BACKGROUND:Paramagnetic rim lesions are a highly specific magnetic resonance imaging biomarker for multiple sclerosis now incorporated into the 2024 McDonald Criteria. However, paramagnetic rim lesion identification remains underutilized in clinical practice. This study evaluates the effectiveness of an online, educational platform for improving paramagnetic rim lesion identification. DESIGN/METHODS:We conducted a prospective pre-post intervention study using a web-based, asynchronous educational platform. The intervention included baseline assessment, didactic education on paramagnetic rim lesion identification, interactive case-based learning with 10 examples, and post-intervention assessment. The primary efficacy endpoint was ⩾80% of participants achieving ⩾80% accuracy on post-intervention assessment. Wilcoxon signed-rank test was used to compare pre- and post-intervention scores. RESULTS:A total of 182 participants completed the educational intervention. The proportion of respondents achieving the primary efficacy endpoint increased from 65% (n = 118) to 91% (n = 166) (McNemar's χ2 = 36.8, p < 0.001). Mean accuracy scores improved significantly from 3.84 ± 0.85 (76.8%) to 4.39 ± 0.77 (87.8%) correct responses out of 5 (mean difference = 0.55 points, 95% confidence interval = [0.43, 0.67], p < 0.001). CONCLUSIONS:In this pilot study, an interactive web-based educational platform improved healthcare providers' ability to identify paramagnetic rim lesions, with 91% achieving target proficiency. This scalable approach can facilitate broader implementation of the 2024 McDonald Criteria in clinical practice.

Background and Objectives Generic formulations of glatiramer acetate have been available since 2015 yet remain underprescribed relative to the branded product. We sought to characterize the association between branded glatiramer prescribing in the Medicare program and financial payments from the manufacturer (Teva Pharmaceuticals). Methods Using publicly available Medicare Part D and Open Payments data from the Centers for Medicare and Medicaid Services, we evaluated overall utilization from 2012 to 2021 and compared the prevalence, frequency, and magnitude of financial payments made in 2019 to neurologists who prescribed branded and generic versions of glatiramer in 2020. A multivariable logistic regression model assessed the association between receiving payments from the manufacturer and branded glatiramer prescribing while adjusting for neurologist demographic and practice characteristics. Results In 2021, 52% of glatiramer prescriptions were for a branded formulation. Of 2,886 neurologists who prescribed glatiramer in 2020, 1,323 (46%) only prescribed branded, 364 (22%) only prescribed generic, and 929 (32%) prescribed both branded and generic versions of glatiramer. Of branded glatiramer prescribers, 53% (702 of 1,323) received a payment from the manufacturer compared with 39% (247 of 634) of generic-only prescribers (p < 0.001). Neurologists who received more than $120 per year had significantly increased odds ($121 to $230 per year, adjusted odds ratio [AOR]1.47, 95% CI 1.03-2.10; >$230 per year, AOR 1.87, 95% CI 1.28-2.73) of prescribing branded glatiramer compared with neurologists who received no payments. Discussion Although branded drugs often rapidly lose market share with generic competition, branded glatiramer prescribing may persist because of ongoing financial relationships between neurologists and the manufacturer.

In February 2023, following extensive discussions with stakeholders and data review, the Institute for Clinical and Economic Review issued final policy recommendations for treatment of relapsing multiple sclerosis (RMS)

Multiple sclerosis (MS) involves the episodic development of focal inflammatory lesions causing demyelination and, to a lesser extent, axotomies within the central nervous system (CNS) [1Frohman E.M. Racke Mk Raine C.S. Multiple sclerosis—the plaque and its pathogenesis.New Engl J Med. 2006; 354: 942-955Crossref PubMed Scopus (1462) Google Scholar]. As a consequence of inflammation and demyelination, axons initially are unable to conduct action potentials, and if the lesions affect functionally exquisite pathways, like in the optic nerve or corticospinal tract, result in clinical symptoms. These acute inflammatory lesions or plaques go through a healing process consisting of resolution of inflammation, remodeling of demyelinated axons and variable degrees of remyelination. Remyelination can be extensive as demonstrated by the presence of "shadow plaques," but more commonly occurs at the edges of plaques leaving within the core of MS plaques chronically demyelinated axons [2Patrikios P. Stadelmann C. Kutzelnigg A. Rauschka H. Schmidbauer M. Laursen H.et al. Remyelination is extensive in a subset of multiple sclerosis patients.Brain. 2006; 129: 3165-3172Crossref PubMed Scopus (622) Google Scholar]. On the short-term, because of redistribution of sodium channels on the axon, chronically demyelinated axons can resume conducting action potentials, albeit at slower speeds than when myelinated [3Waxman S.G. Axonal conduction and injury in multiple sclerosis: the role of sodium channels.Nat Rev Neurosci. 2006; 7: 932-941Crossref PubMed Scopus (318) Google Scholar]. Long-term, however, chronically demyelinated axons are at risk of degeneration. Oligodendrocytes, which make and maintain myelin sheaths, provide metabolic support to the underlying axons [4Lee Y. Morrison B.M. Li Y. Lengachaer S. Farah M.H. Hoffman P.N. et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2021; 487: 443-448Crossref Scopus (1213) Google Scholar]. The absence of metabolic support in chronically demyelinated axons ultimately results in dysfunctional mitochondria, increased axoplasmic calcium and activation of "death pathways" [4Lee Y. Morrison B.M. Li Y. Lengachaer S. Farah M.H. Hoffman P.N. et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2021; 487: 443-448Crossref Scopus (1213) Google Scholar, 5Duncan G.J. Ingram S.D. Emberley K. Hill J. Cordano C. Abdelhak A. et al.Remyelination protects neurons from DLK-mediated neurodegeneration.bioRxiv. 2023; 12 (2023. 09.30.560267)Google Scholar, 6Trapp B.D. Nave K.A. Multiple sclerosis: an immune or neurodegenerative disorder?.Ann Rev Neurosci. 2008; 31: 247-269Crossref PubMed Scopus (1380) Google Scholar]. These changes result in axonal degeneration and neuronal cell death. It is believed that chronic demyelination of axons leads to neurodegeneration, which is a major driver of progressive disability in MS [6Trapp B.D. Nave K.A. Multiple sclerosis: an immune or neurodegenerative disorder?.Ann Rev Neurosci. 2008; 31: 247-269Crossref PubMed Scopus (1380) Google Scholar]. Given the long-term deleterious effects of chronic demyelination, there is considerable interest in the development of therapies that stimulate remyelination. Our concepts about how remyelination occurs and why it is incomplete influence the attempts at developing remyelinating therapies. Developmentally, neural stem cells generate oligodendrocyte precursor cells (OPCs) that proliferate and migrate throughout the CNS (Fig. 1). OPCs extend processes that make contact with axons and differentiate into oligodendrocytes that wrap concentric circles of their membrane around the axons to form compact myelin. It has been broadly assumed that remyelination recapitulates the developmental stages of myelination, particularly with regards to OPC proliferation, migration and differentiation into oligodendrocytes that generate new myelin [7Fancy S.P.J. Chan J.R. Baranzini S.E. Franklin R.J.M. Rowitch D.D. Myelin regeneration: a recapitulation of development?.Annu Rev Neurosci. 2011; 34: 21-43Crossref PubMed Scopus (261) Google Scholar]. Why remyelination is not more robust and tends to fail over time is uncertain. Theories about remyelination failure broadly focus on inhibitors of the process and failure of OPC proliferation and differentiation. Targeting OPC inhibitors is one approach to develop remyelinating therapies. Inhibitors of OPC differentiation reside in the chronic MS plaques and include myelin debris and substances released by activated microglia and astrocytes, such as hyaluronic acid and soluble mediators of inflammation [8Back S.A. Tuohy T.M. Chen H. Wallingford N. Craig A. Struve J. et al.Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation.Nat Med. 2005; 11: 966-972Crossref PubMed Scopus (519) Google Scholar]. There is an example of a monoclonal antibody that targeted another inhibitor of remyelination that went into clinical trials. Expression of leucine rich repeat and immunoglobulin-like domain containing protein 1 (LINGO-1) on OPCs and neurons inhibits differentiation of OPCs and remyelination in animal models [9Mi S. Miller R.H. Lee X. Scott M.L. Shulaq-Morskaya S. Shao Z. et al.LINGO-1 negatively regulates myelination by oligodendrocytes.Nat Neurosci. 2005; 8: 745-751Crossref PubMed Scopus (543) Google Scholar,10Mi S. Pepinsky R.B. Cadavid D. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic.CNS Drugs. 2013; 27: 493-503Crossref PubMed Scopus (142) Google Scholar]. Anti-LINGO-1 antibody administration increased remyelination in animal models and led to clinical trials of the anti-LINGO-1 monoclonal antibody, opicinumab, in acute optic neuritis and MS [11Mi S. Hu B. Hahm K. Kam Hui E.S. Yuan Q. Wong W.M. et al.LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.Nat Med. 2007; 13: 1228-1233Crossref PubMed Scopus (443) Google Scholar, 12Cadavid D. Balcer L. Galetta S. Aktas O. Ziemssen T. Vanopdenbosch L. et al.Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomized, plaebo-controlled, phase 2 trial.Lancet Neurol. 2017; 16: 189-199Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 13Cadavid D. Mellion M. Hupperts R. Edwards K.R. Calabresi P.A. Drolović J. et al.Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNDERGY): a randomized, placebo-controlled, phase 2 trial.Lancet Neurol. 2019; 18: 845-856Abstract Full Text Full Text PDF PubMed Google Scholar]. Unfortunately, these trials did not provide convincing evidence that the monoclonal antibody stimulated remyelination. It is also possible that stimulation of OPCs to proliferate and differentiate could overcome any impediments to remyelination. A commonly used approach for developing pro-remyelinating drugs is to test their ability to promote OPC proliferation and differentiation in vitro. These in vitro assays use cultures of OPCs isolated from rodents or derived from human inducible pluripotent stem cells. Drugs can be tested for their ability to stimulate proliferation of OPCs and differentiation into oligodendrocytes and assessed using standard markers, such as Olig2 for OPCs and MBP or CC1 for oligodendrocytes. This approach can be used for large scale screens of libraries of approved drugs or as part of the development of novel drugs. Drugs with promising effects in vitro subsequently can be tested in murine models of demyelination. For instance, an in vitro screen of existing approved drugs suggested that anti-muscarinic drugs, such as clemastine, could promote differentiation of murine OPCs [14Mei F. Fancy S.P.J. Shen Y.-A.A. Niu J. Zhao C. Presley B. et al.Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.Nat Med. 2014; 20: 954-960Crossref PubMed Scopus (431) Google Scholar]. Clemastine was tested in humans with optic neuritis and found to result in a modest effect on visual evoked potentials relative to placebo, suggestive of remyelination [15Green A.J. Gelfand J.M. Cree B.A. Bevan C. Boscardin W.J. Mei F. et al.Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial.Lancet. 2017; 390 (24): 2481Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar]. As an example of novel drug development, our group synthesized thyromimetics that could stimulate OPC differentiation in vitro and subsequently showed that the thyromimetics accelerated remyelination in three murine models of de/remyelination [16Hartley M.D. Banerji T. Tagge I.J. Kirkemo L.L. Chaudhary P. Calkins E. et al.Myelin repair stimulated by CNS-selective thyroid hormone action.JCI Insight. 2019; 4e126329Crossref Google Scholar]. Testing approved and novel drugs for their ability to promote differentiation of OPCs in vitro appears to be a useful early tool in the development of remyelinating drugs, but is this approach too simplistic? Do cultured rodent OPCs reflect human OPCs in vivo, and do the carefully controlled in vitro systems adequately replicate the complex inflammatory and gliotic environment in which OPCs reside in the MS tissue? In addition, do MS disease modifying therapies (DMTs) and other drugs that patients may take affect OPC differentiation and remyelination? In this issue of Neurotherapeutics, Jank and colleagues present experiments that highlight the need to assess the effects of DMTs on remyelination and challenge the standard approach to screening drugs in vitro for their potential to promote remyelination in MS [17Jank L. Catenacci R.B. Minney V. Galleguilos D. Calabresi P.A. Pharmacological modulation of inflammatory oligodendrocyte progenitor cells using three multiple sclerosis disease modifying therapies in vitro.Neurotherapeutics. 2024 May; 25e00379https://doi.org/10.1016/j.neurot.2024.e00379Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. Their investigation sought to address two critical issues. First, most MS patients are taking a DMT, which may be present within the MS lesions and have unknown direct effects on OPC proliferation and differentiation. Second, OPCs within MS lesions are exposed to inflammatory cytokines that may alter their function, and this differs from the pristinely cultured OPCs used for in vitro drug screening. One inflammatory cytokine, interferon-gamma (IFN-γ), inhibits OPC differentiation and stimulates the cells to express MHC class I and II molecules [19Chew L.J. King W.C. Kennedy A. Gallo V. Interferon-g inhibits cell cycle exit in differentiating oligodendrocyte progenitor cells.Glia. 2005; 52: 127-143Crossref PubMed Scopus (98) Google Scholar,20Kirby L. Jin J. Cardona J.G. Smith M.D. Martin K.A. Wang J.,et al. Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination.Nat Commun. 2019; 10: 3887Crossref PubMed Scopus (232) Google Scholar]. Importantly, these inflammatory OPCs, referred to by the authors as iOPCs, are present in MS lesions and may represent an important obstacle to remyelination [21Falcão A.M. van Bruggen D. Marques S. Meijer M. Jäkel S. Agirre E. et al.Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis.Nat Med. 2018; 24: 1837-1844Crossref PubMed Scopus (322) Google Scholar]. Through a series of experiments, Jank et al. determined the effects of three MS DMTs, cladribine (CDB), dimethyl fumarate (DMF) and interferon-beta (IFN-β), on OPCs and iOPCs in vitro. The investigators initially assessed the three DMTs for their effects on OPCs cultured from mice. Although none of the DMTs affected OPC viability in vitro, DMF and, to a lesser extent, IFN-β inhibited OPC proliferation. CDB, on the other hand, had no effect on OPC proliferation. Using standard differentiation medium, OPCs were assessed for their ability to differentiate into MBP+ and CC1+ oligodendrocytes in the absence or presence of each DMT. DMF and IFN-β but not CDB inhibited OPC differentiation. Thus, two of the DMTs directly inhibited OPC proliferation and differentiation in vitro, raising the possibility that they might have similar effects in vivo and, thereby, inhibit remyelination. Next, the investigators sought to assess the effects of the three DMTs on iOPCs. OPCs grown from MHC reporter mice exposed to IFN-γ expressed both MHC class I and II and failed to differentiate in vitro when placed in differentiation medium. The three DMTs were tested for their effects on IFN-γ stimulation of MHC expression on OPCs. DMF decreased MHC class I and II expression on OPCs exposed to IFN-γ whereas CDB did not. IFN-β had opposing effects on MHC expression. IFN-β increased MHC class I expression in the presence or absence of IFN-γ but suppressed IFN-γ induction of MHC class II. Interestingly, even though DMF and IFN-β inhibited IFN-γ induced MHC expression on OPCs, neither could prevent IFN-γ inhibition of OPC differentiation into oligodendrocytes. This was surprising as it suggested that the dual effects of IFN-γ on OPCs, namely induction of MHC class I and II expression and inhibition of OPC differentiation, are not mechanistically linked. The experiments that Jank and colleagues performed were eloquent and gave clear results. However, some weaknesses should be noted. The concentrations of the IFN-β and DMF used in the experiments were generally above those achieved within the brains of patients receiving these drugs. Lower concentrations of IFN-β and DMF comparable to those observed in the cerebrospinal fluid of people following administration of these agents were also tested and had similar but less intense responses. Another issue is that following ingestion, DMF is metabolized rapidly to monomethyl fumarate (MMF), which is believed to be the active moiety when DMF is administered to patients. It is assumed that the in vitro effects of DMF translate into the effects of MMF when DMF is administered orally to a patient. While it is likely that MMF would have similar effects on OPCs as DMF, in vitro experiments with MMF remain to be performed. Despite these issues, the findings presented by Jank et al. are important and raise issues pertaining to the effects of DMTs and IFN-γ on remyelination. There are now over 20 Food and Drug Administration approved MS DMTs, and based on their mechanisms of action, they can be divided into seven classes. Given the widespread use of DMTs in MS patients and their varying mechanisms of action, it is important to determine their effects on remyelination. It is possible that some DMTs might have negative effects on remyelination as suggested by the in vitro effects of DMF and IFN-β on OPCs. Other DMTs, such as CDB, might have no effect on remyelination, although CDB may be unique. The lack of effect of CDB on OPCs and potentially in vivo remyelination resulted from the need for intracellular activation of CDB via phosphorylation by deoxycytidine kinase, which is not present at high levels in OPCs. Some DMTs might even enhance remyelination as was shown for the immunosuppressants azathioprine and cyclophosphamide [18Herndon R.M. The effect of drugs on oligodendrocyte proliferation and myelin regeneration.Prog Brain Res. 1987; 71: 485-491Crossref PubMed Google Scholar]. Each class of DMT, thus, needs to be assessed individually for their effects on OPCs, and the methods used by Jank et al. provide a model for testing other DMTs. This study raises questions about the function and fate of iOPCs and the potential effects of IFN-γ and other soluble mediators of inflammation on remyelination in vivo (Fig. 2). Induction of MHC class I and II expression on OPCs by IFN-γ has uncertain effects on OPCs. For instance, iOPCs expressing MHC class I might be exposed to CD8+ T cell mediated cytotoxicity, while iOPCs expressing MHC class II might help activate CD4+ T cells. In addition, IFN-γ renders OPCs unable to differentiate into oligodendrocytes in vitro, suggesting that it may inhibit remyelination within MS lesions. Further research on the function of OPCs exposed to IFN-γ and other soluble mediators of inflammation is clearly needed. Developing therapies that promote remyelination in MS is vital. Successfully stimulating remyelination in people with MS will reduce their disability and will likely slow or even prevent the neurodegeneration that drives progressive MS. Testing drugs for their ability to stimulate OPC differentiation in vitro as a first step in drug development, as is currently performed, may be too simple. The environment in the CNS in which OPCs live is complex and nothing like the highly controlled in vitro system of cultured OPCs. Future studies that take into account the inflammatory milieu that confront OPCs in the MS CNS and the potential effects of DMTs will be important to improving the relevance of in vitro testing of putative remyelinating drugs. Dr. Bourdette decided on the main points of the Commentary and wrote the first draft. Dr. Wooliscroft provided input on the main points of the Commentary, edited the initial draft and provided input on the Figures. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Dennis Bourdette has co-founder stock from Autobahn Therapeutics. He has received Royalty payments from Oregon Health & Science University related to a patent on which he is a co-inventor related to thyromimetics for treatment of multiple sclerosis. Dr. Lindsey Wooliscroft reports a relationship with EMB Serono that includes consulting or advisory and travel reimbursement. The authors thank Ben Emery, PhD, for editorial suggestions and Jennifer Jenks for creating the Figures. Lindsey Wooliscroft, MD, is supported by a K23 Career Development Award from the National Institute of Child Health and Human Health Project L30 HD1065391.

Purpose: To distinguish between multiple sclerosis (MS) and glaucoma by nerve fiber layer (NFL) thinning patterns. Methods: MS patients were diagnosed by the 2017 McDonald Criteria; glaucoma patients had disc rim thinning or an NFL defect, with or without perimetric defect. The peripapillary NFL thickness was divided into eight sectors, and percentage reduction (% reduction) was calculated relative to normative reference values. The MS and glaucoma eyes were grouped based on the severity of NFL thinning in the worst sector: significant reduction (<1 percentile of normal reference), borderline reduction (1%similar to 5%), and no reduction (>5%). We devised four diagnostic indexes, and the area under the curve of receiver operating characteristics (AROC) and accuracy were used to evaluate the indexes. Results: We enrolled 58 control subjects (58 eyes), 56 MS subjects (112 eyes), and 92 glaucoma subjects (92 eyes) at two centers. The most pronounced percent reduction in MS eyes occurred in the temporal-upper and temporal-lower sectors. In glaucoma eyes, this occurred in the inferior-temporal, inferior-nasal, and superior- temporal sectors. The temporal pattern index had the best AROC (0.96, 0.91-1.00) and accuracy (92.6%) in the significant reduction group. It had good AROC (0.88, 0.78-0.99) and accuracy (76.7%) in the borderline reduction group. Conclusions: Normalizing NFL reduction as a percentage of normal reference accentuated patterns characteristic of MS and glaucoma. Quantitative pattern indexes were effective in differentiating the two diseases. Translational Relevance: The utility of optical coherence tomography in the differential diagnosis of optic neuropathies is enhanced by analyzing the retinal nerve fiber layer percentage reduction pattern.

Polypharmacy, the use of ≥ 5 medications, is common in people with multiple sclerosis and is associated with negative outcomes. The use of multiple medications is common for symptom management in people with multiple sclerosis, but risks drug-drug interactions and additive side effects. Multiple sclerosis providers should therefore focus on the appropriateness and risks versus benefits of pharmacotherapy in each patient. This review describes the prevalence and risks associated with polypharmacy in people with multiple sclerosis and offers strategies to identify and mitigate inappropriate polypharmacy. Research in people with multiple sclerosis has identified risk factors and negative outcomes associated with polypharmacy. Medication class-specific investigations highlight their contribution to potentially inappropriate polypharmacy in people with multiple sclerosis. People with multiple sclerosis are at risk for inappropriate polypharmacy. Multiple sclerosis providers should review medications and consider their appropriateness and potential for deprescribing within the context of each patient.

IntroductionThere is an urgent need for remyelinating therapies that restore function in people with multiple sclerosis (pwMS). Aerobic exercise is a promising remyelinating strategy because it promotes remyelination in animal models both independently and synergistically with medications. Here, in this study, we present an innovative, randomised, single-blind, clinical trial designed to explore: the relationship between demyelination and mobility (part 1), and if 24 weeks of aerobic exercise promotes remyelination in pwMS (part 2).Methods and analysisSedentary participants (n=60; aged 18–64 years) with stable MS will undergo a baseline visit with the following outcomes to assess associations between demyelination and mobility (part 1): spinal cord demyelination (somatosensory-evoked potentials, SSEPs), mobility (6-Minute Timed Walk, Timed 25-Foot Walk, Timed Up and Go, 9-Hole Peg Test) and patient-reported outcomes (PROs). After baseline testing, participants with significantly prolonged SSEP latency will advance to the clinical exercise trial (part 2) and will be randomised 1:1 to active or control conditions for 24 weeks. The active condition will be aerobic stationary cycling three times per week with graded virtual supervision. The control condition will be monthly virtual MS symptom education groups (six sessions). SSEP latency (remyelination endpoint), mobility outcomes and PROs will be measured at 12 and 24 weeks in all clinical trial participants. A subset of 11 active and 11 control participants will undergo a brain MRI with quantitative T1myelin water fraction at baseline and 24 weeks (exploratory remyelination endpoint).Ethics and disseminationEthical approval was obtained from the Oregon Health & Science University Institutional Review Board (#21045). Dissemination of findings will include peer-reviewed publications, conference presentations and media releases. The proposed study will inform the feasibility, study design and sample size for a fully powered clinical trial of aerobic exercise to promote remyelination in pwMS.Trial registration numberNCT04539002.

In February 2023, following extensive discussions with stakeholders and data review, the Institute for Clinical and Economic Review issued final policy recommendations for treatment of relapsing multiple sclerosis (RMS)1: "All stakeholders have a responsibility and an important role to play in ensuring that all effective treatment options for patients with RMS, including off-label use of rituximab, are utilized in ways to help improve affordability and access and reduce health inequities." The report calls on payers to remove barriers to rituximab coverage, the American Academy of Neurology and the National MS Society to publicly endorse rituximab for RMS, and clinicians to advocate for coverage of rituximab and its biosimilars. In July 2023, the World Health Organization listed rituximab as an essential medicine for MS.2 Yet not much has changed. Food and Drug Administration (FDA)-approved MS disease-modifying therapies continue to generate enormous profits for pharma, and rituximab remains hidden in plain sight.

Background and Objectives To determine the association between Medicare Part D plan disease-modifying therapy (DMT) restrictiveness and adherence and outcomes among people with multiple sclerosis (MS). Methods We used Medicare claims data from 2010 to 2014 to identify individuals with a full year enrollment (Parts A, B, and D), an MS diagnosis, and 1 or more self-administered DMT prescription. Plans were considered restrictive if all available DMTs required a prior authorization or step therapy restriction; otherwise they were considered permissive. We compared DMT adherence, defined as a medication possession ratio ≥80%, MS-related emergency department or inpatient admissions, and outpatient visits by Part D plan restrictiveness. We used multivariate regression models to control for patient demographics and comorbidities. Results There were 37,713 Medicare beneficiaries with MS who were enrolled in either restrictive (n = 29,901) or permissive (n = 7812) Part D plans during the study period. Patients enrolled in restrictive plans were older (60 vs 58 years; p < 0.001), more likely to live in the south (38% vs 23%; p < 0.001), eligible through disability (67% vs 60%; p < 0.001), and more likely to have several chronic comorbid conditions. Patients enrolled in restrictive plans were less likely to be adherent to their DMT (54% vs 57%; p < 0.001; adjusted odds ratio [aOR] 0.92, 95% confidence interval [CI] 0.88–0.98) and had a higher rate of MS-related outpatient visits (1.7 vs 1.4 per year; p < 0.001; aRR 1.27, 95% CI 1.23–1.31). Discussion Medicare beneficiaries with MS enrolled in restrictive Part D plans were less adherent to their DMT and had higher rates of MS-related outpatient visits.

RCTs have changed little in 70 years… the rocketships of modern biology culminate their final stage of delivery in a wagon train.