Multiple Sclerosis Therapy Research Articles

Comparative transcriptome profile of mouse macrophages treated with the RhoA/Rock pathway inhibitors Y27632, Fingolimod (Gilenya), and Rezurock (Belumosudil, SLx-2119).

Macrophages play a crucial role in, the currently uncurable, chronic rejection of transplants. In rodent transplantation models, inhibition of the RhoA/Rock pathway disrupts actin-related functions of macrophages, preventing them from entering the graft, and reducing vessel occlusion, fibrosis, and chronic rejection. Among RhoA/Rock inhibitors that inhibit chronic rejection in mouse transplantation are Y27632, Fingolimod, and Rezurock. In a mouse model, Rezurok is more effective in preventing fibrosis and less effective in preventing vessel occlusion than Y27632 or Fingolimod. Fingolimod is FDA-approved for treating multiple sclerosis (MS) and Rezurock for chronic graft versus host disease (GVHD). Still, none had been tested for chronic rejection in humans. To explain the differences in the anti-chronic rejection properties of Y27632, Fingolimod, and Rezurock, we compared the transcriptome profile of mouse macrophages treated with these compounds separately. Treatment with Y27632 or Fingolimod downregulated GTPase and actin pathways involved in cell migration. Rezurock downregulated genes related to fibrosis, such as PTX3, CCR2, CCL2, cell cycle, DNA replication, adaptive immune response, and organelle assembly, while Fingolimod also specifically downregulated NOTCH1 at mRNA . The result of this study not only uncovers which pathways are shared or specific for these drugs but will help in the development of macrophage pathway-targeted therapies in human transplantation, MS, and GVHD. Because macrophages are the major players in immune response, tissue regeneration, renewal, and homeostasis, and development of many diseases, including cancer, the data compiled here will help in designing novel or improved therapies in many clinical applications.

Clostridium epsilon toxin is excessive in multiple sclerosis and provokes multifocal lesions in mouse models.

Multiple sclerosis (MS) is an inflammatory disease of the CNS. In this issue of the JCI, Ma and Sannino et al. show that two strains of intestinal Clostridium perfringens, known to produce epsilon toxin (ETX), were frequently found in patients with MS. Tiny amounts of this toxin added to immunization with myelin antigens provoked MS-like brain lesions in mice. The distribution of these lesions was diffuse, as in MS, in contrast to the spinal cord-restricted lesions of most animal models. ETX bound to endothelial cells of the CNS to enhance immune cell trafficking through the blood-brain barrier into inflammatory brain lessons. ETX also binds to human, but not murine, white blood cells, perhaps altering immune responses. Barrier disruption and changes in immunity due to the toxin could alter the benefits of immune-modulatory MS therapies and are likely to interact with the complex genetics and environmental influences seen in MS.

Disease-modifying therapies and cost-of-illness progression among people newly diagnosed with multiple sclerosis: a national register-based cohort study covering treatment initiation with interferons, glatiramer acetate or natalizumab

ObjectivesDisease-modifying therapies (DMTs) can slow disease progression in multiple sclerosis (MS). The objective of this study was to explore the cost-of-illness (COI) progression among newly diagnosed people with MS in...

Lysophospholipid (S1P) receptors in GtoPdb v.2023.1

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [96]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 123], the receptors are currently designated as S1P1R through S1P5R [73, 16, 123]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [18, 53]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [101, 103]. The structures of S1P1 [180, 69, 108, 184], S1P2 [32], S1P3[116, 187], and S1P5 [110, 185] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [69, 17]. fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [35]. Second-generation S1PR modulators siponimod, ozanimod, and ponesimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [16, 123]. In 2021, ozanimod became the first S1PR modulator to be FDA approved for the treatment of ulcerative colitis [145]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [141, 37, 63, 64].

Subacute cutaneous lupus erythematosus as a rare complication of disease-modifying therapy administration in multiple sclerosis: case report

BackgroundTeriflunomide, the active metabolite of leflunomide, is a disease-modifying therapy drug used for the treatment of multiple sclerosis (MS), yet the complications associated with this drug remain not fully understood. Here we present the rare case of a 28-year-old female MS patient who developed subacute cutaneous lupus erythematosus (SCLE) following teriflunomide treatment. Though SCLE has been reported to be associated with leflunomide, the current report represents the first documented evidence demonstrating SCLE as a potential teriflunomide treatment-related complication. Additionally, a literature review on the leflunomide-induced SCLE was conducted to emphasize the association of SCLE with teriflunomide, specifically amongst the female demographic with a preexisting autoimmune diathesis.Case presentationA 28-year-old female first presented with MS symptoms in the left upper limb along with blurred vision in the left eye. Medical and family histories were unremarkable. The patient exhibited positive serum biomarkers including ANA, Ro/SSA, La/SSB, and Ro-52 antibodies. Relapsing–remitting MS was diagnosed according to the 2017 McDonald’s diagnostic criteria, and remission was achieved upon intravenous administration of methylprednisolone followed by teriflunomide sequential therapy. Three months post-teriflunomide treatment, the patient developed multiple facial cutaneous lesions. SCLE was subsequently diagnosed and was attributed to treatment-related complication. Interventions include oral administration of hydroxychloroquine and tofacitinib citrate effectively resolved cutaneous lesions. Discontinuation of hydroxychloroquine and tofacitinib citrate treatment led to recurring SCLE symptoms under continuous teriflunomide treatment. Full remission of facial annular plaques was achieved after re-treatment with hydroxychloroquine and tofacitinib citrate. The patient’s clinical condition remained stable in long-term outpatient follow-ups.ConclusionsAs teriflunomide has become a standard disease-modifying therapy for MS, the current case report highlights the importance of monitoring treatment-related complications, specifically in relation to SCLE symptoms.

Progressive Multifocal Leukoencephalopathy (PML) With Anti-CD20 and Other Monoclonal Antibody (mAb) Therapies in Multiple Sclerosis (P8-3.016)

<h3>Objective:</h3> To review the incidence of progressive multifocal leukoencephalopathy (PML) associated with monoclonal antibody (mAb) therapies, specifically anti-CD20 medications used in multiple sclerosis (MS). <h3>Background:</h3> PML is an opportunistic and fatal inflammatory disease of the central nervous system, which occurs almost exclusively in immunocompromised hosts; therefore, patients receiving mAb immunotherapy become an at-risk population. B cell-depleting mAbs targeting CD20+ cells have become widely used in MS. Although their efficacy is well-known, their associated risk of PML, especially among those without previous disease-modifying therapy (DMT) exposure, has been insufficiently studied. <h3>Design/Methods:</h3> A systematic literature review of PubMed, Google Scholar, EMBASE, and Scopus was conducted by two independent researchers from June 1, 1997, to July 10, 2022. Further data was obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and individual pharmaceutical companies (Genentech, Novartis, and TG Therapeutics). Carryover cases from prior exposure to other immunosuppressants were excluded. <h3>Results:</h3> Between 2015 and 2017, 10 cases of PML were reported in the FAERS database among 334 MS patients taking rituximab; two had previously received natalizumab, leaving eight cases in total. Rituximab-associated PML was also seen in lymphoproliferative disorders (n=52), rheumatoid arthritis (n=9), and granulomatosis with polyangiitis (n=2). Two fatal PML cases were found in MS patients taking ocrelizumab. No cases of PML were reported with ofatumumab in MS; however, 5 cases were reported in chronic lymphocytic leukemia. PML has not been observed with ublituximab, which is currently under FDA review. Among other DMTs, PML was frequently reported with natalizumab (n=884), fingolimod (n=30), dimethyl fumarate (n=12), and alemtuzumab (n=1). <h3>Conclusions:</h3> Anti-CD20 therapies are a safe class of medications with a low infectious risk for PML, especially compared to other mAbs used in MS, such as natalizumab. Nonetheless, risk stratification in susceptible individuals, as done with natalizumab, could prove beneficial with all mAb treatments. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Dr. Srivastava has nothing to disclose. Dr. JENA has nothing to disclose. Dr. Kakara has nothing to disclose. Dr. Sriwastava has nothing to disclose. Maha Daimee has nothing to disclose. Dr. Xu has nothing to disclose.

Comparison of Strategies to Address Hypogammaglobulinemia Secondary to B-cell Depleting Therapies in Neuroimmunology Patients (P7-3.012)

<h3>Objective:</h3> To compare the efficacy of strategies to manage hypogammaglobulinemia in neuroimmunology patients on anti-CD20 agents, including the effect of anti-CD20 dose reduction and reduced dosing frequency, IVIG/SCIG, anti-CD20 cessation, and DMT switches. <h3>Background:</h3> Anti-CD20 monoclonal agents are increasingly used as therapies for multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Few studies have compared strategies to address hypogammaglobulinemia. <h3>Design/Methods:</h3> All MS, NMOSD, and MOGAD patients at our institution with hypogammaglobulinemia on anti-CD20 agents from 2001–2022 were analyzed. The median change in IgG, infection frequency, and infection severity before and after the treatment was calculated. <h3>Results:</h3> In total, 257 patients were screened, and 30 had a treatment for hypogammaglobulinemia. IVIG/SCIG yielded the largest increase in IgG per year (674.0 mg/dL), followed by B-cell therapy cessation (34.7 mg/dL), and DMT switch (5.9 mg/dL). Dose reduction had the largest decrease in yearly infection frequency (2.7 fewer infections), followed by IVIG/SCIG (2.5 fewer), DMT switch (2 fewer), and reduced dosing frequency (0.5 fewer). Infection grade decreased by 1.9 for reduced dosing frequency (less severe infections), by 1.3 for IVIG/SCIG, and by 0.6 for DMT switch. <h3>Conclusions:</h3> This data suggests that IVIG/SCIG may yield the greatest recovery in IgG while also reducing infection frequency and severity. Stopping anti-CD20 therapy and/or switching DMTs also increase IgG and may lower infection risk. Overall, longer follow-up is needed to assess IgG recovery and infection risk with these interventions. <b>Disclosure:</b> Ms. Kelly has nothing to disclose. The institution of Dr. Vishnevetsky has received research support from National MS Society. The institution of Dr. Vishnevetsky has received research support from NIH (NeuroNext). Lori B. Chibnik has nothing to disclose. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Pharma. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Levy has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various law firms. The institution of Dr. Levy has received research support from National Institutes Health.

Delayed Onset Cryptogenic Organizing Pneumonia in Alemtuzumab Treatment Patient (P14-3.004)

<h3>Objective:</h3> NA <h3>Background:</h3> Alemtuzumab is a highly effective disease modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). However, its use carries known risk of immune-mediated conditions, including autoimmune thyroid disease, nephropathies, immune thrombocytopenia, acquired hemophilia, and rheumatoid arthritis. Numerous other autoimmune-related adverse effects are rare but have also been reported. We report a case of alemtuzumab-associated cryptogenic organizing pneumonia. <h3>Design/Methods:</h3> We present a 40-year-old female who was diagnosed RRMS at age 19, in 2001. She was initially treated with interferon beta-1a and glatiramer acetate injections, but discontinued due to drug intolerance. In 2003, she received 2 cycles of alemtuzumab as part of the Ilex/Campath-1H drug trial. <h3>Results:</h3> In 2018, she was identified to have persistent perihilar ground-glass infiltrates on CT thorax in the context of developing dyspnea on exertion, pleuritic pain and productive cough. Serologies and repeated bronchoscopies were unremarkable. She underwent lung biopsy which showed evidence of cryptogenic organizing pneumonia. She was started on prednisone which improved her pulmonary symptoms and perihilar infiltrates. Unfortunately, she did not tolerate prednisone taper and developed worsening symptoms and radiographic findings on lower dose of prednisone. Due to concern for worsening lower extremity edema and obesity, she was eventually transitioned from prednisone to mycophenolate mofetil. From a RRMS standpoint, she remained relapse-free following alemtuzumab and was not treated with additional DMT. <h3>Conclusions:</h3> We present a rare, non-infectious steroid-responsive lung disorder following alemtuzumab administration. While autoimmunity is common following alemtuzumab treatment, delayed onset cryptogenic organizing pneumonia has not been reported with its use in the literature. <b>Disclosure:</b> Dr. Cheng has nothing to disclose. Dr. Lannen has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Genentech. Dr. Lannen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for TG Therapeutics.

Efficacy of Intrathecal Mesenchymal Stem Cell-Neural Progenitor Therapy in Progressive MS: Results from a Phase II Clinical Trial (S16.005)

<h3>Objective:</h3> To determine safety and efficacy of intrathecal (IT) mesenchymal stem cell-neural progenitor (MSC-NP) treatment in patients with progressive multiple sclerosis (MS). <h3>Background:</h3> MSC-NPs are bone marrow-derived cells with trophic and immunomodulatory properties with therapeutic potential in MS. In an open-label phase I clinical study in 20 progressive MS subjects, the safety and tolerability of the treatment was demonstrated, and was associated with functional neurological improvement, particularly in ambulatory patients. <h3>Design/Methods:</h3> A phase II randomized, double-blind, placebo-controlled clinical trial was performed to investigate the clinical efficacy of multiple intrathecal (IT) injections of autologous MSC-NPs s associated with clinical efficacy. Study subjects (n=54) were stratified according to EDSS (3.0–6.5) and disease subtype (SPMS/PPMS) and randomized into either treatment or placebo group to receive 6 IT injections of MSC-NPs or placebo every 2 months. In year 2, subjects crossed over into the opposite group. The primary outcome was improvement in either EDSS, timed 25-foot walk or 9-hole peg test (EDSS Plus). Secondary outcomes included 6-minute walk test (6MWT), brain volume, and muscle strength. <h3>Results:</h3> Subjects were randomized into treatment (n=24) or placebo (n=27) groups and 3 subjects dropped out of the study. There were 9 serious adverse events, none of which were related to the study intervention. There were no significant differences in the primary endpoint between the two groups in year 1. In the 6MWT, the placebo group showed significant worsening in distance walked compared to the MSC-NP group, specifically in subjects with higher EDSS (6.0–6.5). Overall, 50% of SPMS subjects in the MSC-NP group demonstrated improved muscle strength compared to 33% of SPMS in the placebo group. Preliminary results from the crossover group in year 2 show similar trends in muscle strength and 6MWT after MSC-NP treatment. <h3>Conclusions:</h3> These results suggest that IT-MSC-NP treatment may correlate with therapeutic response in a subgroup of MS patients. <b>Disclosure:</b> Ms. Roche has nothing to disclose. Miss Malin has nothing to disclose. Dr. Stark has nothing to disclose. Dr. Williams has nothing to disclose. Violaine K. Harris, PhD has nothing to disclose. Dr. Sadiq has nothing to disclose.

Misdiagnosis of Multiple Sclerosis in Neuromyelitis Optica: Results from multi-institutional database analysis from the United States (P13-5.004)

Misdiagnosis of Multiple Sclerosis in Neuromyelitis Optica: Results from multi-institutional database analysis from the United States (P13-5.004)

Real-world effectiveness of switching treatment after initial platform injectable disease-modifying therapies in pediatric multiple sclerosis in the US (P14-3.008)

Real-world effectiveness of switching treatment after initial platform injectable disease-modifying therapies in pediatric multiple sclerosis in the US (P14-3.008)

Symptom stability throughout Ocrelizumab infusion cycle in patients with Multiple Sclerosis: final results of SYMptom Burden on Ocrelizumab, a Longitudinal Study (SYMBOLS) (P7-3.017)

<h3>Objective:</h3> To determine whether symptom burden in Ocrelizumab (OCR)-treated MS patients varies over the 6-month infusion cycle. <h3>Background:</h3> OCR is a humanized anti-CD20 antibody therapy for multiple sclerosis (MS) given at 6-month intervals. Some patients report an increase in symptoms toward the end of the infusion cycle (“wearing off”). <h3>Design/Methods:</h3> One-year, prospective, observational, two-center study (NCT04855617) enrolled MS patients aged 18–80 with EDSS scores between 0–7 who were treated with OCR for ≥ 1 year or were initiated on OCR. All patients were followed at NYU MS Care Center (NYU), New York, NY, and the Elliot Lewis MS Center (ELC), Wellesley, MA. Patients completed NeuroQol short forms, SymptoMScreen, work productivity (WPAI:MS), and medical screening questionnaires at 4-, 12-, and 24-weeks post-infusion for two consecutive infusion cycles as well as a post-study completion questionnaire. <h3>Results:</h3> 115 participants were included in the study (n=53 NYU/n=62 ELC); 64% were female; 36% - non-White; baseline age - 46.2±12.5 years; disease duration −15.3±10.7 years; OCR treatment duration - 2.54 ±1.04 years; median (IQR) EDSS - 3.0 (1.5, 5.3); EDSS was &gt;= 4 in 48 patients (42%). Paired Wilcoxon nonparametric tests used to evaluate the changes in outcome scores from pre- to post-infusion showed no significant changes on any NeuroQol and SymptoMScreen scales. Scores on two WPAI-MS subscales (“impairment while working due to health” and “overall work impairment”) increased by 10% during the 2^nd cycle (p-values=0.02 and 0.001) but not the 1^st cycle. On the post-completion questionnaire, the percentage of patients who reported ‘wearing off’ always was 4%, usually - 33%, sometimes - 45%, and never - 17%. <h3>Conclusions:</h3> Although symptom burden remained stable throughout two OCR infusion cycles on multiple scales, most patients reported “wearing off” at least sometimes. We will discuss possible explanations for this discrepancy. <b>Disclosure:</b> Dr. Kister has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech-Roche. The institution of Dr. Kister has received research support from Genentech. Dr. Kister has received publishing royalties from a publication relating to health care. Prof. Oh has nothing to disclose. Ms. Douglas has nothing to disclose. Ms. O’Shea has nothing to disclose. An immediate family member of Tamar Bacon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of an immediate family member of Tamar Bacon has received research support from Gentech. An immediate family member of Tamar Bacon has received publishing royalties from a publication relating to health care. Dr. Bouley has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Banner Life Sciences. Dr. Bouley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Bouley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Bouley has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Genentech. Dr. Bouley has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Bouley has received research support from Novartis. Dr. Lathi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. The institution of Dr. Katz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Theraputics. The institution of Dr. Katz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jansen Pharmaceuticals. The institution of Dr. Katz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viela Bio. The institution of Dr. Katz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Katz has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Novartis. The institution of Dr. Katz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Sanofi-Genzyme. The institution of Dr. Katz has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Genentech. The institution of Dr. Katz has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD-Serono.

Herpes Simplex Virus (HSV), Varicella-Zoster Virus (VZV), and Cryptococcal Infections Associated With Sphingosine-1-Phosphate Receptor (S1PR) Modulators: A Review (P12-10.005)

<h3>Objective:</h3> To summarize the existing data on the incidence of herpes simplex virus (HSV), varicella-zoster virus (VZV), and Cryptococcus sp. infections with sphingosine-1-phosphate receptor (S1PR) modulators. <h3>Background:</h3> S1PR modulators are a novel class of disease-modifying therapies for multiple sclerosis (MS) that produce immunosuppression and potential lymphopenia. Herpesvirus and cryptococcal diseases were the most common opportunistic infections in clinical trials. Several post-hoc analyses have subsequently been published with revised incidence rates (IRs) for these conditions. <h3>Design/Methods:</h3> A literature review and descriptive analysis of phase-3 trials (n=6), post-marketing studies (n=8), and case reports (n=17) were conducted using PubMed and Google Scholar. Further data was accessed through Novartis AG, Bristol-Myers Squibb, and Janssen Pharmaceuticals. <h3>Results:</h3> <h3>FINGOLIMOD:</h3> Herpesvirus infection rates were similar between placebo (2.8%) and 0.5 mg (2.1%) but increased with 1.25 mg (5.5%) in the TRANSFORMS study. VZV rates were higher with fingolimod 0.5 mg (3.0%; 11 per 1000 patient-years [PY]) than with placebo (1.0%; 6 per 1000 PY), but comparable post-marketing. Cryptococcal infections (n=74) had an IR of 9 per 100,000 PY, and 13 cases were individually reported. <h3>SIPONIMOD:</h3> VZV reactivation occurred more frequently with siponimod (2%) than with placebo (1%); EXPAND extension analyses calculated an IR of 0.9 for HSV and 1.8 for VZV infections. One case of cryptococcal meningitis (from 7236 PY of exposure) was documented. <h3>OZANIMOD:</h3> An integrated safety analysis reported oral herpes at 1.5%, VZV at 1.4%, and HSV at 0.5% from all clinical trials versus 0.7%, 0.6%, and 0.1% from the phase-3 trials. The IR of herpes zoster was 5.3/1000 PY. <h3>PONESIMOD:</h3> The incidence of herpetic infections was equal between both groups (4.8%) in the OPTIMUM trial. Cryptococcal infections have not yet been reported with ozanimod or ponesimod. <h3>Conclusions:</h3> Overall, the incidence of these opportunistic infections associated with S1PR modulators in MS was low, with favorable outcomes and limited fatalities. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Mr. JHA has nothing to disclose. Dr. Khanal has nothing to disclose. Dr. Sriwastava has nothing to disclose.

Evaluation of B-cell Abnormalities in Infants of Breastfeeding Mothers on anti-CD20 Therapies for Multiple Sclerosis (S31.001)

<h3>Objective:</h3> Evaluation for B-cell abnormalities in breastfed infants of mothers with multiple sclerosis (MS) who are on anti-CD20 therapies (rituximab, ocrelizumab, ofatumumab). <h3>Background:</h3> Patients with MS are at high risk of relapses in the postpartum period. Breastfeeding has been demonstrated to have some protective effect against postpartum relapses. However, data in regard to safety of most MS disease modifying therapies in breastfeeding is poorly established, leading to a decision between either early reinitiation of DMT postpartum versus breastfeeding. <h3>Design/Methods:</h3> We retrospectively evaluated 7 patients in our practice at the Rocky Mountain MS Center at the University of Colorado who had breastfed their infants on anti-CD20 therapies. These infants had a CBC and B-cell panel checked through their pediatricians as standard of care after treatment with anti-CD20 postpartum. <h3>Results:</h3> In all seven of these infants, there were no abnormalities found in either their CD19 or CD20 cell counts. The average age of the mothers with MS was 35.4 years. Typically, B-cell depleting agents were resumed between 1–6 months postpartum. The B-cell panels were checked between 2–12 weeks after their mother had received their infusion (rituximab, ocrelizumab) or 2 weeks after an injection (ofatumumab). <h3>Conclusions:</h3> In our small retrospective case series, we do not identify any B-cell abnormalities in breastfed infants whose mothers are receiving anti CD20 therapies early in the postpartum period for treatment of multiple sclerosis. Additional patients will likely be added to this case series before presentation as well as further details about the subjects. This data provides additional safety information to this treatment strategy for the infant while maintaining the mother with highly effective immunotherapy treatments for multiple sclerosis. <b>Disclosure:</b> The institution of Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. The institution of Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Shah has received personal compensation in the range of $5,000-$9,999 for serving as a Educational Speaker with Rocky Mountain MS Center. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Alvarez has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. The institution of an immediate family member of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB.

A Case Report: Simultaneous Presentation of Morphea and Multiple Sclerosis, a Diagnostic and Management Challenge. (P8-3.018)

<h3>Objective:</h3> To describe a unique case of a patient with multiple sclerosis and concurrent morphea complicating the diagnostic and therapeutic picture. <h3>Background:</h3> Localized scleroderma, also called morphea, is an inflammatory skin condition causing excess collagen deposition and thickened skin. Parry-Romberg Syndrome is one subtype characterized by linear facial involvement. Rarely, neurologic symptoms manifest as seizures, neuropathy, CNS vasculitis, and white matter abnormalities on MRI. Prior case reports of CNS involvement are associated with T2 hyperintense lesions, predominantly subcortical and juxtacortical, ipsilateral to the cutaneous lesions and often localized to one brain area. Multiple sclerosis (MS) is a primary CNS demyelinating condition, most frequently with a relapsing remitting presentation. It is characterized by white matter abnormalities on MRI, usually with periventricular, juxtacortical, cortical or brainstem and spinal cord lesions. We present a 41-year-old African American female previously diagnosed with MS and started on ofatumumab. She presented in hopes of switching therapies due to injection fatigue. On exam, she exhibited left facial discoloration and hemifacial atrophy, progressively worsening for years. She was referred to a dermatologist and subsequently diagnosed with morphea via skin biopsy. MRI showed bihemispheric periventricular, subcortical, and juxtacortical demyelinating lesions and global atrophy. She also had cervical and thoracic spinal cord involvement. Imaging was more suggestive of MS than CNS morphea, and the concomitant diagnosis of both conditions was made. Given that none of the disease modifying therapies approved for MS are compatible with treatment of morphea, this presented a challenging scenario. The patient was continued on a B-cell therapy for MS and started on monthly methylprednisolone infusions for morphea, with clinical stability to date. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> We present a unique diagnostic dilemma of concomitant presentation of MS and morphea versus CNS involvement of morphea. Ultimately, the distinct imaging features of both disorders on MRI guided this patient’s diagnosis and treatment. <b>Disclosure:</b> Dr. Thakkar has nothing to disclose. Dr. Sharkus has nothing to disclose. Dr. McMahon has nothing to disclose. An immediate family member of Dr. Thon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon. An immediate family member of Dr. Thon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. An immediate family member of Dr. Thon has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genentech. Dr. Thon has received personal compensation in the range of $500-$4,999 for serving as a Focus group participant with Alexion. Olga Thon has nothing to disclose.

The Bruton’s Tyrosine Kinase Inhibitor Evobrutinib Demonstrates Superior Efficacy in Targeting Compartmentalized Neuroinflammation Compared to Anti-CD20 Treatment. (S16.004)

<h3>Objective:</h3> To evaluate the efficacy of evobrutinib, a central nervous system (CNS)-penetrant Bruton’s tyrosine kinase inhibitor (BTKi), versus anti-CD20 treatment, on compartmentalized neuroinflammation and disease outcomes in a novel mouse model recapitulating key features of disease progression in multiple sclerosis (MS). <h3>Background:</h3> In MS, compartmentalized neuroinflammation often starts early and is characterized by an accumulation of persistent B cell rich aggregates. Compartmentalized neuroinflammation is predictive of both poor clinical outcomes and rapid disability progression. B cells within the CNS may be protected from established MS therapies such as anti-CD20 antibodies. CNS-penetrant small molecules directed against BTK – with its critical role in B cell activation, proliferation, and survival – have emerged to potentially target chronic neuroinflammation. <h3>Design/Methods:</h3> Preclinical assessments compared the therapeutic potential of evobrutinib and anti-CD20 antibodies on MS progression using the experimental autoimmune encephalomyelitis mouse model with features of progression (pEAE). Clinical outcomes and their correlation with CNS immunopathological parameters were assessed in pEAE mice to recapitulate key aspects of MS disease progression. <h3>Results:</h3> Evobrutinib, versus anti-CD20 (clone: SA271G2) treatment, reduced disease severity (65% reduction; P&lt;0.0001) and immunopathological parameters of disease (56% reduction; P&lt;0.01) in pEAE mice. The beneficial effects of BTKi were paralleled by body-weight gain and a decrease in maximum disease score versus anti-CD20 treatment. Evobrutinib lessened neuroinflammation by significantly reducing the number and activation of lymphoid and myeloid cells as well as the extent of submeningeal demyelination both in the brain (44% reduction; P&lt;0.01) and the spinal cord (42% reduction; P&lt;0.01). <h3>Conclusions:</h3> The improvements in clinical, immunological, and neuropathological parameters of disease observed in pEAE mice treated with evobrutinib illustrate the importance of compartmentalized neuroinflammation for disease progression. The limited effect of anti-CD20 treatment confirms the insufficient disease inhibition potential of antibody-based therapies when targeting intrathecal B cells. These findings support the notion that evobrutinib targets persistent neuroinflammation in MS. <b>Disclosure:</b> Ms. Kebir has received research support from Fonds de Recherche du Québec-Santé. Ms. Kebir has received intellectual property interests from a discovery or technology relating to health care. Cen Li has received research support from Chinese Scholarship Council. The institution of Michael May has received research support from NIH. Molly Church has nothing to disclose. Ursula Boschert has nothing to disclose. Jorge Alvarez has nothing to disclose.

Adaptive and innate immune responses in multiple sclerosis with anti-CD20 therapy: Gene expression and protein profiles.

Anti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells. Anti-CD20 therapy depletes B cells, which alters antibody production and has diverse effects on B cell immunity. These changes potentially affect immunity beyond B cells in MS. Determine if anti-CD20 therapy effects non-B cell, as well as B cell, gene expression, and serum protein levels. Samples were collected from 10 healthy controls and from clinically stable relapsing-remitting MS - 10 untreated, 9 interferon-β-treated, and 15 ocrelizumab-treated patients were studied before, and 2 weeks and 6 months after, the first anti-CD20 infusion. Peripheral blood mononuclear cells (PBMC) were analyzed with sensitive, 135,000-transcript RNA expression microarrays, using stringent criteria. Gene expression was compared to 43 MS-relevant serum immune and neurotrophic proteins, using multiplex protein assays. Anti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2 weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes returned toward baseline by 6 months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 regulatory T-cell (Treg) development, differentiation, and proliferation also quieted. In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways. These findings have clinical implications. B cell gene expression diminishes 2 weeks after anti-CD20 antibody infusion, but begins to rebound by 6 months. This suggests that the optimum time for vaccination is soon before reinfusion of anti-CD20 therapy. In addition, at 6 months, there is enhanced Th1 cell gene expression and induction of innate immune response genes and TLR expression, which can enhance anti-viral and anti-tumor immunity. This may compensate for diminished B cell gene expression after therapy. These data suggest that anti-CD20 therapy has dynamic effect on B cells and causes a compensatory rise in Th1 and myeloid immunity.

Presentation of Human Neural Stem Cell Antigens Drives Regulatory T Cell Induction.

Transplantation of human neural stem cells (hNSCs) is a promising regenerative therapy to promote remyelination in patients with multiple sclerosis (MS). Transplantation of hNSCs has been shown to increase the number of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in the spinal cords of murine models of MS, which is correlated with a strong localized remyelination response. However, the mechanisms by which hNSC transplantation leads to an increase in Tregs in the CNS remains unclear. We report that hNSCs drive the conversion of T conventional (Tconv) cells into Tregs invitro. Conversion of Tconv cells is Ag driven and fails to occur in the absence of TCR stimulation by cognate antigenic self-peptides. Furthermore, CNS Ags are sufficient to drive this conversion in the absence of hNSCs invitro and invivo. Importantly, only Ags presented in the thymus during T cell selection drive this Treg response. In this study, we investigate the mechanisms by which hNSC Ags drive the conversion of Tconv cells into Tregs and may provide key insight needed for the development of MS therapies.

A backpack-based myeloid cell therapy for multiple sclerosis

Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles ("backpacks") for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on TH1 and TH17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype invivo, demonstrating the utility of myeloid cells as a therapeutic modality and target.

Real-world use of natalizumab in Austria: data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR)

IntroductionWith the approval of natalizumab in Europe in 2006, the Austrian Multiple Sclerosis Therapy Registry (AMSTR) was established. Here, we present data from this registry about effectiveness and safety of natalizumab in patients treated up to 14 years.Patients/methodsData retrieved from the AMSTR contained baseline characteristics and biannual documentation of annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score as well as adverse events and reasons for discontinuation on follow-up visits.ResultsA total of 1596 natalizumab patients (71% women, n = 1133) were included in the analysis and the observed treatment duration ranged from 0 to 164 months (13.6 years). The mean ARR was 2.0 (SD = 1.13) at baseline, decreasing to 0.16 after 1 year and 0.01 after 10 years. A total of 325 patients (21.6%) converted to secondary progressive multiple sclerosis (SPMS) during the observational period. Of 1502 patients, 1297 (86.4%) reported no adverse events (AE) during follow-up visits. The most common reported AEs were infections and infusion-related reactions. John Cunningham virus (JCV) seropositivity was the most common specified reason for treatment discontinuation (53.7%, n = 607). There were five confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) with 1 death.ConclusionThe effectiveness of natalizumab in patients with active relapsing–remitting multiple sclerosis (RRMS) could be confirmed in our real-world cohort even after follow-up of up to 14 years, though after year 10, there were less than 100 remaining patients. A low number of AE were reported in this nationwide registry study, establishing Natalizumab’s favourable safety profile during long-term use.