Multiple Sclerosis Disease-modifying Therapies Research Articles

Trajectories of self-reported fatigue following initiation of multiple sclerosis disease-modifying therapy

BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing–remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with...

Temporal and spatial patterns in the prescriptions of disease-modifying therapies for multiple sclerosis. Results from the Italian Multiple Sclerosis and Related Disorders Register

BackgroundThe therapeutic scenario in multiple sclerosis (MS) has evolved over recent years with the progressive introduction of new drugs focused to better balance efficacy, safety and management requirements. The objective of this study was to examine the prescribing patterns of disease-modifying therapies (DMT) over time and across different geographic areas, and the latency between disease onset, first Register center visit, disease diagnosis, and the start of treatment in a large cohort of persons with MS from the Italian Multiple Sclerosis and Related Disorders Register. MethodsUp to 2022, the Register collected data from 124 centers on more than 78,000 persons, of whom 56,872 received at least one DMT prescription. Beside baseline demographic and clinical characteristics, we focused on DMT according to their efficacy distinguishing between moderate-efficacy (ME), or high-efficacy (HE). ResultsThere was a higher probability of prescribing HE-DMT for increasing calendar years (multivariable odds ratio, OR=11.51 in 2021 or thereafter vs before 2000), in males (OR=1.08 vs females), patients with primary progressive with or without relapse (OR=3.00 vs clinically isolated syndrome), those with a higher Expanded Disability Status Scale score (OR=3.85 for >4 versus 0–1), and those from larger referral centers (OR=1.89 vs smaller ones). Conversely, higher age at onset was associated to a lower probability of prescribing HE-DMT (OR=0.74 at 40 or more vs <20 years). A trend to shorter times was observed in subsequent calendar years for disease onset, first center visit, diagnosis and first DMT prescription. No trend was detected based on the location of the geographic referral centers. The times between disease onset, first center visit, and diagnosis and the first DMT prescription showed significant decreases according to the year, while differences were less evident for the geographic areas. ConclusionThis study highlights some factors influencing the choice of HE-DMT, including aspects of both healthcare and clinical phenotype. The absence of a geographic pattern may indicate some homogeneity in DMT prescriptions across different Italian MS centers.

Clinical trial evidence of quality-of-life effects of disease-modifying therapies for multiple sclerosis: a systematic analysis.

Increasingly, patients, clinicians, and regulators call for more evidence on the impact of innovative medicines on quality of life (QoL). We assessed the effects of disease-modifying therapies (DMTs) on QoL in people with multiple sclerosis (PwMS). Randomized trials assessing approved DMTs in PwMS with results for at least one outcome referred to as "quality of life" were searched in PubMed and ClinicalTrials.gov. We identified 38 trials published between 1999 and 2023 with a median of 531 participants (interquartile range (IQR) 202 to 941; total 23,225). The evaluated DMTs were mostly interferon-beta (n = 10; 26%), fingolimod (n = 7; 18%), natalizumab (n = 5; 13%), and glatiramer acetate (n = 4; 11%). The 38 trials used 18 different QoL instruments, with up to 11 QoL subscale measures per trial (median 2; IQR 1-3). QoL was never the single primary outcome. We identified quantitative QoL results in 24 trials (63%), and narrative statements in 15 trials (39%). In 16 trials (42%), at least one of the multiple QoL results was statistically significant. The effect sizes of the significant quantitative QoL results were large (median Cohen's d 1.02; IQR 0.3-1.7; median Hedges' g 1.01; IQR 0.3-1.69) and ranged between d 0.14 and 2.91. Certain DMTs have the potential to positively impact QoL of PwMS, and the assessment and reporting of QoL is suboptimal with a multitude of diverse instruments being used. There is an urgent need that design and reporting of clinical trials reflect the critical importance of QoL for PwMS.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Real-world persistence of multiple sclerosis disease-modifying therapies.

Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

Treatment discontinuation in older people with multiple sclerosis.

The aim of this review was to examine the evidence for disease-modifying therapies (DMTs) discontinuation in older people with multiple sclerosis (MS). We first summarized aging-associated biological changes that influence MS progression and DMT effectiveness, and then summarized recent evidence in evaluating clinical outcomes of discontinuing DMTs in older people with MS. Recent findings provide mixed evidence regarding the outcomes of DMT discontinuation in older people with MS. Retrospective observational studies suggested older age and longer stable duration on DMT before DMT discontinuation were associated with lower risk of relapse in people with MS. However, one randomized clinical trial did not demonstrate the noninferiority of DMT discontinuation. The available clinical evidence examining DMT discontinuation in older people with MS remains inconclusive. More robust evidence from clinical trials and real-world data will be necessary to guide clinical decisions regarding DMT discontinuation in older people with MS.

Headache in Multiple Sclerosis: A Narrative Review.

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by autoimmune-mediated damage to oligodendrocytes and subsequent myelin destruction. Clinical implications: Clinically, the disease presents with many symptoms, often evolving over time. The insidious onset of MS often manifests with non-specific symptoms (prodromal phase), which may precede a clinical diagnosis by several years. Among them, headache is a prominent early indicator, affecting a significant number of MS patients (50-60%). Results: Headache manifests as migraine or tension-type headache with a clear female predilection (female-male ratio 2-3:1). Additionally, some disease-modifying therapies in MS can also induce headache. For instance, teriflunomide, interferons, ponesimod, alemtuzumab and cladribine are associated with an increased incidence of headache. Conclusions: The present review analyzed the literature data on the relationship between headache and MS to provide clinicians with valuable insights for optimized patient management and the therapeutic decision-making process.

Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis

Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS). Differentiating MS-ON from non-MS-ON acutely is challenging but important; non-MS ON often requires urgent immunosuppression to preserve vision. Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON; one standard deviation of MS-GRS increased the Hazard of MS 1.3-fold (95% confidence interval 1.07–1.55, P < 0.01). Participants stratified into quartiles of predicted risk developed incident MS at rates varying from 4% (95%CI 0.5–7%, lowest risk quartile) to 41% (95%CI 33–49%, highest risk quartile). The model replicated across two cohorts (Geisinger, USA, and FinnGen, Finland). This study indicates that a combined model might enhance individual MS risk stratification, paving the way for precision-based ON treatment and earlier MS disease-modifying therapy.

Use of multiple sclerosis disease-modifying therapies during pregnancy in France: Nationwide study between 2010 and 2021.

Multiple sclerosis (MS) frequently affects women of childbearing age and pregnant women. To assess the use of MS disease-modifying therapies (DMTs) during pregnancy in France over the last decade, marked by an increasing DMTs availability. All pregnancies ended from April 2010 to December 2021 in women with MS were identified based on the nationwide Mother-Child Register EPI-MERES, built from the French National Health Data System (Système National des Données de Santé (SNDS)). Of a total of 20,567 pregnancies in women with MS, 7587 were exposed to DMT. The number of DMT-exposed pregnancies markedly increased from 1079 in 2010-2012 to 2413 in 2019-2021 (+124%), especially those exposed to glatiramer acetate, natalizumab, dimethyl fumarate, and anti-CD20. Among pregnancies of women on DMT 6 months before pregnancy, 78.0% underwent DMT discontinuation and 7.6% switched DMT, generally before (33.0% and 77.0%, respectively) or during the first trimester of pregnancy (58.3% and 17.8%, respectively). DMT discontinuation decreased from 84.0% in 2010-2012 to 72.4% in 2019-2021 and was less frequent among women aged ⩾35 years and those socioeconomically disadvantaged. Despite MS therapeutic management adaptations to pregnancy, exposure during pregnancy to treatments whose safety profile has not yet been clearly established has increased sharply over the last decade.

University education facilitates uptake of disease-modifying therapies for multiple sclerosis: A community-based study using the UK MS Register.

Higher education is associated with better job opportunities and higher income. Herein, the impact of education on the uptake of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a publicly funded health care system was examined using the UK MS Register. All adult participants with relapsing remitting MS diagnosed between 2008 and 2021 were included. Those without data regarding their education levels were excluded. Binary, multinomial and Cox regression models were used to examine the association between education levels and uptake of DMTs. A total of 6317 participants fulfilled all inclusion and exclusion criteria. A total of 1826/2923 (62%) participants with a university education were treated with DMTs, compared to 1788/3394 (53%) participants with school/diploma received DMTs with an odds ratio of 1.318 (1.178-1.473). Participants with a university education were more likely to be treated with both moderate- and high-efficacy DMTs, compared to others, with odds ratios of 1.227 (1.087-1.385) and 1.545 (1.325-1.802), respectively. University education was also a positive predictor for faster initiation of DMTs, and, importantly, higher-efficacy DMTs. In a publicly funded health care system, despite intended equality of access, university education was associated with a higher uptake of DMTs.

The Impact of Insurance Restrictions in Newly Diagnosed Individuals With Multiple Sclerosis.

The medical system in the United States has been riddled with insurance restrictions used by insurance companies to limit health care costs. The effects of insurance restrictions on patients receiving disease-modifying therapies for multiple sclerosis (MS) have not been specifically studied. A retrospective cross-sectional study of 52 individuals recently diagnosed with MS at a tertiary neurology clinic was conducted to measure the association between prior authorization (PA) duration and other variables of interest. The Cox proportional hazards model was used to determine likelihood of approval. Further analysis included multivariable logistic regression to assess the influence of variables of interest on the initial decision from the insurance company and the effect of the PA on disease activity. Of 52 PAs, 50% were initially denied. An initial denial decreased the likelihood of approval by 98% (HR, 0.02; 95% CI, <0.01-0.09; P < .001). The odds of denial for oral medications (odds ratio [OR], 4.91; 95% CI, 1.33-21.52; P = .02) and infusions (OR, 8.35; 95% CI, 1.10-88.77; P = .05) were significantly higher than for injections. Medicaid had higher odds of denial compared with commercial insurance (OR, 4.51; 95% CI, 1.13-22.01; P = .04). An initial denial by insurance significantly increased the likelihood of disease activity (OR, 6.18; 95% CI, 1.33-44.86; P = .03). Insurance restrictions delay necessary treatments, increase the likelihood of disease activity, and rarely change the approved disease-modifying therapy. Reducing PAs may lead to improved outcomes for patients with MS.

The role of ocrelizumab in recommendations and in the Polish therapeutic programme

Multiple sclerosis is a heterogeneous and chronic disease, and the primary goal of treatment is to prevent relapses and slow the progression of disability. Ocrelizumab is a generally well-tolerated disease-modifying therapy for multiple sclerosis, with high efficacy in the treatment of active relapsing forms, and a valuable treatment method for delaying the progression of the disease in patients with the primary progressive form. The activity of relapsing multiple sclerosis is defined on the basis of the clinical course of the disease or radiological findings assessed over a year. The occurrence of clinical relapses and/or activity on magnetic resonance imaging is taken into account. In line with the recommendations of the European Committee for Treatment and Research in Multiple Sclerosis and the European Academy of Neurology, as well as in accordance with the guidelines of the American Academy of Neurology, updated in 2021, depending on the disease activity in the early stage of multiple sclerosis, the choice of a disease-modifying drug should be motivated by higher efficacy. Recommendations for the treatment of multiple sclerosis in most countries in Europe and around the world are based on the above-mentioned guidelines. In Poland, recommendations for treatment modifying the course of multiple sclerosis were developed in 2023 by experts from the Multiple Sclerosis and Neuroimmunology Section of the Polish Neurological Society. Treatment based on the B.29 drug programme of the National Health Fund in Poland allows, from 1 July 2023, in addition to escalation, using the induction model based on highly effective therapies as first-line treatment.

Dynamic changes in patient admission and their disabilities in multiple sclerosis and neuromyelitis optica: A Japanese nationwide administrative data study

BackgroundThe real-world data evidences how establishment of neuromyelitis optica (NMO) disease concept and development disease modifying therapy affect the patients with multiple sclerosis (MS) and NMO are lacking. The aim of this study is to clarify the diachronic trend of the severity and admissions of patients with MS and NMO. MethodsWe retrospectively investigated the trends in admissions, treatments, and disabilities in the patients with MS and NMO using the Japanese administrative data between 2012 and 2017. ResultsWe analyzed acute stage 9545 and 2035 admissions in each 6100 MS and 1555 NMO patients. The annual number of admission in MS significantly decreased in 6 years; however, those in NMO consistently increased. The patient proportion with lower disability was significantly increased in MS and NMO. These trends were especially observed in patients admitted to centralized hospitals with more active treatments, such as second-line disease modifying therapy for MS and plasmapheresis for NMO. Patients with NMO using DMT for MS diminished in 6 years. ConclusionA gradual improvement of disability in patients with MS and NMO was observed, probably due to advanced treatments, increased NMO awareness, and decreased misdiagnosis, which seems to be the key for better prognosis in MS and NMO.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis.

In multiple sclerosis, only immunomodulatory and immunosuppressive drugs are recognized as disease-modifying therapies. However, in recent years, several data from pre-clinical and clinical studies suggested a possible role of physical exercise as disease-modifying therapy in multiple sclerosis. Current evidence is sparse and often conflicting, and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated. Data, mainly derived from pre-clinical studies, suggest that exercise could enhance long-term potentiation and thus neuroplasticity, could reduce neuroinflammation and synaptopathy, and dampen astrogliosis and microgliosis. In humans, most trials focused on direct clinical and MRI outcomes, as investigating synaptic, neuroinflammatory, and pathological changes is not straightforward compared to animal models. The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Real-world treatment preferences among health care providers in the United States in selecting disease modifying therapies for patients with multiple sclerosis: a discrete choice experiment

AimsHealth care providers (HCPs) treating multiple sclerosis (MS) in clinical practice have numerous disease-modifying therapies (DMTs) to consider when evaluating treatment options. This study assessed the treatment preferences of HCPs in the United States, both direct (explicit) and derived (explicit and implicit), when selecting MS DMTs based on clinical and logistical treatment attributes.Materials and methodsA 45-minute web-enabled questionnaire was administered to HCPs who manage patients with MS to assess the importance of treatment attributes. HCPs were recruited through an online panel. This study examined treatment attributes relevant to treatment decisions in MS, with a focus on the burden to HCPs and their staff, as well as HCP attitudes toward various aspects of MS care such as diagnosis, treatment prioritization, and ease of initiating or switching DMTs. The study also employed a discrete choice experiment (DCE) to assess direct and derived treatment preferences.ResultsThe study recruited 145 HCPs. Direct assessments (a score of greater than 7.0 was considered important) suggested that safety (mean importance rating = 7.8/9) and relative risk reduction in relapses (7.6/9) and disability progression (7.5/9) were most important when selecting DMTs. In contrast, derived importance from the DCE (higher points corresponding to greater importance) suggested that logistical attributes such as dose frequency (mean relative attribute importance = 17.5%), dose titration (10.3%), formulation (9.4%), and volume of calls (9.1%) were important considerations, along with efficacy (16.5%), safety (9.8%), and gastrointestinal tolerability (9.4%).LimitationsThis study may have been subject to selection bias due to the application of eligibility criteria, the convenient sampling recruitment methodology, and recruitment of HCPs with internet access.ConclusionIn the direct assessment, clinical attributes were chosen as the most important treatment attributes by HCPs. However, in the DCE, derived treatment decisions rated logistical attributes as also being as important in treatment choice.

Barriers to accessing multiple sclerosis disease-modifying therapies in the Middle East and North Africa region: A regional survey-based study.

Multiple sclerosis (MS) management varies markedly between different countries of the Middle East and North Africa (MENA) region based on the availability and accessibility of disease-modifying therapies (DMTs). To evaluate the accessibility to DMTs in each MENA country, identify barriers to treatment and make recommendations for improved access to DMTs across the region. This is a descriptive, survey-based study whereby we extracted data collected, between October 2019 and April 2020, for countries in the MENA region by the Multiple Sclerosis International Federation (MSIF) through their Atlas of MS survey. 16 out of 19 countries in the MENA region were included in this study. Sudan and Syria did not have any originator DMTs approved. Interferons were the most widely low-efficacy originator approved DMTs. Three countries did not have any high efficacy DMTs approved. Moreover, follow-on DMTs were approved in half (50%) of the countries. Cost of treatment was the most important barrier, reported in nearly half (47%) of the MENA countries. Although most MENA countries have access to DMTs, more than half of countries report problems with treatment continuation, highlighting the need for a targeted regional strategy to address the variations in access to MS treatments.

Ocrelizumab exposure in relapsing-remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension.

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing-remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000mg or 600mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000mg or 600mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600mg every 24weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.

Multiple Sclerosis, Disease-Modifying Therapies, and Infections.

The use of highly effective multiple sclerosis (MS) disease-modifying therapies (DMTs) is rapidly increasing. Yet, little is known about their real-world risks of infections. The goals of this study were to assess the comparative risk of outpatient and serious infections across DMTs in a large, diverse, U.S. cohort and determine whether such risks are attributable to DMTs, having MS, or other factors. We conducted a retrospective cohort study of Kaiser Permanente Southern California members from 2008 through 2020 with MS and non-MS controls matched on age, sex, race, and ethnicity. MS treatments, serious (those requiring hospitalization) and outpatient infections, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHR) and risk ratios (aRR) were estimated using the Cox and Poisson regression, respectively. Six thousand, six hundred and twenty-six patients with MS with 11,929 treatment episodes (2,487 rituximab, 546 natalizumab, 298 fingolimod, 4,629 interferon-beta/glatiramer acetate, IFN/GLAT, and 3,969 untreated) and 33,550 population controls were included in the analyses. The average age at treatment start ranged from 38.9 to 49.2 years, and 74% were women. Untreated (aRR = 1.39, [95% CI = 1.35-1.44]) and IFN/GLAT-treated patients with MS (aRR = 1.60, [95% CI = 1.56-1.65]) had a higher risk of outpatient infections and serious infections (aHR = 2.97, [95% CI = 2.65-3.32 and aHR = 2.31, [95% CI = 2.04-2.62], respectively) compared with controls. Rituximab (aRR = 1.19, [95% CI = 1.14-1.25]), fingolimod (aRR = 1.22, [95% CI = 1.09-1.37]), and to a lesser extent, natalizumab treatment (aRR = 1.08, [95% CI = 0.97-1.20]) were associated with an increased risk of outpatient infections compared with IFN/GLAT. Rituximab (aHR = 1.41, [95% CI = 1.09-1.84]) and natalizumab (aHR = 1.40, [95% CI = 0.96-2.04]) treatment were associated with a similar increased risk of serious infections compared with IFN/GLAT. The only treatment-specific association identified was fingolimod with outpatient herpetic infections. Higher comorbidity index, previous hospitalization for infections, and advanced disability significantly increased the risk of serious infections independent of DMTs. Hospitalization for UTI-related pseudorelapses accounted for 24%-48% of serious infections. Patients with MS have higher risks of outpatient and serious infections compared with patients without MS. The risk of outpatient infections was similarly increased by rituximab and fingolimod and serious infections by rituximab and natalizumab compared with IFN/GLAT. Steps to minimize risks include optimizing bladder care, comorbidity prevention, varicella vaccination, and considering discontinuing or avoiding DMT use in patients with advanced disability and/or previous hospitalizations for infections.

Humoral immune response after Ad26.COV2.S vaccination in patients with multiple sclerosis treated with natalizumab

The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson &amp; Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.

A retrospective claims analysis of fatigue in patients with multiple sclerosis on disease-modifying therapy.

Fatigue, one of the most common symptoms in patients with multiple sclerosis (MS), severely impairs quality of life and the ability to work or perform activities of daily living. Real-world data on fatigue in MS can help inform healthcare decisions and identify care gaps. We identified fatigue in patients with MS, using existing codes for fatigue and proxies of fatigue in healthcare claims database records and characterized cohorts with and without markers of fatigue who had been prescribed disease-modifying therapies for MS (MS-DMTs). In this cohort study, we retrospectively analyzed Optum's de-identified Clinformatics® Data Mart database from 1 January 2015 to 31 December 2019. The index date was defined as the first prescription record date for any MS-DMT during the study identification period. Included patient records were from adults (≥18 years) with ≥2 MS diagnosis claims listed within 12 months prior to the index date. Patients had ≥1 claim for any MS-DMT during the identification period (1 January 2016-31 December 2018), continuous enrollment in a health plan with medical and pharmacy benefits for 12 months before the index date (assessment one), and 12 months following the index date or to end of data availability (assessment two). After exploratory analyses, we applied the following definition to sort patient records into two cohorts according to presence or absence of markers of fatigue: ≥1 diagnosis (International Classification of Diseases, Ninth/Tenth Revisions code) claim for fatigue or ≥2 claims for stimulant drugs or ≥2 procedure claims for a sleep study or ≥2 pharmacy claims for sleep aid drugs; we used the broadest definition of fatigue so meeting any of these criteria qualified patients with MS as having fatigue. To minimize assessment one differences in selected patient characteristics between cohorts, we applied 1:1 propensity score matching with age, sex, US geographic region, and Charlson Comorbidity Index score as covariates. We analyzed demographic data, markers of fatigue, comorbidities at assessment one, and physical disabilities and neurologic impairment at assessment two. Of 4077 patient records that met the eligibility criteria, 1976 had markers of fatigue. The propensity score-matched cohorts included 1519 patients each with and without fatigue. Assessment one comorbidities including anxiety (25.3% vs 10.5%; P<0.0001), arthritis (17.6% vs 12.9%; P=0.0003), depression (15.0% vs 3.5%; P<0.0001), and gastrointestinal disorders (20.3% vs 14.2%; P<0.0001) were significantly more prevalent in the cohort with markers of fatigue at assessment one compared with those without fatigue. At assessment two, the cohort with baseline fatigue upon initial assessment was more likely to have indication of physical impairments (spasticity [63.5% vs 35.8%; P<0.0001], bladder dysfunction [37.8% vs 24.0%; P<0.0001], cognitive/behavioral dysfunction [27.0% vs 18.6%; P<0.0001]), neurologic impairments (pain [59.1% vs 44.0%; P<0.0001], depression [29.2% vs 9.9%; P<0.0001], and sensory disturbances [54.2% vs 36.7%; P<0.0001]), compared with the cohort without markers of fatigue at assessment one. In our analysis, patients with MS and fatigue were more likely to have comorbidities at assessment one and to develop physical disabilities and neurologic impairments at assessment two. Appropriate identification of patients with MS and fatigue may facilitate targeted care interventions to a group of patients at higher risk for disease progression and disability.