Benefits of early highly effective versus escalation treatment strategies in relapsing multiple sclerosis estimated using a treatment-sequence model.

BACKGROUND: Uncertainty about disproportionate impact on health care budgets limits implementation of early highly effective treatment (EHT) in multiple sclerosis (MS). OBJECTIVE: To estimate cost-effectiveness of escalation versus EHT disease-modifying treatment (DMT) sequences. METHODS: Using a health-economic approach, we analysed health benefits (relapse rate reduction, disability prevention), direct/indirect DMT and societal costs of escalation versus EHT DMT sequences. In scenario analyses, we allowed (1) earlier use of alemtuzumab (ALE) and (2) a single retreatment with cladribine (CLA). RESULTS: In our model, we showed that the ratio between costs and quality-adjusted life years (QALYs) for the most cost-effective EHT and escalation sequence results into a similar net health benefit with higher costs and also higher QALYs associated with an EHT versus escalation strategy. Earlier use of ALE is more cost-effective than in later lines, even when aggravating the impact of its side-effects tenfold. Retreatment with CLA was more cost-effective in both escalation and EHT sequences. CONCLUSIONS: Certain EHT sequences are equally cost-effective to escalation sequences and are likely to result in more health at uncertain additional costs. The favourable cost-benefit ratio of CLA and ALE suggests that a wider application of affordable highly effective therapies could promote the cost-effectiveness both EHT and escalation approaches.

Clinical effectiveness of coronavirus disease 2019 vaccination in patients with multiple sclerosis stratified by disease-modifying treatment.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. METHODS: Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. RESULTS: On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. CONCLUSIONS: Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.

European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).

BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.

Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

BACKGROUND: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. METHODS: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. RESULTS: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]. CONCLUSIONS: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Clinical implications for the association of psoriasis and multiple sclerosis: an observational study.

BACKGROUND: Multiple sclerosis (MS) and psoriasis (PsO) are distinct chronic autoimmune conditions with varying impacts on patients' lives. While the co-occurrence of MS and PsO has been reported, the underlying pathogenic link remains unclear. This study aimed to investigate the prevalence of PsO in a MS outpatient clinic population and explore the potential interplay between these conditions. METHODS: 316 MS patients who had at least one visit at our MS center in the last year, were selected from our outpatient MS Clinic electronic database and were e-mailed in August 2023 and inquired about a previous diagnosis of PsO. Demographic and MS history data were retrospectively gathered for two groups: MS patients without and with PsO. Information about MS phenotype, Expanded Disability Status Scale (EDSS) score at the diagnosis and at last follow-up, disease modifying therapy (DMT) were collected retrospectively from our MS data set. PsO diagnosis was confirmed by an experienced dermatologist and severity was assessed with the Psoriasis Area and Severity Index (PASI). RESULTS: Among 253 respondents, 5.85% reported a PsO diagnosis that was confirmed after the dermatological evaluation Among patients with psoriasis 66.67% had progressive course of MS (p = 0.032) and the onset of PsO typically occurred after MS diagnosis. 9 out 15 patients had a PASI score of 0 and 6 are currently undergoing treatment with an anti-CD20 therapy. Notably, a subset of our patients were on anti-CD20 therapy and did not experience a worsening of dermatological symptoms. DISCUSSION AND CONCLUSION: The prevalence of PsO in our outpatient MS population aligns with previous studies. Treatment approaches should be tailored to individual patient needs, emphasizing collaboration between neurologists and dermatologists. Medications like dimethyl fumarate, effective in both conditions, could be considered. The data from our study also suggest that anti-CD20 therapy may be a viable option for some patients with concurrent MS and mild PsO, without a significant worsening of dermatological symptoms. Further research is needed to elucidate the complex relationship between MS and PsO and to develop more effective therapeutic strategies for patients with both conditions.

Therapeutic targeting of Huntington's disease: Molecular and clinical approaches.

Huntington's disease (HD) is an autosomal dominant ailment that affects a larger population. Due to its complex pathology operating at DNA, RNA, and protein levels, it is regarded as a protein-misfolding disease and an expansion repeat disorder. Despite the availability of early genetic diagnostics, disease-modifying treatments are still missing. Importantly, potential therapies are starting to make their way through clinical trials. Still, clinical trials are ongoing to discover potential drugs to relieve HD symptoms. However, now being aware of the root cause, the clinical studies are focused on molecular therapies to target it. The road to success has not been without bumps since a big phase III trial of tominersen was unexpectedly discontinued due to exceeding risks than drug's benefit to the patients. Although the trial's conclusion was disappointing, there is still cause to be optimistic about what this technique may achieve. We have reviewed the present disease-modifying therapies in clinical development for HD and examined the current landscape of developing clinical therapies. We further investigated the pharmaceutical development of Huntington's medicine in the pharma industries and addressed the existing challenges in their therapeutic success.

Is immunology doing well? A look at 100 immune-mediated inflammatory diseases for 100 years of the Journal.

It is now 60 years since Ian Mackay and Macfarlane Burnet published their seminal text "The Autoimmune Diseases" in which they examined the full scope of human inflammatory pathology as a manifestation of the underlying structure and function of the immune system. Here I revisit this approach to ask to what extent has the promise of Mackay and Burnet's work been exploited in clinical medicine as currently practiced. In other words, is immunology doing well? Despite spectacular headline contributions of immunology in clinical medicine, I present evidence suggesting a performance ceiling in our capacity to answer the relatively straightforward questions that patients frequently ask about their own diseases and find that this ceiling exists across almost all of the 100 immune-mediated inflammatory diseases examined. I propose that these questions are difficult, not so much because the immune system is overwhelmingly complex but rather that we have more to learn about the relatively simple agents and rules that may underpin self-organizing complex interacting systems as revealed in studies from other disciplines. The way that the immune system has evolved to exploit the ancient machinery determining three independent cell fate timers as described in this Journal would be a great place to start to decode the self-organizing principles that underpin the emergent pathology that we observe in the clinic.

Preparedness of the Brazilian health-care system to provide access to a disease-modifying Alzheimer's disease treatment.

BACKGROUND: While the majority of patients with Alzheimer's disease resides in low and middle-income countries, little is known of their preparedness for emerging disease-modifying treatments. We analyze the preparedness of Brazil, one of the most populous middle-income countries, from a capacity and institutional preparedness perspective. METHODS: Desk research and 12 interviews for background and capacity data. Markov model to estimate wait times for access to treatment. FINDINGS: Brazil has no national dementia strategy or established pathway for evaluation of cognitive concerns, and dementia is typically diagnosed late if at all. While members of private health plans have ready access to elective specialty care, wait times in the public sector are long. Assuming potentially treatment-eligible patients are referred from primary to specialty care based on a brief cognitive exam and a blood test for the Alzheimer's pathology, available capacity will not be sufficient to match the projected demand. The biggest obstacle is availability of dementia specialist visits, and the effect of population growth and ageing means that the wait list for specialist appointment will continue to grow from around 400,000 in 2022 to over 2.2 million in 2040. We do not project substantial wait times for confirmatory biomarker testing and treatment delivery but note that this is a consequence of patients waiting for their specialist appointments. These queues will result in estimated persistent wait times for treatment of around two years on average with substantial differences between the public and private sectors, as capacity growth is insufficient to keep up with increasing demand. DISCUSSION: Our findings suggest that Brazil is ill-prepared to provide timely access to an Alzheimer's treatment with predicted wait times of about two years, largely because of a limited number of dementia specialists.

Preparedness of China's health care system to provide access to a disease-modifying Alzheimer's treatment.

INTRODUCTION: Although the majority of patients with Alzheimer's disease (AD) reside in low-and middle-income countries, little is known of the infrastructure in these countries for delivering emerging disease-modifying treatments. METHODS: We analyze the preparedness of China, the world's most populous middle-income country, using desk research, expert interviews and a simulation model. RESULTS: Our findings suggest that China's health care system is ill-prepared to provide timely access to Alzheimer's treatment. The current pathway, in which patients seek evaluation in hospital-based memory clinics without a prior assessment in primary care, would overwhelm existing capacity. Even with triage using a brief cognitive assessment and a blood test for the AD pathology, predicted wait times would remain over 2 years for decades, largely due to limited capacity for confirmatory biomarker testing despite adequate specialist capacity. DISCUSSION: Closing this gap will require the introduction of high-performing blood tests, greater reliance on cerebrospinal fluid (CSF) testing, and expansion of positron emission tomography (PET) capacity.

[Amyotrophic lateral sclerosis-Motor neuron disease with a wide clinical and genetic spectrum]. / Amyotrophe Lateralsklerose ­ Motoneuronerkrankung mit großem klinischem und genetischem Spektrum.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Besides a timely diagnosis, precise knowledge of the clinical manifestations and differential diagnoses is essential. While most patients develop the disease at an older age, hereditary causes play a more frequent role in the juvenile forms. OBJECTIVE: What is the current state of ALS diagnostics, which new treatment options exist? MATERIAL AND METHOD: Literature search using Pubmed.gov. RESULTS: The main focus is on an individualized symptomatic treatment as no curative treatment approaches exist. However, new insights into the genetic and pathophysiological principles of the different forms of ALS open the way for future disease-modifying treatment options. CONCLUSION: In cases of a clinical suspicion of ALS molecular genetic diagnostics should be considered, particularly in juvenile and young adult patients, to exclude differential diagnoses and to enable patients access to new treatment approaches.

Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

Olfactory threshold predicts treatment response in relapsing multiple sclerosis.

BACKGROUND: Olfactory threshold (OT) is associated with short-term inflammatory activity in relapsing multiple sclerosis (RMS). OBJECTIVE: We aimed to investigate OT for prediction of treatment response in RMS. METHODS: In this 5-year prospective study on 123 RMS patients, OT was measured at disease-modifying treatment (DMT) initiation (M0), after 3 months (M3), and 12 months (M12) by Sniffin' Sticks test. Primary endpoint was defined as an absence of relapse during the observation period, with Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) activity being the secondary endpoints. Optimal cutoff values were determined by receiver operating characteristic analyses and their predictive value assessed by multivariable Cox regression models. RESULTS: Higher OT scores at M0, M3, and M12 were independently associated with decreased relapse probability with the strongest risk reduction at M3 (hazard ratio (HR) = 0.44, p < 0.001). Improvement of OT scores from M0 to M3 (ΔOTM3) was also associated with reduced relapse risk (HR = 0.12, p < 0.001). OT score > 6.5 at M3 was the strongest predictor of relapse freedom (HR = 0.10, p < 0.001) with high diagnostic accuracy (positive predictive value (PPV) = 87%), closely followed by ΔOTM3 ⩾ 0.5 (HR = 0.12, p < 0.001, PPV = 86%). CONCLUSIONS: OT is an independent predictor of freedom of disease activity upon DMT initiation within 5 years and may be a useful biomarker of treatment response.

Impact of COVID-19 on multiple sclerosis care and management: Results from the European Committee for Treatment and Research in Multiple Sclerosis survey.

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.

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

International consensus on diagnosis and management of Dravet syndrome.

OBJECTIVE: This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS-specific therapies and emerging disease-modifying treatments. METHODS: A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease-modifying therapies) and nominated the 31-member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. RESULTS: There was strong consensus that infants 2-15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first- to third-line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease-modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. SIGNIFICANCE: This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease-modifying therapies.

Progression models for repeated measures: Estimating novel treatment effects in progressive diseases.

Mixed models for repeated measures (MMRMs) are ubiquitous when analyzing outcomes of clinical trials. However, the linearity of the fixed-effect structure in these models largely restrict their use to estimating treatment effects that are defined as linear combinations of effects on the outcome scale. In some situations, alternative quantifications of treatment effects may be more appropriate. In progressive diseases, for example, one may want to estimate if a drug has cumulative effects resulting in increasing efficacy over time or whether it slows the time progression of disease. This article introduces a class of nonlinear mixed-effects models called progression models for repeated measures (PMRMs) that, based on a continuous-time extension of the categorical-time parametrization of MMRMs, enables estimation of novel types of treatment effects, including measures of slowing or delay of the time progression of disease. Compared to conventional estimates of treatment effects where the unit matches that of the outcome scale (eg, 2 points benefit on a cognitive scale), the time-based treatment effects can offer better interpretability and clinical meaningfulness (eg, 6 months delay in progression of cognitive decline). The PMRM class includes conventionally used MMRMs and related models for longitudinal data analysis, as well as variants of previously proposed disease progression models as special cases. The potential of the PMRM framework is illustrated using both simulated and historical data from clinical trials in Alzheimer's disease with different types of artificially simulated treatment effects. Compared to conventional models it is shown that PMRMs can offer substantially increased power to detect disease-modifying treatment effects where the benefit is increasing with treatment duration.

Impact of vaccination on COVID-19 outcome in multiple sclerosis.

BACKGROUND: COVID-19 continues to challenge neurologists in counselling persons with multiple sclerosis (pwMS) regarding disease-modifying treatment (DMT) and vaccination. The objective here was to characterize predictors of COVID-19 outcome in pwMS. METHODS: We included pwMS with PCR-confirmed COVID-19 diagnosis from a nationwide population-based registry. COVID-19 outcome was classified as either mild or severe. Impact of DMT, specifically anti-CD20 monoclonal antibodies, and vaccination on COVID-19 outcome was determined by multivariable models adjusted for a-priori-risk (determined by a cumulative risk score comprising age, disability and comorbidities). RESULTS: Of 317 pwMS with COVID-19 (mean age 41.8 years [SD 12.4], 72.9% female, median EDSS 1.5 [range 0-8.5], 77% on DMT [16% on antiCD20]), 92.7% had a mild course and 7.3% a severe course with 2.2% dying from COVID-19. Ninety-seven pwMS (30.6%) were fully vaccinated. After a median 5 months from vaccination to SARS-CoV-2 infection (range 1-9), severe COVID-19 occurred in 2.1% of fully vaccinated pwMS compared to 9.5% in unvaccinated pwMS (p=0.018). A-priori-risk robustly predicted COVID-19 severity (R2 0.605; p<0.001). Adjusting for a-priori-risk, anti-CD20 treatment was associated with increased COVID-19 severity (odds ratio [OR] 3.3; R2 0.113; p=0.003), but exposure to any other DMT was not. Fully vaccinated pwMS showed a significantly decreased risk for severe COVID-19 (OR 0.21, R2 0.144, p<0.001). CONCLUSIONS: In a population-based MS cohort, COVID-19 course is primarily predicted by a-priori-risk (depending on age, disability and comorbidities) explaining about 60% of variance. Anti-CD20 treatment is associated with a moderately increased risk, while reassuringly vaccination provides protection from severe COVID-19.

Signs and symptoms of COVID-19 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. METHOD: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. RESULTS: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. CONCLUSION: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

Cost-utility analysis of teriflunomide in naïve vs. previously treated patients with relapsing-remitting multiple sclerosis in Italy.

BACKGROUND: Multiple sclerosis (MS) accounts for 176 cases per 100,000 inhabitants (female/male ratio = 2:1) in Italy. For most of the patients (67%), the disease course is relapsing-remitting MS (RRMS). OBJECTIVE: To compare the costs and quality-adjusted life years (QALYs) of teriflunomide in RRMS naïve patients vs. RRMS patients previously treated (experienced) with other disease-modifying therapies in Italy. METHODS: A four health states Markov model-supported cost-utility analysis (CUA) covering a 7-year timespan through annual cycles was developed, following the healthcare sector and the societal viewpoints. Part of the parameters that populated the Markov model was obtained from a questionnaire administered to four primary Italian MS centres. Costs of healthcare and non-healthcare resources, expressed in euro (€) 2019, and QALYs were discounted at 3% real social discount rate. One-way, scenario and probabilistic sensitivity analyses tested the uncertainty of the baseline findings. RESULTS: Baseline CUA shows that teriflunomide in RRMS naïve patients is strongly dominant vs. experienced patients (healthcare sector perspective: - €1042.68 and + 0.480 QALYs; societal perspective: - €6782.81 and + 0.480 QALYs). Sensitivity analyses confirmed the robustness of the baseline results. CONCLUSION: Teriflunomide in RRMS naïve vs. experienced patients is cost-effective and possibly strongly dominant from both the healthcare sector and the society viewpoints in Italy. Our findings need further confirmation from real-world studies.

Lung involvement correlates with disability in MS patients with COVID-19 pneumonia.

INTRODUCTION: The visual-well aerated lung (V-WAL) is a score for the visual quantification of the well aerated lung on CT scan in COVID-19 patients and its value at admission seems to predict future COVID-19 severity. The aim of the present study was to analyze the association between V-WAL and risk factors for severe COVID-19 evolution in people with multiple sclerosis. MATERIALS AND METHODS: This is an observational retrospective study, including people with multiple sclerosis and concomitant COVID-19, who were investigated with a lung CT scan at Hospital admission. The association of V-WAL with age, sex, EDSS, comorbidities, recent steroid use, and treatment (anti-CD20 vs other) was assessed by a multivariate linear regression model. RESULTS: In this observational retrospective study, the only factor that was significantly associated to a lower V-WAL at multivariable analysis was an increasing level of the EDSS (R2 = 0.41, p = 0.001), with an average decrease of 8% of V-WAL for each additional EDSS point. DISCUSSION AND CONCLUSION: This analysis shows that a high EDSS level is the main factor associated to the severity of lung involvement in a group of people with multiple sclerosis who were hospitalized for Covid-19.