Neurology(R) neuroimmunology & neuroinflammation最新文献

{"title":"Rate of Retinal Layer Thinning as a Biomarker for Conversion to Progressive Disease in Multiple Sclerosis.","authors":"Nabil K El Ayoubi,&nbsp;Hadi M Sabbagh,&nbsp;Nicole Bou Rjeily,&nbsp;Salem Hannoun,&nbsp;Samia J Khoury","doi":"10.1212/NXI.0000000000200030","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200030","url":null,"abstract":"<p><strong>Background and objectives: </strong>The diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed because of the lack of objective clinical tools, which increases the diagnostic uncertainty and hampers the therapeutic development in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) has been proposed as a promising biomarker of progressive neurodegeneration. To explore longitudinal changes in the thicknesses of retinal layers on OCT in individuals with relapsing-remitting MS (RRMS) who converted to SPMS vs matched patients with RRMS who did not convert to SPMS. Our hypothesis is that the 2 cohorts exhibit different rates of retinal thinning.</p><p><strong>Methods: </strong>From our prospective observational cohort of patients with MS at the American University of Beirut, we selected patients with RRMS who converted to SPMS during the observation period and patients with RRMS, matched by age, disease duration, and Expanded Disability Status Scale (EDSS) at the first visit. Baseline retinal measurements were obtained using spectral domain OCT, and all patients underwent clinical and OCT evaluation every 6-12 months on average throughout the study period (mean = 4 years). Mixed-effect regression models were used to assess the annualized rates of retinal changes and the differences between the 2 groups and between converters to SPMS before and after their conversion.</p><p><strong>Results: </strong>A total of 61 participants were selected (21 SPMS and 40 RRMS). There were no differences in baseline characteristics and retinal measurements between the 2 groups. The annualized rates of thinning of all retinal layers, except for macular volume, were greater in converters before conversion compared with nonconverters by 112% for peripapillary retinal nerve fiber layer (<i>p</i> = 0.008), 344% for tRNFL (<i>p</i> < 0.0001), and 82% for cell-inner plexiform layer (GCIPL) (<i>p</i> = 0.002). When comparing the annualized rate of thinning for the same patients with SPMS before and after conversion, no significant differences were found except for tRNFL and GCIPL with slower thinning rates postconversion (46% and 68%, respectively).</p><p><strong>Discussion: </strong>Patients who converted to SPMS exhibited faster retinal thinning as reflected on OCT. Longitudinal assessment of retinal thinning could confirm the transition to SPMS and help with the therapeutic decision making for patients with MS with clinical suspicion of disease progression.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/24/NXI-2022-200036.PMC9562042.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33506343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timing of SARS-CoV-2 Vaccination Matters in People With Multiple Sclerosis on Pulsed Anti-CD20 Treatment.","authors":"Christina Woopen,&nbsp;Marie Dunsche,&nbsp;Rocco Haase,&nbsp;Catarina Raposo,&nbsp;Rosetta Pedotti,&nbsp;Katja Akgün,&nbsp;Tjalf Ziemssen","doi":"10.1212/NXI.0000000000200031","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200031","url":null,"abstract":"<p><strong>Background and objectives: </strong>Our objective was to investigate cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of people with multiple sclerosis (pwMS) on pulsed B-cell-depleting treatment (BCDT). In particular, we intended to evaluate a possible association between immune responses and the timing of vaccination under BCDT.</p><p><strong>Methods: </strong>We conducted a cross-sectional study among pwMS on pulsed BCDT or without disease-modifying treatment after completed SARS-CoV-2 vaccination. Samples were collected during routine clinical visits at the Multiple Sclerosis Center Dresden, Germany, between June 2021 and September 2021. Blood was analyzed for SARS-CoV-2 spike protein-specific antibodies and interferon-γ release of CD4 and CD8 T cells on stimulation with spike protein peptide pools. Lymphocyte subpopulations and total immunoglobulin levels in the blood were measured as part of clinical routine.</p><p><strong>Results: </strong>We included 160 pwMS in our analysis, comprising 133 pwMS on BCDT (n = 132 on ocrelizumab and n = 1 on rituximab) and 27 without disease-modifying treatment. Humoral and cellular anti-SARS-CoV-2 responses were reciprocally regulated by the time between the last BCDT cycle and vaccination. Although antibody responses increased with prolonged intervals between the last BCDT cycle and vaccination, CD4 and CD8 T-cell responses were higher in pwMS vaccinated at early time points after the last BCDT cycle compared with untreated pwMS. T-cellular vaccination responses correlated with total, CD3 CD4, and partly with CD3 CD8 lymphocyte counts. Humoral responses correlated with CD19 lymphocyte counts. Status post coronavirus disease 2019 infection led to significantly increased SARS-CoV-2-specific T-cell and antibody responses.</p><p><strong>Discussion: </strong>Delaying BCDT is currently discussed as a strategy to optimize humoral responses to SARS-CoV-2 vaccination. However, T cells represent an important line of defense against SARS-CoV-2 infection as well, especially in light of emerging variants of concern. We observed enhanced CD4 and CD8 T-cellular responses in pwMS receiving vaccination at early time points after their last BCDT cycle. These data may influence clinical decision making with respect to vaccination strategies in patients receiving BCDT.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/05/50/NXI-2022-200037.PMC9558629.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33525538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of NEDA-4 With No Long-term Disability Progression in Multiple Sclerosis and Comparison With NEDA-3: A Systematic Review and Meta-analysis.","authors":"Dalia Rotstein,&nbsp;Jacqueline M Solomon,&nbsp;Maria Pia Sormani,&nbsp;Xavier Montalban,&nbsp;Xiang Y Ye,&nbsp;Dina Dababneh,&nbsp;Alexandra Muccilli,&nbsp;Georges Saab,&nbsp;Prakesh Shah","doi":"10.1212/NXI.0000000000200032","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200032","url":null,"abstract":"<p><strong>Background and objectives: </strong>No evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression.</p><p><strong>Methods: </strong>English-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression.</p><p><strong>Results: </strong>Five studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4-6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36-3.37; I² = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses.</p><p><strong>Discussion: </strong>In patients with RRMS, NEDA-4 at 1-2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/ac/NXI-2022-200038.PMC9558627.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33525539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pachymeningitis in Biopsy-Proven Sarcoidosis: Clinical Course, Radiographic Findings, Response to Treatment, and Long-term Outcomes.","authors":"Pressley A Chakales,&nbsp;Max C Herman,&nbsp;Ling Chen Chien,&nbsp;Spencer K Hutto","doi":"10.1212/NXI.0000000000200028","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200028","url":null,"abstract":"<p><strong>Background and objectives: </strong>Meningeal inflammation is one of the most common manifestations of neurosarcoidosis, occurring in 16%-69% of affected patients. While the clinical and radiographic features of leptomeningitis in neurosarcoidosis are well known, those of pachymeningitis are far less clear. Our primary aim was to study the clinicoradiographic features of pachymeningeal involvement in neurosarcoidosis and its evolution over time in response to treatment.</p><p><strong>Methods: </strong>Patients with a diagnosis of neurosarcoidosis seen at Emory University (January 2011-August 2021) were included if pachymeningeal involvement was evident by MRI and the patient's sarcoidosis was pathologically confirmed (from a CNS or non-CNS site).</p><p><strong>Results: </strong>Twenty-six of 215 (12.1%) patients with neurosarcoidosis qualified for inclusion. Pathologic confirmation came from CNS tissue in 50%. The median age of onset was 43.5 years; most were male (16/26, 61.5%). Symptoms were primarily related to pachymeningitis in 20/26 (76.9%). Headache (19/26, 73.1%), visual dysfunction (12/26, 46.2%), and seizures (7/26, 26.9%) were the most common symptoms. All patients had cranial pachymeningitis; only a single patient undergoing spinal imaging (1/11, 9.1%) had spinal pachymeningitis. The falx cerebri (16/26, 61.5%) was the most commonly affected dural structure, but the anterior and middle cranial fossae and tentorium cerebelli were frequently involved (12/26 each, 46.2%). The pachymeningeal lesions were unifocal (11/26, 42.3%) or multifocal (15/26, 57.7%) in distribution, nodular morphologically (23/25, 92.0%), and homogeneously enhancing (24/25, 96.0%). Symptomatic improvement occurred with steroids initially in 22/25 (88.0%). Ultimately, 23/26 (88.5%) required initiation of steroid-sparing immunosuppressants, including 8/26 (30.8%) eventually undergoing TNF inhibition. Pachymeningeal relapses occurred in 7/26 (26.9%). The median clinical follow-up was 48 months. The median modified Rankin scale score at last follow-up improved to 1.0 from 2.0 at presentation.</p><p><strong>Discussion: </strong>Pachymeningitis due to sarcoidosis often presents with headaches, visual dysfunction, and seizures; it usually affects the dura of the falx cerebri, anterior and middle cranial fossae, and tentorium cerebelli and tends to require steroid-sparing immunosuppressants. It has the potential to relapse, but the prospect for recovery is good.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/61/e9/NXI-2022-200034.PMC9513981.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40373152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Area Postrema Syndrome in Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: A Case Series and Literature Review.","authors":"Bo Deng,&nbsp;Jingguo Wang,&nbsp;Hai Yu,&nbsp;Lei Jin,&nbsp;Yue Qiu,&nbsp;Xiaoni Liu,&nbsp;Pengyu Wang,&nbsp;Xiang Zhang,&nbsp;Xiangjun Chen","doi":"10.1212/NXI.0000000000200029","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200029","url":null,"abstract":"<p><strong>Background and objectives: </strong>To report the frequency of area postrema syndrome (APS) in glial fibrillary acidic protein-immunoglobulin G (GFAP-IgG)-positive patients and emphasize the importance of APS among the phenotypes in autoimmune GFAP astrocytopathy.</p><p><strong>Methods: </strong>Eight GFAP-IgG-positive cases with APS were retrospectively identified during 2015-2021. The APS phenotypes were described. A literature review of 8 previously reported cases was also included in analysis.</p><p><strong>Results: </strong>A total of 8 patients (11%) (1 woman, 7 men; mean age: 52.4 ± 18.4 years) presented with APS in a cohort of 74 GFAP-IgG-positive patients, 3 of whom (4%) had disease onset with APS. All patients had hiccups, and hiccups was the unique symptom of APS in 5 patients. The median time from disease onset to APS occurrence was 2 days (range 0-20), and the mean duration of APS episodes was 23.6 ± 11.4 days. No patient had isolated APS attack. All episodes were completely resolved with a mean duration of 9.3 ± 5.4 days after immunotherapy. APS manifestations of 8 cases in previous studies showed similar features with our cases. In total, coexisting aquaporin-4-IgG was only detected in one of the 16 cases.</p><p><strong>Discussion: </strong>APS could be an early, but not isolated clinical manifestation of autoimmune GFAP astrocytopathy. Hiccups was the predominant symptom of APS in this disorder. APS attacks of autoimmune GFAP astrocytopathy have good response to immunotherapy.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9c/1e/NXI-2022-200035.PMC9513980.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40373550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLMP Promotes Leukocyte Migration Across Brain Barriers in Multiple Sclerosis.","authors":"Antoine Philippe Fournier,&nbsp;Stephanie Zandee,&nbsp;Marc Charabati,&nbsp;Evelyn Peelen,&nbsp;Olivier Tastet,&nbsp;Jorge Ivan Alvarez,&nbsp;Hania Kebir,&nbsp;Lyne Bourbonnière,&nbsp;Sandra Larouche,&nbsp;Boaz Lahav,&nbsp;Wendy Klement,&nbsp;Fiona Tea,&nbsp;Alain Bouthillier,&nbsp;Robert Moumdjian,&nbsp;Romain Cayrol,&nbsp;Pierre Duquette,&nbsp;Marc Girard,&nbsp;Catherine Larochelle,&nbsp;Nathalie Arbour,&nbsp;Alexandre Prat","doi":"10.1212/NXI.0000000000200022","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200022","url":null,"abstract":"<p><strong>Background and objectives: </strong>In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS.</p><p><strong>Methods: </strong>Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP.</p><p><strong>Results: </strong>Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP⁺ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP⁺ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS.</p><p><strong>Discussion: </strong>Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7b/f7/NXI-2022-200028.PMC9465835.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33511965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRI Characteristics of Autoimmune Encephalitis With Autoantibodies to GABAA Receptor: A Case Series.","authors":"","doi":"10.1212/NXI.0000000000200040","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200040","url":null,"abstract":"","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453698/pdf/NXI-2022-200047.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40465233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia as Central Protagonists in the Chronic Stress Response.","authors":"Eva Schramm,&nbsp;Ari Waisman","doi":"10.1212/NXI.0000000000200023","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200023","url":null,"abstract":"<p><p>Chronic stress is a major risk factor for developing psychiatric conditions. In addition to elevating the levels of stress hormones released in the body, chronic stress activates the immune system, resulting in increased levels of proinflammatory cytokines and innate immune cells in the circulation of rodents and humans. Furthermore, exposure to chronic stress alters the phenotype of microglia, a population of innate immune cells that reside in the CNS parenchyma. In rodent models, chronic stress activates microglia in defined brain regions and induces changes in their phenotype and functional properties. In this review, we discussed how microglia are activated in stressful situations. Furthermore, we described how microglia affect the CNS environment during chronic stress, through the production of cytokines, the induction of reactive oxygen species, and phagocytosis. We suggested that, due to their strategic location as immune cells within the CNS, microglia are important players in the induction of psychopathologies after chronic stress.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453699/pdf/NXI-2022-200029.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40465232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis.","authors":"Jason R Thonhoff,&nbsp;James D Berry,&nbsp;Eric A Macklin,&nbsp;David R Beers,&nbsp;Patricia A Mendoza,&nbsp;Weihua Zhao,&nbsp;Aaron D Thome,&nbsp;Fabio Triolo,&nbsp;James J Moon,&nbsp;Sabrina Paganoni,&nbsp;Merit Cudkowicz,&nbsp;Stanley H Appel","doi":"10.1212/NXI.0000000000200019","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200019","url":null,"abstract":"<p><strong>Background and objectives: </strong>In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.</p><p><strong>Methods: </strong>Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 10⁶ cells/kg) IV every 4 weeks and IL-2 (2 × 10⁵ IU/m²) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 10⁶ cells/kg and 3 × 10⁶ cells/kg at 4-week intervals.</p><p><strong>Results: </strong>The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of -2.7 points per the ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of -10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.</p><p><strong>Discussion: </strong>Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/df/76/NXI-2022-200025.PMC9423710.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33446196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.","authors":"Steve Simpson-Yap,&nbsp;Ashkan Pirmani,&nbsp;Tomas Kalincik,&nbsp;Edward De Brouwer,&nbsp;Lotte Geys,&nbsp;Tina Parciak,&nbsp;Anne Helme,&nbsp;Nick Rijke,&nbsp;Jan A Hillert,&nbsp;Yves Moreau,&nbsp;Gilles Edan,&nbsp;Sifat Sharmin,&nbsp;Tim Spelman,&nbsp;Robert McBurney,&nbsp;Hollie Schmidt,&nbsp;Arnfin B Bergmann,&nbsp;Stefan Braune,&nbsp;Alexander Stahmann,&nbsp;Rod M Middleton,&nbsp;Amber Salter,&nbsp;Bruce Bebo,&nbsp;Anneke Van der Walt,&nbsp;Helmut Butzkueven,&nbsp;Serkan Ozakbas,&nbsp;Cavit Boz,&nbsp;Rana Karabudak,&nbsp;Raed Alroughani,&nbsp;Juan I Rojas,&nbsp;Ingrid A van der Mei,&nbsp;Guilherme Sciascia do Olival,&nbsp;Melinda Magyari,&nbsp;Ricardo N Alonso,&nbsp;Richard S Nicholas,&nbsp;Anibal S Chertcoff,&nbsp;Ana Zabalza de Torres,&nbsp;Georgina Arrambide,&nbsp;Nupur Nag,&nbsp;Annabel Descamps,&nbsp;Lars Costers,&nbsp;Ruth Dobson,&nbsp;Aleisha Miller,&nbsp;Paulo Rodrigues,&nbsp;Vesna Prčkovska,&nbsp;Giancarlo Comi,&nbsp;Liesbet M Peeters","doi":"10.1212/NXI.0000000000200021","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200021","url":null,"abstract":"<p><strong>Background and objectives: </strong>Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed.</p><p><strong>Methods: </strong>Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab.</p><p><strong>Results: </strong>Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19.</p><p><strong>Discussion: </strong>Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.</p>","PeriodicalId":520720,"journal":{"name":"Neurology(R) neuroimmunology & neuroinflammation","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2022-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9c/15/NXI-2022-200027.PMC9423711.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33446198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}