Background Relapse prevention in multiple sclerosis (MS) is accomplished with disease-modifying therapy (DMT). Relapse rates typically decrease with age while DMT-associated risks increase, complicating treatment of older persons with MS (PwMS). Objectives This follow-up study aims to guide treatment decisions by evaluating clinical and patient-reported outcomes among older PwMS who discontinue DMT. Methods This study included PwMS aged ≥60 evaluated at the Cleveland Clinic from 2010 to 2016, categorized as DMT continuers or discontinuers. Follow-up timeframe was February 2018–April 2024. Outcomes included relapses, magnetic resonance imaging (MRI) activity, and Neuro-QoL and MS Performance Test scores. Mixed-effects regression and survival models were used. Results In total, 600 PwMS were included. Median follow-up time was 10.5 years (interquartile range 7.7–13.4), 66.0% discontinued DMT, and 3.3% had ≥1 relapse. Relapse risk did not differ significantly between groups (hazard ratio for discontinuers vs. continuers, 1.80, 95% confidence interval 0.51–6.39, p = 0.365). T2 lesions developed in 37.5% of continuers and 36.6% of discontinuers. Gadolinium-enhancing lesions developed in 10.1% and 7.9%, respectively. Neuro-QoL Fatigue T-scores slightly worsened for discontinuers over time. Conclusion Findings demonstrate low relapse risk among PwMS over age 60, however, MRI changes were common. DMT discontinuation may be considered in this population, though further studies are needed to better understand radiological disease activity.

Diroximel fumarate (DRF) and dimethyl fumarate (DMF) are established disease-modifying therapies for relapsing multiple sclerosis (RMS). While DRF has demonstrated improved gastrointestinal tolerability compared to DMF, there is limited research evaluating whether this difference in tolerability translates into a difference in clinical effectiveness. This study evaluated the real-world effectiveness of DRF versus DMF on relapse outcomes in persons with MS (pwMS) in a large US population. This retrospective cohort study utilized the Forian administrative claims database (January 1, 2018–June 30, 2025). Adult pwMS initiating DRF or DMF were identified and propensity score-matched (1:3 ratio) based on baseline demographic and clinical characteristics. Endpoints were assessed over 1- and 2-year follow-up periods. The primary endpoint was annualized relapse rate (ARR). The 1-year analysis included 1780 DRF-treated and 5340 DMF-treated pwMS; the 2-year analysis included 739 DRF-treated and 2217 DMF-treated pwMS. At 1 year of treatment, DRF was associated with a significantly lower ARR compared to DMF (0.12 vs. 0.16; p = 0.03), representing a 21

AIM:Ozanimod is a second-generation sphingosine 1-phosphate receptor (S1PR) modulator approved for treatment of relapsing multiple sclerosis (MS). Data are lacking for ozanimod use in real-world clinical practice. This study aims to determine characteristics of people with MS (pwMS) prescribed ozanimod as well as ozanimod persistence, tolerability, safety, and effectiveness over one year. METHODS:Data were retrospectively collected for adults with MS or clinically isolated syndrome who received ozanimod at two tertiary MS centers. RESULTS:We identified 206 pwMS for inclusion. Many (n = 146, 71%) had prior disease-modifying therapy (DMT) experience. The most common reasons for switching to ozanimod were cost (n = 48, 33%) and prior DMT intolerance (n = 29, 20%). Most individuals (n = 149, 72%) remained on ozanimod at last data collection. The most frequent reason for discontinuation was side effects (n = 21, 37% of discontinuers, 10.2% of total cohort). Few pwMS reported tolerability concerns (7.5% at 12 months). When comparing pre-ozanimod baseline to 12-month data, the annualized relapse rate was reduced by 56% (p = 0.034), and fewer pwMS had new/enlarging brain MRI T2 lesions (6.6% versus 40%, p < 0.001) and gadolinium-enhancing lesions (3.9% versus 27%, p = 0.027). CONCLUSION:Ozanimod was well-tolerated with good treatment persistence, a favorable safety profile, and reductions in clinical and radiographic disease.

AimsTo describe the 12-month effectiveness, persistence, tolerability, and safety of ofatumumab (OMB), a highly effective disease-modifying therapy (DMT) for relapsing multiple sclerosis (MS), in a real-world MS population.Patients & methodsElectronic medical records of patients starting OMB from October 2020 to August 2022 at two comprehensive MS centers were reviewed. Demographics and disease characteristics and 6- and 12-month clinical, patient-reported, and radiologic outcome measures were analyzed.ResultsA total of 175 patients started OMB with mean age 44.9 (SD 10.4) and disease duration 13.6 (SD 9.6) years. The cohort was 74% female, included 81% White and 13% Black American patients, and consisted of 80% relapsing-remitting MS or clinically isolated syndrome. Most (87%) had prior DMT exposure with 38% switching from high efficacy DMT. Over 12 months, 9.7% discontinued OMB (mean 117 days, SD 99.2), with tolerability issues being the most common reason. Thirty-nine (22%) had relapses in the year before starting OMB. By 12 months, only 1 relapse had occurred after approximately 4 months post-treatment initiation.DiscussionThis real-world study demonstrated that OMB is highly effective with robust persistence and good safety and tolerability by 12-month follow-up. Further analyses are planned to examine longer-term outcomes.

Background Cladribine tablets (CladT) are a multiple sclerosis (MS) disease-modifying therapy (DMT) with safety and efficacy established in the CLARITY trial and extension. A better understanding of the role of CladT in real-world populations is needed, including the clinical and radiographic trajectories of persons with MS (PwMS) treated with CladT and how CladT compares to other MS DMTs. Methods PwMS receiving CladT at 4 tertiary MS centers were identified and characterized. A validated electronic neuroperformance test adapted from the Multiple Sclerosis Functional Composite was administered at each visit, which provides z-scores for the Walking Speed Test (zWST), Manual Dexterity Test (zMDT), and the Processing Speed Test (zPST). The Patient Determined Disease Steps (PDDS) and NeuroQoL patient-reported outcomes are also administered. Regression modeling using generalized estimating equations was used to compare neuroperformance testing and brain MRI metrics at 6-, 12-, 18-, and 24-months to baseline. In a comparative effectiveness analysis, PwMS receiving other DMTs were propensity matched to CladT treated PwMS on variables including age, race, and disease duration. Outcomes were then compared at the same time points. Results We identified 117 PwMS treated with CladT who had an average age of 46.7 years (SD=10.5) and average disease duration of 13.2 years (SD=5.6). Relative to baseline, there were no significant differences in zMDT and zPST at any time point. There were significant increases in zWST over the study duration, suggesting improvement in walking speed, and PDDS scores remained stable during the study period. The odds of new T2 lesions relative to baseline were lower at all time points, but this did not reach significance. There were significantly lower odds of gadolinium enhancing (GdE) lesions at 6- and 18- months relative to baseline. Twelve PwMS (11%) started a post-CladT DMT. We matched 476 PwMS on alternative DMT (most commonly ocrelizumab, n=280, 58.8%) to CladT-treated PwMS. zWST scores were significantly better among those receiving other CladT at 12-, 18-, and 24 months, and NeuroQoL fatigue scores also favored the CladT-treated group. Odds of new T2 and GdE lesions were higher among those receiving CladT initially, but the disparity was no longer evident at 24-months (p=0.77 and p=0.55 respectively). Conclusion Real-world data for PwMS receiving CladT suggest it is prescribed to older patients with longer disease durations than in the pivotal trials. The pre-post analysis and the comparative effectiveness analysis suggested good performance of CladT in this broader population. There may be a delayed effect of CladT on radiographic outcomes relative to other DMTs.

Background The role of obesity in persons with multiple sclerosis (PwMS) is incompletely understood. Obesity predisposes individuals to a pro-inflammatory state and cardiovascular comorbidities, both of which can negatively impact MS disease course. A better understanding of weight trends in PwMS will inform optimal management of those who are overweight or obese. Objectives To determine body mass index (BMI) trends in newly diagnosed PwMS and individual characteristics associated with weight gain after diagnosis. Also, to determine the impact of physical disability on BMI changes in PwMS. Methods We conducted two longitudinal retrospective cohort analyses using the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) database. The first characterized BMI trends in newly diagnosed PwMS. Multivariable linear regression was used to determine characteristics associated with baseline BMI. Multivariable logistic regression was used to determine characteristics associated with annualized BMI changes of ≥0.5 kg/m2/year and ≥2.0 kg/m2/year in PwMS who were overweight or obese at baseline. The second analysis evaluated BMI trends in individuals with more longstanding MS to determine the impact of disability on weight changes. Multivariable logistic regression was used with consolidated Patient Determined Disease Steps (PDDS) categories as a disability measure. Results There were 942 PwMS in the newly diagnosed cohort, of whom 265 (27.9%) were overweight and 403 (42.4%) were obese. The average follow-up time was 2.1 years, and the average annualized BMI change was 0.19 kg/m2/year (SD=1.5). Greater education was associated with lower baseline BMI (β=-0.31, p=0.003) but no other characteristics were significantly associated. Greater education was also associated with lower odds of rapid weight gain at ≥2.0 kg/m2/year (OR=0.88, p=0.001), while female sex was associated with higher odds of rapid weight gain (OR=1.84, p=0.047) at the same threshold. The disability analysis included 10,394 PwMS, of whom 5,699 (54.8%) had low disability (PDDS 0-1), 3,221 (31.0%) had moderate disability (PDDS 2-4), and 1,474 (14.2%) had high disability. The average annualized BMI change was 0.08 kg/m2/year for all subjects (SD=1.7), 0.10 kg/m2/year (SD=1.6) for those with low baseline disability, 0.06 kg/m2/year (SD=1.9) for those with moderate baseline disability, and 0.04 kg/m2/year (SD=1.9) for those with high baseline disability. Relative to those with low disability, moderate disability (β=1.09, p<0.001) and severe disability (β=1.274, p<0.001) were both associated with higher baseline BMI. Greater disability was not associated with odds of meeting thresholds for annualized BMI increases. However, women had 22% higher odds of a ≥0.5 kg/m2/year increase (p=0.002) and 31.6% higher odds of a ≥2.0 kg/m2/year increase (p=0.01). Conclusions Being overweight or obese is common at MS diagnosis. Women with MS are especially susceptible to rapid weight gain, both at diagnosis and later in the disease course. Greater education is protective against rapid weight gain in newly diagnosed MS patients. Baseline disability did not have a significant relationship with annualized BMI change, but the relationship appears to vary according to the patient's age. The frequency of overweight and obese PwMS suggests that weight management is an important part of MS care.

Abstract Introduction Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. Methods and analysis We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson’s Disease, or Alzheimer’s disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants’ neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. Perspectives The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. Trial registration The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

Abstract Background We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response‐mediator protein 5 (CRMP5)‐IgG paraneoplastic neurologic disorders (PND). Methods This is a retrospective study of patients with CV2/CRMP5‐IgG PND evaluated between 2002–2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan–Meier estimates were used to determine the probability of survival. Results Twenty‐seven patients (56% female) with CV2/CRMP5‐IgG PND were identified with a median follow‐up of 54 months (IQR = 11–102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow‐up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87–30.64, P = 0.005). Moderate–severe mRS = 3–5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18–41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55–93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. Interpretation In this retrospective longitudinal study of CV2/CRMP5‐IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.

Natalizumab is a monoclonal antibody that antagonizes α4-integrin on circulating leukocytes, thereby inhibiting their trafficking into the central nervous system. It is a highly effective treatment for relapsing-remitting multiple sclerosis, and standard dosing is comprised of 300 ​mg natalizumab infusions every four weeks (standard-interval dosing, SID) [[1]Polman C.H. O'Connor P.W. Havrdova E. Hutchinson M. Kappos L. Miller D.H. et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2006; 354: 899-910Crossref PubMed Scopus (2791) Google Scholar]. Initial studies demonstrated leukocyte α4-integrin surface receptor saturation (>80%) with SID, and therapeutic adequacy supported by efficacy in the pivotal trials [[2]Rudick R.A. Sandrock A. Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS.Expert Rev Neurother. 2004; 4: 571-580Crossref PubMed Scopus (152) Google Scholar]. Shortly after approval, progressive multifocal leukoencephalopathy (PML) was recognized as a potential natalizumab-related complication, resulting in it being briefly pulled from the market. Subsequent work to define the incidence of natalizumab-related PML and its risk factors has been extensive. A French study from 2007 to 2016 found 2 cases of natalizumab-related PML per 1000 person years [[3]Vukusic S. Rollot F. Casey R. Pique J. Marignier R. Mathey G. et al.Progressive multifocal leukoencephalopathy incidence and risk stratification among natalizumab users in France.JAMA Neurol. 2020; 77: 94Crossref PubMed Scopus (37) Google Scholar], but risk mitigation strategies such as John Cunningham virus (JCV) testing led to declining PML incidence after 2013. Longer natalizumab treatment duration increases the risk of PML, prompting speculation that greater intervals between doses may partially mitigate PML risk. An early retrospective observational study based on the Tysabri Outreach: Unified Commitment to Health (TOUCH) database showed that extended interval dosing (EID), with a mean of 35–43 days between infusions, reduced PML risk by half compared to SID [[4]Ryerson L.Z. Foley J. Chang I. Kister I. Cutter G. Metzger R.R. et al.Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.Neurology. 2019; 93Crossref PubMed Scopus (112) Google Scholar]. Subsequent pharmacologic studies demonstrated that individuals receiving SID maintain concentrations more than 10 times the 2 ​μg/mL believed to be the minimal drug therapeutic level of natalizumab [[5]Zhovtis Ryerson L. Li X. Goldberg J.D. Hoyt T. Christensen A. Metzger R.R. et al.Pharmacodynamics of natalizumab extended interval dosing in MS.Neurol Neuroimmunol Neuroinflamm. 2020; 7: e672Crossref PubMed Scopus (20) Google Scholar]. In a cross-sectional study of 214 patients receiving SID natalizumab, stepwise regression modeling was used to determine that infusions every six weeks (9 times yearly) was optimal dosing to maintain drug levels above 2 ​μg/mL [[5]Zhovtis Ryerson L. Li X. Goldberg J.D. Hoyt T. Christensen A. Metzger R.R. et al.Pharmacodynamics of natalizumab extended interval dosing in MS.Neurol Neuroimmunol Neuroinflamm. 2020; 7: e672Crossref PubMed Scopus (20) Google Scholar]. Dosing calculations, however, are complicated by the fact that drug concentrations and target receptor saturation correlate inversely with increasing body mass index (BMI) [5Zhovtis Ryerson L. Li X. Goldberg J.D. Hoyt T. Christensen A. Metzger R.R. et al.Pharmacodynamics of natalizumab extended interval dosing in MS.Neurol Neuroimmunol Neuroinflamm. 2020; 7: e672Crossref PubMed Scopus (20) Google Scholar, 6Van Kempen Z.L. Leurs C.E. Witte B.I. De Vries A. Wattjes M.P. Rispens T. et al.The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing.Mult Scler. 2018; 24: 805-810Crossref PubMed Scopus (0) Google Scholar, 7Serra López-Matencio J.M. Pérez García Y. Meca-Lallana V. Juárez-Sánchez R. Ursa A. Vega-Piris L. et al.Evaluation of natalizumab pharmacokinetics and pharmacodynamics: toward individualized doses.Front Neurol. 2021; 12: 716548Crossref PubMed Scopus (9) Google Scholar], and adjustment of dosing interval by weight has been proposed as an extra step toward optimizing risks and benefits [[5]Zhovtis Ryerson L. Li X. Goldberg J.D. Hoyt T. Christensen A. Metzger R.R. et al.Pharmacodynamics of natalizumab extended interval dosing in MS.Neurol Neuroimmunol Neuroinflamm. 2020; 7: e672Crossref PubMed Scopus (20) Google Scholar,[7]Serra López-Matencio J.M. Pérez García Y. Meca-Lallana V. Juárez-Sánchez R. Ursa A. Vega-Piris L. et al.Evaluation of natalizumab pharmacokinetics and pharmacodynamics: toward individualized doses.Front Neurol. 2021; 12: 716548Crossref PubMed Scopus (9) Google Scholar]. The NOVA study was a randomized, controlled, open-label trial meant to examine the safety and efficacy of EID. Clinically stable participants who had been receiving natalizumab for at least 12 months were randomized to remain on SID or switch to 6-week EID [[8]Foley J.F. Defer G. Ryerson L.Z. Cohen J.A. Arnold D.L. Butzkueven H. et al.Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial.Lancet Neurol. 2022; 21: 608-619Abstract Full Text Full Text PDF PubMed Google Scholar]. The primary endpoint was new or enlarging T2 lesions on MRI scans at 72 weeks, and there were significantly more in the EID group compared to the SID group. This result, though, was primarily driven by a single EID participant with 25 new lesions, many of which may have been related to the asymptomatic PML that this participant was eventually diagnosed with [[9]Stüve O. Tugemann B. Extended-interval dosing of natalizumab in NOVA.Lancet Neurol. 2023; 22: 199-200Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. When the PML patient was excluded from the analysis, there were no meaningful differences in MRI brain outcomes between the two groups [[10]Foley J.F. Campbell N. Kong G. Extended-interval dosing of natalizumab in NOVA – authors' reply.Lancet Neurol. 2023; 22: 200-201Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Prospectively collected data, as part of natalizumab monitoring or as part of collaborative research networks in MS, serve as an important resource for observational studies assessing the effectiveness and safety of EID in comparison to SID. A two-center North American study from 2014 (361 SID, 96 EID) showed similar relapse rates in those treated with SID in comparison to 6–8 week EID [[11]Bomprezzi R. Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience.Ther Adv Neurol Disord. 2014; 7: 227-231Crossref PubMed Scopus (60) Google Scholar]. A later and larger study based on the Italian MS Register (1254 SID, 838 EID) with EID defined as 33–49 days (median 43 days) showed no difference for annualized relapse rate or disability progression at 12 and 24 month follow-ups [[12]Chisari C.G. Grimaldi L.M. Salemi G. Ragonese P. Iaffaldano P. Bonavita S. et al.Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis.J Neurol Neurosurg Psychiatry. 2020; 91: 1297-1303Crossref PubMed Scopus (24) Google Scholar], while a study based on the international Tysabri Observational Program (219 propensity-matched), with EID defined as 6 weeks, also showed no difference for annualized relapse rate or cumulative probability of 6-month disability worsening [[13]Butzkueven H. Kappos L. Spelman T. Trojano M. Wiendl H. Su R. et al.No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score–matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP).Ther Adv Neurol Disord. 2021; 14175628642110424Crossref Scopus (8) Google Scholar]. The latter study noted 2 cases of PML in the EID group, but none in SID [[13]Butzkueven H. Kappos L. Spelman T. Trojano M. Wiendl H. Su R. et al.No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score–matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP).Ther Adv Neurol Disord. 2021; 14175628642110424Crossref Scopus (8) Google Scholar]. A study based on Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) data assessing quantitative MRI outcomes in SID (<35 days) vs. EID (>35 days) showed no differences for annualized percentage change in T2 lesion volume and brain parenchymal fraction [[14]Ryerson L.Z. Naismith R.T. Krupp L.B. Charvet L.E. Liao S. Fisher E. et al.No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: real-world evidence from MS PATHS.Mult Scler Relat Disord. 2022; 58: 103480Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. This issue of Neurotherapeutics features a study by Ruggieri et al. that expands on previous observational studies of EID [[15]Ruggieri S, Ianniello A, Copetti M, Altieri M, Centonze D, Cortese A, et al. Treatment modifiers across different regimens of natalizumab treatment in MS: an Italian real-world experience. Neurotherapeutics.Google Scholar]. The authors conducted a retrospective analysis of a cohort from 8 Italian centers. The primary aim was to compare outcomes among those receiving SID versus those receiving EID (defined as >5 weeks–7 weeks). In a secondary analysis, EID was defined as >7 weeks–8 weeks. An exploratory analysis evaluating the impact of BMI on outcomes in SID and EID groups was also conducted. The primary outcome was evidence of disease activity (EDA), defined as clinical relapses, MRI activity, or disability worsening per the Expanded Disability Status Scale (EDSS). Un-adjusted, adjusted (sex, age, disease duration, previous treatment, baseline EDSS, baseline MRI activity, number of relapses during 2 previous years), and (inverse probability treatment) weighted approaches were applied to time-to-event analyses. The cohort included 745 adults with a mean follow-up of 3.3 years. Most participants were female (>65%) with an average disease duration of 8.5 years. A majority had received previous disease-modifying therapy (>80%), and those starting an SID natalizumab regimen had more relapses in the 2 preceding years. In the primary analysis, there were no differences between SID and EID (5–7 weeks) for the specified outcomes. Similar results were seen for SID vs. EID (7–8 weeks), but the authors noted a trend toward greater hazard for clinical relapses with EID (HR 1.74, 95% CI 0.99–3.02, p ​= ​0.054). In the exploratory BMI analysis, there was a significant interaction between BMI and treatment regimen with respect to EDA, suggesting that BMI is a relevant factor when choosing a dosing regimen. This applied both when BMI was treated as continuous or binarized as above or below the median (23.74 ​kg/m2). Notably, no differences in EDA were seen between the binarized BMI groups when the inverse probability treatment weighted models were applied. The study from Ruggieri et al. has several strengths: a robust sample size, mean follow-up of >3 years, MRI acquisition protocols adhering to shared standards (MAGNIMS guidelines for MS treatment monitoring), and central computing of natalizumab dosing. Several analytical approaches were applied to increase robustness of the analysis and affirm the results and interpretation. However, selection bias is an important limitation inherent to the chosen methodology. As the authors acknowledge, higher baseline levels of disease activity were present in the SID group. Although these discrepancies were adjusted for statistically, caution is necessary when applying the results to patients with more active disease. Most participants received prior treatment, and carry-over or additive effects are possible. Also, natalizumab serum levels or target receptor saturation levels were unavailable as covariates, both of which have previously been shown to be relevant when studying the effects of BMI on natalizumab therapeutic effectiveness. Finally, the cohort was exclusively Italian, and predominantly comprised of individuals with a normal BMI, which limits generalizability of the finding, especially for North American populations in which obesity is more common. Overall, the main findings of the study by Ruggieri et al. are in line with previous observational studies demonstrating similar benefits with EID versus SID at a dosing interval of 6 weeks. This supports the notion of being able to extend the natalizumab dosing interval without compromising expected benefits, and potentially reducing harm of PML. Reductions in infusion frequency also have the benefits of decreasing cost and increasing patient convenience. Nevertheless, EID natalizumab has not been studied as a first line approach, and most participants in the current study were on previous treatments. Additional data are needed in patients with more recently diagnosed, and likely more active, disease. Although the exploratory BMI analysis is a valuable addition to the literature, further studies are needed, ideally including parallel information on natalizumab concentrations and target receptor saturation. An ongoing prospective Dutch study is poised to provide further high-quality evidence regarding the feasibility, risks, and benefits of personalized EID of natalizumab based on drug concentrations (NCT04225312) [[16]Toorop A.A. Van Lierop Z.Y. Gelissen L.M. Hoitsma E. Zeinstra E.M. Van Rooij L.C. et al.Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).J Neurol Neurosurg Psychiatry. 2023; (jnnp-2023-332119)Crossref Scopus (2) Google Scholar]. An initial analysis reporting outcomes for 376 participants showed adequate disease control with personalized dosing based on target trough levels (10 ​μg/mL or 5 ​μg/mL) being comparable to the SID arm and historical SID data [[16]Toorop A.A. Van Lierop Z.Y. Gelissen L.M. Hoitsma E. Zeinstra E.M. Van Rooij L.C. et al.Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).J Neurol Neurosurg Psychiatry. 2023; (jnnp-2023-332119)Crossref Scopus (2) Google Scholar]. Finally, the true impact of EID on PML risk is challenging to assess due to the relative rarity of natalizumab associated PML. Continued monitoring of the TOUCH database and other large registries is needed to further elucidate the risk reduction provided by EID. Karlo Toljan: Writing and editing. Devon S Conway: Writing and editing. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Devon Conway reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and funding grants. Devon Conway reports a relationship with Biogen Inc that includes: funding grants and speaking and lecture fees. Karlo Toljan reports a relationship with National Multiple Sclerosis Society that includes: funding grants. Devon Conway reports a relationship with Novartis Pharmaceuticals Corporation that includes: consulting or advisory and funding grants. Devon Conway reports a relationship with Horizon Therapeutics USA Inc that includes: funding grants. Devon Conway reports a relationship with Alexion that includes: consulting or advisory. Devon Conway reports a relationship with EMD Serono Inc that includes: funding grants. Devon Conway reports a relationship with US Department of Defense that includes: funding grants. Devon Conway reports a relationship with TG Therapeutics Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.