium (7%), and Acidobacterium (3%).

As time goes by: Treatment challenges in elderly people with multiple sclerosis.

A demographic shift in multiple sclerosis (MS) is leading to an increased number of elderly people with MS (pwMS) and a rise in late-onset MS (LOMS) cases. This shift adds complexity to the treatment management of these patients, due to enhanced treatment-associated risks and the possible interplay between immunosenescence and disease-modifying therapies (DMTs). In the present paper, we performed a systematic review of the current evidence concerning the relationship between aging and treatment management in elderly pwMS. Our literature search identified 35 original studies relevant to this topic. The gathered evidence consistently indicates a diminished efficacy of DMTs in older pwMS, particularly in preventing disability accrual. Against this background, high-efficacy therapies (HETs) appear to show less benefit over moderate-low-efficacy DMTs in older patients. These data mainly derive from observational retrospective studies or meta-analyses conducted on randomized clinical trials (RCTs). RCTs, however, exclude pwMS older than 55 years, limiting our ability to acquire robust evidence regarding this patient group. Regarding treatment discontinuation in elderly pwMS with stable disease, the available data, which mainly focuses on older injectable DMTs, suggests that their suspension appears to be relatively safe in terms of disease activity. Nevertheless, the first RCT specifically targeting treatment discontinuation recently failed to demonstrate the non-inferiority of treatment discontinuation over continuation, in terms of MRI activity. On the other hand, the evidence on the impact of discontinuation on disease progression is more conflicting and less robust. Furthermore, there is an important lack of studies concerning sequestering DMTs and virtually no data on the discontinuation of anti-CD20 monoclonal antibodies. De-escalation strategy is gaining attention as a de-risking approach alternative to complete treatment discontinuation. It may be defined as the decision to shift from HETs to less potent DMTs in elderly pwMS who have a stable disease. This strategy could reduce treatment-related risks, while minimizing the risk of disease activity and progression potentially associated with treatment discontinuation. This approach, however, remains unexplored due to a lack of studies. Given these findings, the present scenario underlines the urgent need for more comprehensive and robust studies to develop optimized, data-driven treatment strategies for elderly pwMS and LOMS, addressing the unique challenges of MS treatment and aging.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab.

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Headache and Other Pain Syndromes in Multiple Sclerosis: A Narrative Review.

Multiple sclerosis is a chronic and progressive neurological disease, with an important socio-economic burden. Over time, an increased incidence of headaches like migraines and tension headaches has been observed among these patients. Headaches have not been considered as multiple sclerosis-related symptoms, even representing a red flag for multiple sclerosis diagnosis. It is uncertain whether the headache-multiple sclerosis association could be explained by the presence of common triggers or a common physiopathological mechanism (involvement of tertiary B-cell follicles). An important differential diagnosis is between multiple sclerosis attacks and migraines with aura, which can also be associated with neurological deficits. Another important aspect is the occurrence or exacerbation of the cephalalgic syndrome after the initiation of therapy for multiple sclerosis (DMTs), or the improvement of headache after the initiation of certain DMT drugs. In addition to headaches, individuals diagnosed with multiple sclerosis often report experiencing diverse pain syndromes, contributing to an additional decline in their overall quality of life. These syndromes are frequently neglected, the focus being on slowing down the progression of neurological deficits. This review aims to evaluate the characteristics of multiple-sclerosis-related headaches (frequency, possible correlation with attacks, and disease-modifying therapies) and the key distinctions in imaging characteristics between demyelinating lesions in multiple sclerosis and those observed in cases of primary headaches.

Recent trends in disease-modifying therapy use and associated sickness absence and disability pension among people with multiple sclerosis in Sweden.

BACKGROUND: Disease-modifying therapies (DMTs) have led to improved health and work productivity among people with multiple sclerosis (PwMS). OBJECTIVES: To describe trajectories of recent DMT use and their association with sickness absence and/or disability pension (SADP) among PwMS in Sweden. METHODS: A longitudinal register-based study was conducted among 1395 PwMS with treatment start in 2014/2015. While DMT use over 5 years was assessed using sequence analysis resulting in four clusters, a 7-year (Y-2 toY4) trend of SADP was analyzed using zero-inflated negative binomial regression. RESULTS: Four clusters of DMT use trajectories were identified: long-term non-high-efficacy (483, 34.6%), long-term high-efficacy (572, 41%), escalation (221, 15.8%), and discontinuation (119, 8.5%). Progressive MS and higher expanded disability status scale scores were associated with the escalation, long-term high-efficacy, or discontinuation clusters. PwMS in the long-term high-efficacy and escalation clusters had higher likelihood of being on SADP. However, PwMS initiating high-efficacy DMTs demonstrated steeper decline in SADP than others. CONCLUSION: Using sequence analysis, this study showed recent DMT use trajectories among PwMS where initiation of high-efficacy DMTs has become more common. The trend of SADP was stable and lower in those using non-high-efficacy DMTs and larger improvements were shown in those initiating high-efficacy DMTs.

The evolution of multiple sclerosis disease-modifying therapies: An update for pharmacists.

PURPOSE: Multiple sclerosis (MS) and the evolution of disease-modifying therapies (DMTs) and their indications, mechanisms of action, efficacy, pregnancy class, and cost are discussed. SUMMARY: MS is an immune-mediated, demyelinating, and progressive neurological disorder that can cause both motor and cognitive deficits. Onset of MS typically occurs between the ages of 20 and 40 years, and the disease can result in significant disability over time. Since the introduction of the first DMT for the treatment of MS in 1993, significant progress has been made in the development of new classes of DMTs with different mechanisms of action, higher efficacy, and simpler administration schedules, offering patients better alternatives. However, drawbacks with the use of DMTs include their increasing cost and formulary restrictions. CONCLUSION: The treatment landscape of MS has significantly changed over the past 2 decades, and the introduction of newer classes of DMTs provides an opportunity for pharmacists to play an important role in the management of this patient population.

The Development of the Combination Drug Leukovir® Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review.

The review is devoted to the development and study of the drug Leukovir® (cladribine+ ribavirin) and its use in the treatment of relapsing-remitting and secondary progressive forms of multiple sclerosis, a chronic neurodegenerative disease aiming the risk reduction of relapse and progression of a disability. In clinical trials Leukovir® has proved to be efficient by up to 56 weeks for the treatment of relapsing-remitting and secondary progressive forms of multiple sclerosis. The drug is registered in the Republic of Belarus. The efficacy, safety and tolerability profile of the drug Leukovir® suggests that it is well suited for disease-modifying therapy of multiple sclerosis. Patients require four 35-day courses of treatment, each consisting of seven days of treatment followed by a break of 28 days. The use of Leukovir® has contributed to the suppression of inflammatory process activity according to MRI data and stabilization of the clinical condition. It has reduced the number of relapses in patients with relapsing-remitting and secondary-progressive forms of multiple sclerosis.

Current knowledge on multiple sclerosis pathophysiology, disability progression assessment and treatment options, and the role of autologous hematopoietic stem cell transplantation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects nearly 2.8 million people each year. MS distinguishes three main types: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). RRMS is the most common type, with the majority of patients eventually progressing to SPMS, in which neurological development is constant, whereas PPMS is characterized by a progressive course from disease onset. New or additional insights into the role of effector and regulatory cells of the immune and CNS systems, Epstein-Barr virus (EBV) infection, and the microbiome in the pathophysiology of MS have emerged, which may lead to the development of more targeted therapies that can halt or reverse neurodegeneration. Depending on the type and severity of the disease, various disease-modifying therapies (DMTs) are currently used for RRMS/SPMS and PPMS. As a last resort, and especially in highly active RRMS that does not respond to DMTs, autologous hematopoietic stem cell transplantation (AHSCT) is performed and has shown good results in reducing neuroinflammation. Nevertheless, the question of its potential role in preventing disability progression remains open. The aim of this review is to provide a comprehensive update on MS pathophysiology, assessment of MS disability progression and current treatments, and to examine the potential role of AHSCT in preventing disability progression.

The effect of glatiramer acetate, IFNß-1a, fingolimod, and dimethyl fumarate on the expression of T-bet, IFN-γ, and MEG3 in PBMC of RRMS patients.

OBJECTIVE: Multiple sclerosis (MS) is a progressing neurodegenerative disease marked by chronic central nervous system inflammation and degeneration.This study investigates gene expression profiles of T-box transcription factor TBX21 (T-bet), interferon-gamma (IFN-γ), and long non-coding RNA MEG3 in peripheral blood mononuclear cells (PBMCs) from treatment-naïve Relapsing-Remitting Multiple Sclerosis patients (RRMS), healthy controls, and RRMS patients on different Disease Modifying Therapies (DMTs). The aim is to understand the role of T-bet, IFN-γ, and MEG3 in MS pathogenesis and their potential as diagnostic and therapeutic targets. RESULTS: Elevated T-bet expression is observed in treatment-naïve RRMS patients compared to healthy individuals. RRMS patients treated with Interferon beta-1alpha (IFNß-1a) and fingolimod exhibit downregulated T-bet and MEG3 expression levels, respectively, with more pronounced effects in females. Healthy individuals show a moderate positive correlation between T-bet and MEG3 and between IFN-γ and T-bet. In RRMS patients treated with Glatiramer Acetate (GA), a strong positive correlation is observed between MEG3 and IFN-γ. Remarkably, RRMS patients treated with Dimethyl Fumarate (DMF) exhibit a significant positive correlation between T-bet and MEG3. These findings underscore the diagnostic potential of T-bet in RRMS, warranting further exploration of MEG3, T-bet, and IFN-γ interplay in RRMS patients.

The effect of disease modifying therapies on fatigue in multiple sclerosis.

INTRODUCTION: Fatigue is one of the most common and debilitating symptoms in people with multiple sclerosis (PwMS). Disease-modifying therapies (DMTs) are currently the gold standard in the treatment of MS and their effectiveness has been assessed through randomized clinical trials (RCTs). However, there is limited evidence on the impact of DMTs on fatigue in (PwMS). We conducted a systematic review to 1) understand whether fatigue is included as an outcome in MS trials of DMTs; 2) determine the effects on fatigue of treating MS with DMTs and 3) assess the quality of MS trials including fatigue as an outcome. METHODS: Two independent researchers systematically searched MEDLINE, EMBASE and ClinicalTrials.gov from 1993 to January 2023 for RCTs that measured fatigue as an outcome. Adherence to reporting standards was assessed with the Consolidated Standards of Reporting Trials (CONSORT)-Patient-Reported Outcomes (PRO), while the risk of bias (RoB) was assessed with the RoB 2 tool by the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review protocol was registered in PROSPERO (CRD42022383321). RESULTS: The search strategy identified 130 RCTs of DMTs of which 7 (5%) assessed fatigue as an outcome. Of the 7 trials, only two presented statistically significant results. In addition, the reporting of fatigue among RCTs was suboptimal with a mean adherence to the CONSORT-PRO Statement of 36% across all trials. Of the 7 trials included, four were assessed as 'high' RoB.. CONCLUSIONS: Fatigue has a major impact on PwMS yet there is limited trial-based evidence on the impact of DMTs on fatigue. Assessment of fatigue as an outcome is underrepresented in trials of DMTs and the reporting of PRO trial data is suboptimal. Thus, it is imperative that MS researchers conduct RCTs that include fatigue as an outcome, to support clinicians and people with MS (PwMS) to consider the impact of the different DMTs on fatigue.

Impact of COVID-19 and system recovery in delivering healthcare to people with multiple sclerosis: a population-based Study.

BACKGROUND: COVID-19 pandemic has affected the management of multiple sclerosis (MS). OBJECTIVE: To explore the impact of COVID-19 on healthcare delivery to people with MS and the subsequent recovery of the system. METHODS: In this population-based study in the Campania Region (Italy), we included people with MS across pre-COVID-19, lockdown, pre-vaccination, and vaccination periods. Differences in continuous outcomes between periods were explored using linear mixed models (annualized hospitalization rate (AHR) and adherence measured as medication possession ratio (MPR)). Differences in disease-modifying treatment (DMT) prescription rates (first DMT prescription, any DMT switch, switch from platform to highly effective DMT, and combination of first DMT prescription and any DMT switch) were assessed using an interrupted time series design. RESULTS: Compared with pre-COVID-19, AHR decreased during the lockdown (Coeff = 0.64;95%CI = -0.69, -0.59; p < 0.01), and remained lower during pre-vaccination and vaccination periods. Adherence decreased during pre-vaccination (Coeff = -0.04;95%CI = -0.05, -0.03; p < 0.01) and vaccination periods (Coeff = -0.07;95%CI = -0.08, -0.07; p < 0.01). After the lockdown, there was an increase in any DMT switch (IRR 2.05 95%CI 1.38,3.05; p < 0.01), in switch from platform to highly effective DMTs (IRR 4.45;95%CI 2.48,8.26; p < 0.01) and in first DMT prescriptions (IRR 2.48;95%CI 1.64,3.74; p < 0.01). CONCLUSIONS: DMT prescriptions quickly returned to pre-pandemic levels, reflecting good health system recovery. However, adherence has remained lower than the past, as from suboptimal care. Assessing long-term COVID-19 impact on MS healthcare is warranted.

Restless legs syndrome in multiple sclerosis patients: Prevalence, impact, and association with disease-modifying therapies in a Saudi Arabian pilot study.

BACKGROUND: Restless legs syndrome (RLS) emerges as a notable sleep disorder characterized by distressing sensations within the lower extremities. Its prevalence appears to be higher among patients afflicted with multiple sclerosis (MS) compared to the general population. Despite this observation, the understanding of the intricacies of RLS and its repercussions within the context of MS patients in Saudi Arabia remains limited. METHODS: Employing a cross-sectional design, a comprehensive investigation was undertaken at King Fahad Armed Forces Hospital in Jeddah, Saudi Arabia, spanning from November 2021 to March 2022. A cohort of 66 individuals diagnosed with MS was recruited and subjected to an assessment for RLS employing the revised diagnostic criteria outlined by the International Restless Legs Syndrome Study Group (IRLSSG). Furthermore, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Sleepiness Scale were employed to gage the extent of RLS's impact on sleep quality and daily functioning. RESULTS: The prevalence of RLS amidst the MS cohort was determined to be 30.4%. An observable association was discerned between RLS presence and higher scores on the Expanded Disability Status Scale (p < 0.001), along with diminished sleep quality scores (p < 0.001) and elevated fatigue scores based on IRLSSG criteria (p < 0.001). Within the studied MS cases, 98.5 % exhibited the relapsing-remitting subtype. Further investigation demonstrated that patients treated with Fingolimod or Ocrevus presented normal IRLSSG scores, whereas those undergoing Rituximab treatment manifested an even distribution between normal and moderate scores. Correspondingly, patients receiving interferons showcased 72.2 % with normal scores and 27.8 % with mild scores. Notably, a statistically significant variance in IRLSSG scores was observed when contrasting Fingolimod and Aubagio treatments (P < 0.001). CONCLUSION: The presence of RLS as a comorbidity in MS patients within the Saudi Arabian context emerges as a significant finding, exerting a discernible detrimental influence on both disability status and sleep quality. This study underscores the need for further investigations aimed at unraveling the intricate pathophysiological underpinnings, identification of risk factors, and exploration of therapeutic modalities for RLS in this population. Furthermore, additional research endeavors are warranted to elucidate the diverse impact of various disease-modifying therapies on clinical outcomes.

A short washout period from fingolimod to anti-CD20 therapy is safe and decreases the risk of reactivation.

The frequency of switches between Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) has increased considerably over previous years. Between fingolimod and anti-CD20 therapies, a 1-month washout period is usually recommended. However, disease reactivations are frequent after fingolimod (Fg) cessation. Using a retrospective observational monocentric exposed/non-exposed cohort study, we investigated the efficacy and the safety of a shorter washout period (WP) between Fg and anti-CD20. We compared two groups: 25 patients with a short WP (<21 days) and 20 patients with a longer WP (>21 days). We observed no reactivation during WP in patients with a short WP against a relapse in 55% of patients in the longer group. Moreover, clinical and biological safety was excellent. Based on these findings, we recommend a shorter WP between fingolimod and anti-CD20 therapies in MS.

Serological response to SARS-COV-2 vaccines in patients with multiple sclerosis in Argentina / Respuesta serológica a vacunas contra SARS-CoV-2 en pacientes con esclerosis múltiple en Argentina

Abstract Introduction : The objective was to assess the im munogenicity and effectiveness of vaccines against SARSCoV-2 in multiple sclerosis (MS) patients included in the Argentinean MS registry. Methods : A prospective cohort study between May and December 2021. The primary outcome was im munogenicity and effectiveness of vaccines during a three-month follow-up. Immunogenicity was evalua ted based on detection of total antibodies (Ab) against spike protein and neutralizing Ab in serum 4 weeks after the second vaccine dose. A positive COVID-19 case was defined according to Argentinean Ministry of Health. Results : 94 patients were included, mean age: 41.7 ± 12.1 years. Eighty (85.1%) had relapsing remitting mul tiple sclerosis (RRMS); 30 (31.9%) were under fingolimod treatment. The Sputnik V vaccine was the first dose in 33 (35.1%), and AstraZeneca in 61 (64.9%). In 60 (63.8%), the vaccine elicited a specific humoral response. Immu nological response according to the vaccination schemes showed no qualitative differences (p = 0.45). Stratified analysis according to the MS treatment showed that a significantly smaller number of subjects developed anti bodies against spike antigen among those that were on ocrelizumab compared to other groups (p ≤ 0.001), while a reduced number of patients under ocrelizumab where evaluated (n = 7). This was also observed for neutralizing antibodies in the ocrelizumab group (p < 0.001). During the three-month follow-up, two individuals were diag nosed with COVID-19. Conclusion: We found that MS patients that recei ved Sputnik V or AstraZeneca vaccines for SARS-CoV-2 developed a serological response with no differences between the vaccines used.

Resumen Introducción : El objetivo fue evaluar la inmunogeni cidad y efectividad de las vacunas contra el SARS-CoV-2 en pacientes con esclerosis múltiple (EM) incluidos en el registro argentino de EM (RelevarEM, NCT 03375177). Métodos : Estudio de cohorte prospectivo entre mayo y diciembre 2021. Se evaluó la inmunogenicidad (detec ción de anticuerpos totales (Ab) contra proteína espiga y anticuerpos neutralizantes en suero) y eficacia (nueva infección por COVID-19) durante seguimiento de tres meses. El momento de detección de anticuerpos fue 4 semanas después de segunda dosis de vacuna. Un caso positivo de COVID-19 se definió de acuerdo con la defi nición del Ministerio de Salud. Resultados : Se incluyeron 94 pacientes, edad media de 41.7 ± 12.1 años. Ochenta (85.1%) tenían EM remiten te-recurrente; 30 (31.9%) en tratamiento con fingolimod. La vacuna Sputnik V fue usada en 33 (35.1%), mientras que AstraZeneca se administró en 61 (64.9%). En 60 pa cientes (63.8 %), la vacuna provocó respuesta humoral específica. La respuesta inmunológica según esquemas de vacunación (Sputnik V, Astra Zeneca o esquemas he terólogos) no mostró diferencias cualitativas (p = 0.45). El análisis estratificado según tratamiento recibido para la EM mostró que número significativamente menor de sujetos desarrolló anticuerpos contra el antígeno espiga en los pacientes que recibieron ocrelizumab (p ≤ 0.001), aunque con un número reducido de pacientes evaluados bajo este tratamiento (n = 7). Esto también se observó para anticuerpos neutralizantes en el grupo bajo ocrelizumab (p < 0.001). Durante el seguimiento de tres meses, dos personas fueron diagnosticadas con COVID-19. Conclusión : Encontramos que los pacientes con EM que recibieron vacunas Sputnik V o AstraZeneca para el SARS-CoV-2 desarrollaron respuesta serológica sin diferencias entre las vacunas utilizadas.

Risk of COVID-19 in people with multiple sclerosis who are seronegative following vaccination.

BACKGROUND: People with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs) have attenuated IgG response following COVID-19 vaccination; however, the clinical consequences remain unclear. OBJECTIVE: To report COVID-19 rates in pwMS according to vaccine serology. METHODS: PwMS with available (1) serology 2-12 weeks following COVID-19 vaccine 2 and/or vaccine 3 and (2) clinical data on COVID-19 infection/hospitalisation were included. Logistic regression was performed to examine whether seroconversion following vaccination predicted risk of subsequent COVID-19 infection after adjusting for potential confounders. Rates of severe COVID-19 (requiring hospitalisation) were also calculated. RESULTS: A total of 647 pwMS were included (mean age 48 years, 500 (77%) female, median Expanded Disability Status Scale (EDSS) 3.5% and 524 (81%) exposed to DMT at the time of vaccine 1). Overall, 472 out of 588 (73%) were seropositive after vaccines 1 and 2 and 222 out of 305 (73%) after vaccine 3. Seronegative status after vaccine 2 was associated with significantly higher odds of subsequent COVID-19 infection (odds ratio (OR): 2.35, 95% confidence interval (CI): 1.34-4.12, p = 0.0029), whereas seronegative status after vaccine 3 was not (OR: 1.05, 95% CI: 0.57-1.91). Five people (0.8%) experienced severe COVID-19, all of whom were seronegative after most recent vaccination. CONCLUSION: Attenuated humoral response to initial COVID-19 vaccination predicts increased risk of COVID-19 in pwMS, but overall low rates of severe COVID-19 were seen.

Serological response to SARS-CoV-2 vaccines in patients with multiple sclerosis in Argentina.

INTRODUCTION: The objective was to assess the immunogenicity and effectiveness of vaccines against SARSCoV-2 in multiple sclerosis (MS) patients included in the Argentinean MS registry. METHODS: A prospective cohort study between May and December 2021. The primary outcome was immunogenicity and effectiveness of vaccines during a three-month follow-up. Immunogenicity was evaluated based on detection of total antibodies (Ab) against spike protein and neutralizing Ab in serum 4 weeks after the second vaccine dose. A positive COVID-19 case was defined according to Argentinean Ministry of Health. RESULTS: 94 patients were included, mean age: 41.7 ± 12.1 years. Eighty (85.1%) had relapsing remitting multiple sclerosis (RRMS); 30 (31.9%) were under fingolimod treatment. The Sputnik V vaccine was the first dose in 33 (35.1%), and AstraZeneca in 61 (64.9%). In 60 (63.8%), the vaccine elicited a specific humoral response. Immunological response according to the vaccination schemes showed no qualitative differences (p = 0.45). Stratified analysis according to the MS treatment showed that a significantly smaller number of subjects developed antibodies against spike antigen among those that were on ocrelizumab compared to other groups (p = 0.001), while a reduced number of patients under ocrelizumab where evaluated (n = 7). This was also observed for neutralizing antibodies in the ocrelizumab group (p < 0.001). During the three-month follow-up, two individuals were diagnosed with COVID-19. CONCLUSION: We found that MS patients that received Sputnik V or AstraZeneca vaccines for SARS-CoV-2 developed a serological response with no differences between the vaccines used.

Introducción: El objetivo fue evaluar la inmunogenicidad y efectividad de las vacunas contra el SARS-CoV-2 en pacientes con esclerosis múltiple (EM) incluidos en el registro argentino de EM (RelevarEM, NCT03375177). Métodos: Estudio de cohorte prospectivo entre mayo y diciembre 2021. Se evaluó la inmunogenicidad (detección de anticuerpos totales (Ab) contra proteína espiga y anticuerpos neutralizantes en suero) y eficacia (nueva infección por COVID-19) durante seguimiento de tres meses. El momento de detección de anticuerpos fue 4 semanas después de segunda dosis de vacuna. Un caso positivo de COVID-19 se definió de acuerdo con la definición del Ministerio de Salud. Resultados: Se incluyeron 94 pacientes, edad media de 41.7 ± 12.1 años. Ochenta (85.1%) tenían EM remitente-recurrente; 30 (31.9%) en tratamiento con fingolimod. La vacuna Sputnik V fue usada en 33 (35.1%), mientras que AstraZeneca se administró en 61 (64.9%). En 60 pacientes (63.8 %), la vacuna provocó respuesta humoral específica. La respuesta inmunológica según esquemas de vacunación (Sputnik V, Astra Zeneca o esquemas heterólogos) no mostró diferencias cualitativas (p = 0.45). El análisis estratificado según tratamiento recibido para la EM mostró que número significativamente menor de sujetos desarrolló anticuerpos contra el antígeno espiga en los pacientes que recibieron ocrelizumab (p = 0.001), aunque con un número reducido de pacientes evaluados bajo este tratamiento (n = 7). Esto también se observó para anticuerpos neutralizantes en el grupo bajo ocrelizumab (p < 0.001). Durante el seguimiento de tres meses, dos personas fueron diagnosticadas con COVID-19. Conclusión: Encontramos que los pacientes con EM que recibieron vacunas Sputnik V o AstraZeneca para el SARS-CoV-2 desarrollaron respuesta serológica sin diferencias entre las vacunas utilizadas.

Elucidation of the binding mode of organic polysulfides on the human TRPA1 receptor.

Introduction: Previous studies have established that endogenous inorganic polysulfides have significant biological actions activating the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor. Organic polysulfides exert similar effects, but they are much more stable molecules, therefore these compounds are more suitable as drugs. In this study, we aimed to better understand the mechanism of action of organic polysulfides by identification of their binding site on the TRPA1 receptor. Methods: Polysulfides can readily interact with the thiol side chain of the cysteine residues of the protein. To investigate their role in the TRPA1 activation, we replaced several cysteine residues by alanine via site-directed mutagenesis. We searched for TRPA1 mutant variants with decreased or lost activating effect of the polysulfides, but with other functions remaining intact (such as the effects of non-electrophilic agonists and antagonists). The binding properties of the mutant receptors were analyzed by in silico molecular docking. Functional changes were tested by in vitro methods: calcium sensitive fluorescent flow cytometry, whole-cell patch-clamp and radioactive calcium-45 liquid scintillation counting. Results: The cysteines forming the conventional binding site of electrophilic agonists, namely C621, C641 and C665 also bind the organic polysulfides, with the key role of C621. However, only their combined mutation abolished completely the organic polysulfide-induced activation of the receptor. Discussion: Since previous papers provided evidence that organic polysulfides exert analgesic and anti-inflammatory actions in different in vivo animal models, we anticipate that the development of TRPA1-targeted, organic polysulfide-based drugs will be promoted by this identification of the binding site.

Assessing the Health Economic Outcomes from Commercially Insured Relapsing Multiple Sclerosis Patients Who Switched from Other Disease-Modifying Therapies to Teriflunomide, in the United States.

Objective: Assess patient characteristics, healthcare resource utilization (HCRU), and relapses in patients with multiple sclerosis (MS) who switched to teriflunomide from other disease-modifying therapies (DMTs). Methods: Retrospective study of US Merative™ MarketScan® claims database (Jan 1, 2012-July 31, 2020,) including HIPAA-compliant, deidentified data. Patients ≥18 years with MS diagnosis (based on ICD-9/ICD-10 codes), receiving ≥1 DMT prior to teriflunomide and ≥12 months continuous enrollment pre and post index (date of teriflunomide initiation). Outcomes included inpatient and emergency room claims coinciding with MS diagnosis, MS-related healthcare costs, and annualized relapse rates (ARRs) (indirectly assessed using hospitalization/outpatient claims and steroid use coinciding with MS diagnosis). Results: The analyzed cohort (N=2016) was primarily female (79%); age (mean ± standard deviation) 51.4 ± 9.3 years; MS duration 4.7±2.8 years (at index). The majority (89.2%) were treated with one DMT before switching to teriflunomide. Use of outpatient services (event rate/100 person-years) increased post vs pre index; however, MRI visits significantly reduced over the same period (both P<0.0001). Costs for MS-specific outpatient visits decreased by $371 per patient per year (PPPY) after switching to teriflunomide. Despite an increase in use post index (0.024 to 0.033 rate/100 person-years; P<0.0001), costs for MS-specific laboratory services reduced (pre-index: $271 vs $248 PPPY post-index; P=0.02). Fewer patients had relapses after switching (pre-index: n=417 [20.7%]; post-index: n=333 [16.5%]). ARR was significantly lower after switching (pre-index: 0.269 vs post-index: 0.205; P=0.000). Conclusion: Switching to teriflunomide from existing DMTs in patients with relapsing MS resulted in a reduction in outpatient HCRU in this analysis of US claims data. The real-world effectiveness of teriflunomide was generally consistent with efficacy reported in clinical trials, showing a reduction in relapse following a switch to teriflunomide.

The benefits and risks of escalation versus early highly effective treatment in patients with multiple sclerosis.

INTRODUCTION: Multiple sclerosis is a chronic, demyelinating, inflammatory, and neurodegenerative disease of the central nervous system that affects over 2 million people worldwide. Considerable advances have been made in the availability of disease modifying therapies for relapsing-remitting multiple sclerosis since their introduction in the 1990s. This has led to debate regarding the optimal first-line treatment approach: a strategy of escalation versus early highly effective treatment. AREAS COVERED: This review defines the strategies of escalation and early highly effective treatment, outlines the pros and cons of each, and provides an analysis of both the current literature and expected future directions of the field. EXPERT OPINION: There is growing support for using early highly effective treatment as the initial therapeutic approach in relapsing-remitting multiple sclerosis. However, much of this support stems from observational real-world studies that use historic data and lack safety outcomes or randomized control trials that compare individual high versus low-moderate efficacy therapies, instead of the approaches themselves. Randomized control trials (DELIVER-MS, TREAT-MS) are needed to systemically and prospectively compare contemporary escalation versus early highly effective treatment approaches.