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Iris N van Doorn,1 Filip Eftimov,1 Luuk Wieske,1,2 Ivo N van Schaik,1,3 Camiel Verhamme1 1Department of Neurology and Clinical Neurophysiology, Amsterdam Neuroscience and University of Amsterdam, Amsterdam UMC, location AMC, the Netherlands; 2Department of Clinical Neurophysiology, Sint Antonius Hospital, Nieuwegein, the Netherlands; 3Sanquin Blood Supply Foundation, Amsterdam, the NetherlandsCorrespondence: Camiel Verhamme, Department of Neurology and Clinical Neurophysiology, Amsterdam Neuroscience and University of Amsterdam, Meibergdreef 9, Amsterdam UMC, location AMC, 1105AZ, the Netherlands, Email c.verhamme@amsterdamumc.nlAbstract: Diagnosing Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) poses numerous challenges. The heterogeneous presentations of CIDP variants, its mimics, and the complexity of interpreting electrodiagnostic criteria are just a few of the many reasons for misdiagnoses. Early recognition and treatment are important to reduce the risk of irreversible axonal damage, which may lead to permanent disability. The diagnosis of CIDP is based on a combination of clinical symptoms, nerve conduction study findings that indicate demyelination, and other supportive criteria. In 2021, the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) published a revision on the most widely adopted guideline on the diagnosis and treatment of CIDP. This updated guideline now includes clinical and electrodiagnostic criteria for CIDP variants (previously termed atypical CIDP), updated supportive criteria, and sensory criteria as an integral part of the electrodiagnostic criteria. Due to its many rules and exceptions, this guideline is complex and misinterpretation of nerve conduction study findings remain common. CIDP is treatable with intravenous immunoglobulins, corticosteroids, and plasma exchange. The choice of therapy should be tailored to the individual patient’s situation, taking into account the severity of symptoms, potential side effects, patient autonomy, and past treatments. Treatment responses should be evaluated as objectively as possible using disability and impairment scales. Applying these outcome measures consistently in clinical practice aids in recognizing the effectiveness (or lack thereof) of a treatment and facilitates timely consideration of alternative diagnoses or treatments. This review provides an overview of the current perspectives on the diagnostic process and first-line treatments for managing the disease.Keywords: CIDP, treatment, diagnosis, NCS, imaging

Objective: Deep learning methods have shown potential in automating the detection of interictal epileptiform discharges (IEDs) in electroencephalography (EEG). We compared IED detection using our previously trained deep neural network with a group of experts to assess its potential applicability., Methods: First, we performed clinical validation on an internal data set. Seven experts reviewed all EEG studies. Performance agreement between experts and the network was compared at both the EEG and IED levels. All EEG recordings were also processed with Persyst. Subsequently, we performed external validation, with data from four centers, using a hybrid approach, where detections by the deep neural network were reviewed by an expert. In case of disagreement with the original report, the EEG recording was annotated independently by five experts., Results: For internal validation we included 22 EEG studies with IEDs and 28 EEG studies from controls. At the EEG level, our network showed performance similar to that of the experts. For individual IED detection, the sensitivities between experts ranged from 20.7%-86.4%, whereas the sensitivity of our network was 82.5% (confidence interval [CI]: 77.7%-87.4%) at 99% specificity and a false detection rate (FDR) of <.2/min, outperforming Persyst, with 64.6% sensitivity (CI: 61.4%-67.9%) at 98% specificity. External validation in 174 EEG studies demonstrated that all 85 EEG recordings classified as normal in the original report were classified correctly, with an FDR of .10/min. Of the 89 EEG studies with IEDs according to the report, 56 were correctly classified (Cohen's κ = .62). Visual analysis of the remaining 33 EEG recordings showed high interobserver variability among the five experts (Fleiss' κ = .13)., Significance: Our deep neural network detects IEDs on par with clinical experts. The external validation in a hybrid approach showed substantial agreement with the original report. Disagreement was due mainly to high interobserver variability. Our deep neural network may support visual EEG analysis and assist in diagnostics, particularly when human resources are limited., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: SARS-CoV-2 has been associated with a higher proportion of asymptomatic infections and lower mortality in sub-Saharan Africa than high-income countries. However, there is currently a lack of data on cellular immune responses to SARS-CoV-2 in people living in Africa compared with people in high-income regions of the world. We aimed to assess geographical variation in peripheral and mucosal immune responses., Methods: In this retrospective, population-based, cross-sectional study, we analysed peripheral blood and nasal curettage samples from seven clinical studies involving individuals from Senegal (Senegalese cohort), the Netherlands, and Germany (European cohort). Samples were collected between Nov 1, 2018, and Dec 20, 2021. We included samples from individuals with no, mild, or severe COVID-19. A validation cohort of individuals from Senegal and Gabon (n=64) was used to validate key findings from the main cohort. Matching of individuals between geographical regions by age, sex, viral load, and infection severity and duration was used to address confounding factors. We examined the cellular, humoral, and cytokine immune responses using cytometry by time of flight, spectral flow cytometry, ELISA, and Luminex., Findings: We included 133 individuals (59 from the Senegalese cohort and 74 from the European cohort). In contrast to the European cohort, mild COVID-19 in the Senegalese cohort was not associated with any statistically significant perturbations in blood or nasal immune cell profiles, nor with increased pro-inflammatory cytokines, although SARS-CoV-2-specific adaptive immunity was readily induced, as seen in Europeans. In severe COVID-19, both the Senegalese and European cohorts showed lymphopenia (Senegal: 2·9-times decrease, p=0·0010 vs Europe: 1·6-times decrease, p=0·0046) and increased neutrophil frequencies in blood (Senegal: 2·0-times increase, p=0·0044 vs Europe: 1·3-times increase, p=0·026) and the nasal mucosa CD66b + CD16 low neutrophils (Senegal: 9·9-times increase, p=0·045 vs Europe: 392-times increase, p<0·0001). However, in contrast to Europeans, the Senegalese cohort had no significant expansion of immature immune populations, inflammasome activation, or monocyte recruitment to the nasal mucosa., Interpretation: The observed divergent immunological trajectories during SARS-CoV-2 infection offer a potential explanation for the reported attenuated disease course in sub-Saharan Africa and highlight the need to further investigate immune responses to SARS-CoV-2 in understudied populations., Funding: European and Developing Countries Clinical Trials Partnership 2 programme (AIDCO), LUMC Gisela Thier Fellowship, Dutch Research Council (NWO), European Research Council, and Leids Universitair Fonds., Competing Interests: Declaration of interests FE reports research grants from ZonMw (a Dutch governmental agency) for vaccination-induced immunity against SARS-CoV-2 in patients with immune-mediated diseases. SPJ reports grants from ZonMw, BMGF, the EU, and the Dutch Research Council; and travel fees covered by the Dutch Lung Foundation for attending advisory board meetings. TPV is a member of PAN-ASEAN Coalition for Epidemic and Outbreak Preparedness (PACE-UP; German Academic Exchange Service [DAAD] Project ID: 57592343). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: There are concerns for safety regarding SARS-CoV-2 vaccines for patients with autoimmune neuromuscular disease. We compared daily functioning using disease-specific patient-reported outcome measures (PROMs) before and after SARS-CoV-2 vaccinations., Methods: In this substudy of a prospective observational cohort study (Target-to-B!), patients with myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and idiopathic inflammatory myopathy (IIM) vaccinated against SARS-CoV-2 were included. Surveys of daily functioning (Myasthenia Gravis Activities of Daily Living, Inflammatory Rasch-Built Overall Disability Scale, Multifocal Motor Neuropathy Rasch-Built Overall Disability Scale, and Health Assessment Questionnaire-Disability Index) were sent before first vaccination and every 60 days thereafter for up to 12 months. Regression models were constructed to assess differences in PROM scores related to vaccination, compared to scores unrelated to vaccination. We also assessed the proportion of patients with deterioration of at least the minimal clinically important difference (MCID) between before first vaccination and 60 days thereafter., Results: We included 325 patients (median age = 59 years, interquartile range = 47-67, 156 [48%] female sex), of whom 137 (42%) had MG, 79 (24%) had CIDP, 43 (13%) had MMN, and 66 (20%) had IIM. PROM scores related to vaccination did not differ from scores unrelated to vaccination. In paired PROMs, MCID for deterioration was observed in three of 49 (6%) MG patients, of whom none reported a treatment change. In CIDP, MCID for deterioration was observed in eight of 29 patients (28%), of whom two of eight (25%) reported a treatment change., Conclusions: SARS-CoV-2 vaccination had no effect on daily functioning in patients with autoimmune neuromuscular diseases, confirming its safety in these patients., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To analyze long-term clinical and biomarker features of anti-contactin-1 (CNTN1) autoimmune nodopathy (AN)., Methods: Patients with anti-CNTN1 + autoimmune nodopathy detected in our laboratory from which clinical information was available were included. Clinical features and treatment response were retrospectively collected. Autoantibody, serum neurofilament light chain (sNfL), and serum CNTN1 levels (sCNTN1) were analyzed at baseline and follow up., Results: A total of 31 patients were included. Patients presented with progressive sensory motor neuropathy (76.7%) with proximal (74.2%) and distal involvement (87.1%), ataxia (71.4%), and severe disability (median INCAT at nadir of 8). A total of 11 patients (35%) showed kidney involvement. Most patients (97%) received intravenous immunoglobulin, but only 1 achieved remission with intravenous immunoglobulin. A total of 22 patients (71%) received corticosteroids, and 3 of them (14%) did not need further treatments. Rituximab was effective in 21 of 22 patients (95.5%), with most of them (72%) receiving a single course. Four patients (12.9%) relapsed after a median follow up of 25 months after effective treatment (12-48 months). Anti-CNTN1 titers correlated with clinical scales at sampling and were negative after treatment in all patients, but 1 (20/21). sNfL levels were significantly higher and sCNTN1 significantly lower in anti-CNTN1 + patients than in healthy controls (sNfL: 135.9 pg/ml vs 7.48 pg/ml, sCNTN1: 25.03 pg/ml vs 22,186 pg/ml, p < 0.0001). Both sNfL and sCNTN1 returned to normal levels after successful treatment., Interpretation: Patients with anti-CNTN1 + autoimmune nodopathy have a characteristic clinical profile. Clinical and immunological relapses are infrequent after successful treatment, suggesting that continuous treatment is unnecessary. Anti-CNTN1 antibodies, sNfL, and sCNTN1 levels are useful to monitor disease status in these patients. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Background: INCbase is an international, multicenter prospective observational study using a customizable web-based modular registry to study the clinical, biological and electrophysiological variation and boundaries of chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of INCbase is to develop and validate a clinical prediction model for treatment response., Methods: All patients meeting clinical criteria for CIDP can be included in INCbase. Collected data include demographics, clinical history, diagnostics and various domains of clinical outcomes. Data is collected at a minimum of every 6 months for two years, and more frequently at the discretion of the investigational site to allow for assessment of unexpected changes in treatment response or clinical status. Participants can be enrolled in various sub-studies designed to capture data relevant to specific groups of interest. Data is entered directly into the web-based data entry system by local investigators and/or participants. Collection and local storage of biomaterial is optional. To develop a clinical prediction model for treatment response, newly diagnosed patients with active disease warranting start of first-line treatment will be included. The study population will be split into a development and validation cohort. Univariate and multivariate logistic regression analysis will be used to identify and combine predictors at start of treatment for treatment response at six months. Model performance will be assessed through discrimination and calibration in an external validation cohort. The externally validated prediction model will be made available to researchers and clinicians on the INCbase website., Discussion: With this study, we aim to create a clinically relevant and implementable prediction model for treatment response to first line treatments in CIDP. INCbase enrollment started in April 2021, with 29 centers across 8 countries and 303 patients participating to date. This collaborative effort between academia, patient advocacy organizations and pharmaceutical industry will deepen our understanding of how to diagnose and treat CIDP., (© 2024. The Author(s).)

Objectives: Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination., Methods: In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3-6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells., Results: Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients., Conclusion: Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses., Trial Registration Number: NL8900., Competing Interests: Competing interests: FE, GW, SMvH and TWK report (governmental) grants from ZonMw to study immune response after SARS-Cov-2 vaccination in auto-immune diseases. FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSl Behring; honoraria from Grifols. All other authors report no disclosures relevant to the manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking., Objectives: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls., Methods: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection., Results: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases., Conclusions: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Messenger RNA (mRNA) vaccines provide robust protection against SARS-CoV-2 in healthy individuals. However, immunity after vaccination of patients with multiple sclerosis (MS) treated with ocrelizumab (OCR), a B cell-depleting anti-CD20 monoclonal antibody, is not yet fully understood., Methods: In this study, deep immune profiling techniques were employed to investigate the immune response induced by SARS-CoV-2 mRNA vaccines in untreated patients with MS (n=21), OCR-treated patients with MS (n=57) and healthy individuals (n=30)., Results: Among OCR-treated patients with MS, 63% did not produce detectable levels of antibodies (non-seroconverted), and those who did have lower spike receptor-binding domain-specific IgG responses compared with healthy individuals and untreated patients with MS. Before vaccination, no discernible immunological differences were observed between non-seroconverted and seroconverted OCR-treated patients with MS. However, non-seroconverted patients received overall more OCR infusions, had shorter intervals since their last OCR infusion and displayed higher OCR serum concentrations at the time of their initial vaccination. Following two vaccinations, non-seroconverted patients displayed smaller B cell compartments but instead exhibited more robust activation of general CD4 + and CD8 + T cell compartments, as indicated by upregulation of CD38 and HLA-DR surface expression, when compared with seroconverted patients., Conclusion: These findings highlight the importance of optimising treatment regimens when scheduling SARS-CoV-2 vaccination for OCR-treated patients with MS to maximise their humoral and cellular immune responses. This study provides valuable insights for optimising vaccination strategies in OCR-treated patients with MS, including the identification of CD38 and HLA-DR as potential markers to explore vaccine efficacy in non-seroconverting OCR-treated patients with MS., Competing Interests: Competing interests: JK received research grants for multicentre investigator-initiated trials (DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMw) and BLOOMS trial (ZonMw and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees from F Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); and adjudication committee of MS clinical trial of Immunic (payments to institution only)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated., Methods: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination., Results: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based., Conclusions: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Objective disease activity biomarkers are lacking in chronic inflammatory demyelinating polyneuropathy (CIDP), impacting treatment decisions in clinical care and outcomes in clinical trials. Using a proximity extension assay, we aimed to identify candidate serum protein biomarkers for disease activity in CIDP., Method: We collected clinical data and serum of 106 patients with CIDP. Patients starting induction treatment (n=53) and patients on maintenance treatment starting treatment withdrawal (n=40) were assessed at baseline and at 6 months (or at relapse). Patients in remission (n=13) were assessed once. Clinical disease activity was defined based on improvement or deterioration by the minimal clinically important difference on the inflammatory Rasch-built Overall Disability Scale in combination with either grip strength or the Medical Research Council sum score. Using a proximity extension assay (Olink Explore platform), 1472 protein levels were analysed in serum. Candidate proteins were selected based on fold change>0.5 or <-0.5 and p<0.05 between clinically active and inactive disease. Longitudinal changes of candidate proteins between baseline and follow-up were analysed., Results: We identified 48 candidate proteins that differed between clinically active and inactive disease on cross-sectional comparison. Five of these proteins (SUGT1, IRAK4, DCTN1, 5'-nucleotidase cytosolic IIIA (NT5C3A), glutaredoxin (GLRX)) also showed longitudinal changes consistent with disease activity changes. IRAK4 was also identified in a sensitivity analysis, using another definition for disease activity., Conclusion: Our results indicate that IRAK4 and possibly SUGT1, DCTN1, NT5C3A and GLRX are candidate biomarkers for monitoring clinical disease activity in CIDP., Competing Interests: Competing interests: CET reports the following grants: Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CET is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CET has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had speaker contracts for Roche, Grifols, Novo Nordisk. FE reports grants from ZonMw (Dutch Governmental Agency) and Prinses Beatrix Spierfonds (Dutch Charity Organization) and grants from CSLBehring, Kedrion, Terumo BCT, Grifols and Takeda Pharmaceutical Company, outside the submitted work. Grants were paid to institution and are used for investigator-initiated randomized controlled trials and studies within INCbase, an international CIDP registry. In addition, he received consultancy fee from UCB Pharma, Grifols, Sanofi and Dianthus Therapeutics paid to institution, outside the submitted work. INS reports grants from Dutch Governmental grant (ZonMw/Rational Pharmacotherapy program), non-financial support from Sanquin Plasma Products B.V., and grants from CSL-Behring, all outside the submitted work on of competing interest. LW received research grants from Grifols and the GBS/CIDP Foundation for the study of disease activity biomarkers in CIDP. The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

SARS-CoV-2-specific CD8 + T cells recognize conserved viral peptides and in the absence of cross-reactive antibodies form an important line of protection against emerging viral variants as they ameliorate disease severity. SARS-CoV-2 mRNA vaccines induce robust spike-specific antibody and T cell responses in healthy individuals, but their effectiveness in patients with chronic immune-mediated inflammatory disorders (IMIDs) is less well defined. These patients are often treated with systemic immunosuppressants, which may negatively affect vaccine-induced immunity. Indeed, TNF inhibitor (TNFi)-treated inflammatory bowel disease (IBD) patients display reduced ability to maintain SARS-CoV-2 antibody responses post-vaccination, yet the effects on CD8 + T cells remain unclear. Here, we analyzed the impact of IBD and TNFi treatment on mRNA-1273 vaccine-induced CD8 + T cell responses compared to healthy controls in SARS-CoV-2 experienced and inexperienced patients. CD8 + T cells were analyzed for their ability to recognize 32 SARS-CoV-2-specific epitopes, restricted by 10 common HLA class I allotypes using heterotetramer combinatorial coding. This strategy allowed in-depth ex vivo profiling of the vaccine-induced CD8 + T cell responses using phenotypic and activation markers. mRNA vaccination of TNFi-treated and untreated IBD patients induced robust spike-specific CD8 + T cell responses with a predominant central memory and activated phenotype, comparable to those in healthy controls. Prominent non-spike-specific CD8 + T cell responses were observed in SARS-CoV-2 experienced donors prior to vaccination. Non-spike-specific CD8 + T cells persisted and spike-specific CD8 + T cells notably expanded after vaccination in these patient cohorts. Our data demonstrate that regardless of TNFi treatment or prior SARS-CoV-2 infection, IBD patients benefit from vaccination by inducing a robust spike-specific CD8 + T cell response., Competing Interests: Declaration of competing interest No conflict of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Humoral responses after SARS-CoV-2 vaccination are greatly impaired in multiple sclerosis (MS) patients on fingolimod. Effects of repeated vaccination and infections on long-term responses are unclear., Methods: Prospective study in 60 MS patients on fingolimod measuring humoral responses after up to four vaccinations and 8 months after fourth vaccination., Results: Anti-WH1 antibody titers increased with each additional vaccination. At long-term follow-up titers increased further and most patients developed new humoral responses against the BA.1 omicron variant., Conclusion: Repeated SARS-CoV-2 vaccinations boost humoral immunity and, probably together with SARS-CoV-2 infections, induce humoral responses on the long-term in almost all patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FE and TK report (governmental) grants from ZonMw to study immune response after SARS-CoV-2 vaccination in auto-immune diseases. FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSL Behring; honoraria from Grifols. JK has speaking relationships with Merck Serono, Biogen Idec, TEVA, Sanofi, Genzyme, Roche, and Novartis; Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck Serono, Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Roche, Teva, Sanofi, Genzyme, GlaxoSmithKline, and Novartis. No other disclosures were reported.

Background: Rheumatoid factors (RFs) are autoantibodies that target the Fc region of IgG, and are found in patients with rheumatic diseases as well as in the healthy population. Many studies suggest that an immune trigger may (transiently) elicit RF responses. However, discrepancies between different studies make it difficult to determine if and to which degree RF reactivity can be triggered by vaccination or infection., Objective: We quantitatively explored longitudinal RF responses after SARS-CoV-2 vaccination and infection in a well-defined, large cohort using a dual ELISA method that differentiates between true RF reactivity and background IgM reactivity. In addition, we reviewed existing literature on RF responses after vaccination and infection., Methods: 151 healthy participants and 30 RA patients were included to measure IgM-RF reactivity before and after SARS-CoV-2 vaccinations by ELISA. Additionally, IgM-RF responses after a SARS-CoV-2 breakthrough infection were studied in 51 healthy participants., Results: Published prevalence studies in subjects after infection report up to 85% IgM-RF seropositivity. However, seroconversion studies (both infection and vaccination) report much lower incidences of 2-33%, with a trend of lower percentages observed in larger studies. In the current study, SARS-CoV-2 vaccination triggered low-level IgM-RF responses in 5.5% (8/151) of cases, of which 1.5% (2/151) with a level above 10 AU/mL. Breakthrough infection was accompanied by development of an IgM-RF response in 2% (1/51) of cases., Conclusion: Our study indicates that de novo RF induction following vaccination or infection is an uncommon event, which does not lead to RF epitope spreading., Competing Interests: TR and GW are inventors on a patent application based on the use of bioengineered IgG targets for the characterization of rheumatoid factor reactivity patterns. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Keijzer, Oskam, Ooijevaar-de Heer, Steenhuis, Keijser, Wieske, van Dam, Stalman, Kummer, Boekel, Kuijpers, ten Brinke, van Ham, Eftimov, Tas, Wolbink and Rispens.)

Background: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP., Methods: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist., Results: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients., Conclusions: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies., Competing Interests: Competing interests: MB reports grants from the Dutch Prinses Beatrix Spierfonds (W.OR16-18). LW reports grants from Grifols and the GBS/CIDP Foundation for the study of disease activity biomarkers in CIDP. EE is supported by the Scientific and Technological Research Council of Turkey (TUBITAK) BIDEB-2219 Postdoctoral Research Program. MT was supported by the Erasmus MC Pain Foundation, has received funding from ZonMw (Memorabel programme), the Dutch EpilepsieNL Foundation (NEF 19-08), Dioraphte (2001 0403) and E-RARE JTC 2018 (UltraAIE, 90030376505). PAvD reports grants from Prinses Beatrix Spierfonds, The Netherlands Organisation for Health Research and Development (ZonMW), Sanquin Blood supply, Takeda and Grifols, he is a member of Scientific Advisory Committee/Steering Committee Trials for Annexon, Argenx, Hansa, Octapharma, Sanofi and Roche, all grants and fees were paid to his institution. FE reports grants from ZonMw (Dutch Governmental Agency) and Prinses Beatrix Spierfonds (Dutch Charity Organization) and grants from CSLBehring, Kedrion, Terumo BCT, Grifols and Takeda Pharmaceutical Company, outside the submitted work. Grants were paid to institution and are used for investigator-initiated randomised controlled trials and studies within INCbase, an international CIDP registry. In addition, he received consultancy fee from UCB Pharma, Sanofi and Grifols, paid to institution, outside the submitted work. KK reports grants from Takeda and Grifols (SPIN award). LQ reports grant from Instituto de Salud Carlos III – Ministry of Economy and Innovation (Spain), Fundació La Marató, GBS-CIDP Foundation International, Novartis Pharma Spain, Roche, UCB and Grifols, and received speaker or expert testimony honoraria from CSL Behring, Novartis, Sanofi-Genzyme, Merck, Annexon, Biogen, Janssen, ArgenX, UCB, LFB, Octapharma and Roche, and serves at Clinical Trial Steering Committee for Sanofi Genzyme and Roche, and is Principal Investigator for UCB’s CIDP01 trial. BCJ reports grants for research from Baxalta, Grifols, CSL-Behring, Annexon, Hansa Biopharma, Roche, Prinses Beatrix Spierfonds, GBS-CIDP Foundation International and Horizon 2020, and consultancy fees from Roche and Annexon, and he is chair of the Steering Committee of Internation GBS Outcome Study (IGOS) and member of the Steering Committee of International CIDP Outcome Study (ICOS) and INCbase. RH reports grants from Health~Holland, GBS-CIDP Foundation and Grifols. The ICOS was supported by funding from CSL-Behring and Grifols., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop an artificial neural network (ANN) for classification of motor unit action potential (MUAP) duration in real-word, unselected and uncleaned needle electromyography (n-EMG) recordings., Methods: Two nested ANN models were trained, the first discerning muscle rest, contraction and artifacts in n-EMG recordings from 2674 individual muscles from 326 patients obtained as part of daily care. The second ANN model subsequently used segments labeled as contraction for prediction of prolonged, normal and shortened MUAPs. Model performance was assessed in one internal and two external validation datasets of 184, 30 and 50 muscles, respectively., Results: The first model discerned rest, contraction and artifacts with an accuracy of 96%. The second model predicted prolonged, normal and shortened MUAPs with an accuracy of 67%, 83% and 68% in the different validation sets., Conclusions: We developed a two-step ANN that classifies rest, muscle contraction and artifacts from real-world n-EMG recordings with very high accuracy. MUAP duration classification had moderate accuracy., Significance: This is the first study to show that an ANN can classify MUAPs in real-world n-EMG recordings highlighting the potential for AI assisted MUAP classification as a clinical tool., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Abstract: Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of "painful" nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete ("full") or incomplete ("partial") axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

B-cell activating factor (BAFF) is a crucial cytokine for differentiation and survival of B-cells and correlates to disease activity in some auto-immune diseases. To evaluate BAFF as a biomarker for disease activity in chronic inflammatory demyelinating polyneuropathy (CIDP), serum BAFF levels were measured at varying disease stages: patients starting treatment, patients starting treatment withdrawal, patients in remission and healthy controls. Serum BAFF levels were elevated in patients compared to healthy controls, but did not differ between patients starting treatment and patients in remission. Serum BAFF levels did not change with or predict treatment response or relapse. Serum BAFF is not a responsive biomarker reflecting disease activity in CIDP., Competing Interests: Declaration of Competing Interest F. Eftimov reports grants from ZonMw (Dutch Governmental Agency) and Prinses Beatrix Spierfonds (Dutch Charity Organization) and grants from CSLBehring, Kedrion, Terumo BCT, Grifols and Takeda Pharmaceutical Company, outside the submitted work. Grants were paid to institution and are used for investigator-initiated randomized controlled trials and studies within INCbase, an international CIDP registry. In addition, he received consultancy fee from UCB Pharma and Grifols, paid to institution, outside the submitted work. C.E. Teunissen reports the following grants: Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Association, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CET has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had speaker contracts for Roche, Grifols, Novo Nordisk. I.N. van Schaik reports grants from Dutch Governmental grant (ZonMw/Rational Pharmacotherapy program), non-financial support from Sanquin Plasma Products B.V., and grants from CSL-Behring, all outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Paritaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus infection. Its structures had been elusive to the public until recently when one of the crystal forms was solved by MicroED. In this work, we report the MicroED structures of two distinct polymorphic crystal forms of paritaprevir from the same experiment. The different polymorphs show conformational changes in the macrocyclic core, as well as the cyclopropylsulfonamide and methylpyrazinamide substituents. Molecular docking shows that one of the conformations fits well into the active site pocket of the NS3/4A serine protease target, and can interact with the pocket and catalytic triad via hydrophobic interactions and hydrogen bonds. These results can provide further insight for optimization of the binding of acylsulfonamide inhibitors to the NS3/4A serine protease. In addition, this also demonstrate the opportunity of deriving different polymorphs and distinct macrocycle conformations from the same experiments using MicroED.

Background: CD11c + Tbet + B cells are enriched in autoimmunity and chronic infections and also expand on immune challenge in healthy individuals. CD11c + Tbet + B cells remain an enigmatic B-cell population because of their intrinsic heterogeneity., Objectives: We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-specific development and differentiation properties of 3 separate CD11c + B-cell subsets-age-associated B cells (ABCs), double-negative 2 (DN2) B cells, and activated naive B cells-and compared them to their canonical CD11c - counterparts., Methods: Dynamics of the response of the 3 CD11c + B-cell subsets were assessed at SARS-CoV-2 vaccination in healthy donors by spectral flow cytometry. Distinct CD11c + B-cell subsets were functionally characterized by optimized in vitro cultures., Results: In contrast to a durable expansion of antigen-specific CD11c - memory B cells over time, both ABCs and DN2 cells were strongly expanded shortly after second vaccination and subsequently contracted. Functional characterization of antibody-secreting cell differentiation dynamics revealed that CD11c + Tbet + B cells were primed for antibody-secreting cell differentiation compared to relevant canonical CD11c - counterparts., Conclusion: Overall, CD11c + Tbet + B cells encompass heterogeneous subpopulations, of which primarily ABCs as well as DN2 B cells respond early to immune challenge and display a pre-antibody-secreting cell phenotype., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs., Methods: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies., Results: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%)., Conclusion: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild., Trial Registration: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020., (© 2023. The Author(s).)

Background: It is unclear which patients with multiple sclerosis (MS) are most susceptible for omicron breakthrough infections., Methods: We assessed omicron breakthrough infections in vaccinated patients with MS with and without disease-modifying therapies enrolled in an ongoing large prospective study. We longitudinally studied humoral responses after primary and booster vaccinations and breakthrough infections., Results: Omicron breakthrough infections were reported in 110/312 (36%) patients with MS, and in 105/110 (96%) infections were mild. Omicron breakthrough infections occurred more frequently in patients treated with anti-CD20 therapies and sphingosine-1 phosphate receptor (S1PR) modulators, patients with impaired humoral responses after primary immunisation (regardless of treatment) and patients without prior SARS-CoV-2 infections. After infection, antibody titres increased in patients on S1PR modulator treatment while anti-CD20 treated patients did not show an increase., Conclusions: SARS-COV-2 omicron breakthrough infections are more prevalent in patients with MS on anti-CD20 therapies and S1PR modulators compared with other patients with MS, which correlated with decreased humoral responses after vaccination. Humoral responses after infection were higher in S1PR modulator-treated patients in comparison to patients on anti-CD20 therapies, suggesting that immunological protection from contracting infection or repeated exposures may differ between these therapies., Competing Interests: Competing interests: JK reported speaking and consulting relationships with Biogen, Genzyme, Merck, Novartis, Roche, Sanofi and TEVA. Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Sanofi and TEVA. TR reports consulting fees from Novartis. No other disclosures were reported., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment., Competing Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Fehmi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity., Competing Interests: Declaration of competing interest F Eftimov and T Kuijpers report (governmental) grants from ZonMw to study immune response after SARS-Cov-2 vaccination in auto-immune diseases. F Eftimov also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSL Behring; honoraria from Grifols. AJ van der Kooi reports grants from CSL Behring and participation on an advisory board for Argen-X. M Löwenberg reports a grant from Galapagos not related to this study, and honoraria from Bristol Myers Squibb, Pfizer, Takeda, and Tillotts. Ph I Spuls is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of e.g. psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital and is a chief investigator of the TREAT NL registry taskforce and SECURE-AD registry. M.W. Bekkenk is a secretary for Dutch Experimental Dermatology Board and head of the pigmentary disorders group within the Dutch Dermatology Board, and reports honoraria from Pfizer, Sanofi, Novartis and Fondation René Touraine. J Killestein has speaking relationships with Merck Serono, Biogen Idec, TEVA, Sanofi, Genzyme, Roche and Novartis; Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck Serono, Bayer Shcering Pharma, Biogen Idec, GlaxoSmithKline, Roche, Teva, Sanofi, Genzyme, GlaxoSmithKline, and Novartis. B Horváth reports unpaid positions as medical advisor for several patient groups, a board position for ERN-SKIN, and associate editor for The British Journal of Dermatology; reports grants from Abbvie, Akari Therapeutics, Celgene, and Novartis; consulting fees from UCB Pharma, Novartis and Janssen-Cilag; honoraria from Abbvie. J.J.G.M. Verschuuren reports consulting fees from Argenx, Alexion and NMD Pharma; is coinventor on patent applications based on MuSK-related research. DJ Hijnen reports grants from Abbvie, AstraZeneca, Janssen, LEO Pharma and UCB Pharma, and honoraria from Abbvie, Galderma, Janssen, Lilly, Pfizer, Sanofi and UCB Pharma, and a paid position in an advisory board for BIOMAP IMI. P.A. van Doorn participated on an advisory board for Octapharma. P. van Paassen reports grants from Alexion Pharma and GSK; and participation on GSK and Vifor Pharma advisory boards. G.R.A.M. D'Haens reports consulting fees from Abbvie, Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Pfizer, Immunic, Johnson and Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, and Protagonist; honoraria from Abbvie, Arena, Galapagos, Gilead, Pfizer, BMS, Takeda; participation on advisory boards for Abbvie, Seres Health, Galapagos, and AstraZeneca. R.B. Takkenberg reports honoraria from Sobi and Norgine and participation in an advisory board for Norgine. SH Goedee is a board member of the Dutch Society of Clinical Neurophysiology (unpaid), reports grants from Prinses Beatrix Spierfonds, and received speaker fees from Shire/Takeda. AH Zwinderman reports paid data safety monitoring board positions for Torrent Ltd and Foresee Pharmaceuticals Co. No other disclosures were reported. Bar plot showing proportions of self-reported increased disease activity (with corresponding 95% CI's), physician confirmed increased disease activity, and treatment intensification, within each IMID group at 60 days after start of primary immunization. IBD: inflammatory bowel disease; IMID: immune-mediated inflammatory disease; ISP: immunosuppressant; MS: multiple sclerosis; NMO: neuromyelitis optica; SLE: systemic lupus erythematosus. Bar plot showing incidence of self-reported increased disease activity at different timepoints. A) self-reported increased disease activity within 60 days after vaccination: at 60 days after start of primary immunization (prim. imm.), seven to 60 days after first additional vaccination (add. vacc.), and at other follow-up moments within seven to 60 days after a vaccination other than the moments mentioned before (e.g. second vaccination of primary immunization or second additional vaccination). B) self-reported increased disease activity not within 60 days after vaccination, in the two-monthly follow-up surveys starting at first vaccination. Figure showing the results of the multivariate mixed model on determinants of self-reported increased disease activity. RR's with corresponding 95% CI for age, female sex, BMI, IMID group (with gastro-intestinal disease as reference group), recent increased disease activity (self-reported increased disease activity in the three months preceding enrollment), ISP use, and any SARS-CoV-2 vaccination in 60 days before the survey. BMI: body mass index; CI: confidence interval; IMID: immune-mediated inflammatory disease; ISP: immunosuppressant; MS: multiple sclerosis; NMO: neuromyelitis optica; RR: relative risk; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Objectives: There are concerns on the safety of SARS-CoV-2 vaccination in patients with a history of Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). The aim of this study was to determine the risk of recurrence of GBS and exacerbations of CIDP or MMN after SARS-CoV-2 vaccination., Methods: We conducted a prospective, multicenter cohort study from January 2021 to August 2021. Patients known in 1 of 3 Dutch University Medical Centers with research focus on immune-mediated neuropathy and members of the Dutch Patient Association for Neuromuscular Diseases were invited to participate if they were 18 years or older and diagnosed with GBS, CIDP, or MMN. Participants completed a series of questionnaires at 4 different time points: study baseline (1), within 48 hours before any SARS-CoV-2 vaccination (2 and 3, if applicable), and 6 weeks after their last vaccination (4). Participants unwilling to get vaccinated completed the last questionnaire (4) 4 months after study baseline. We assessed recurrences of GBS, any worsening of CIDP or MMN-related symptoms, treatment alterations, and hospitalization., Results: Of 1,152 individuals to whom we sent the questionnaires, 674 (59%) signed informed consent. We excluded 153 individuals, most often because they had already received a SARS-CoV-2 vaccination or had had the infection (84%) before study baseline. Of 521 participants included in analyses, 403 (81%) completed the last questionnaire (time point 4). None of 162 participants with a history of GBS had a recurrence after vaccination. Of 188 participants with CIDP, 10 participants (5%) reported a worsening of symptoms within 6 weeks after vaccination. In 5 (3%) of these patients, maintenance treatment was modified. Two of 53 participants with MMN (4%) reported a worsening of symptoms, and treatment modification was reported by 1 participant., Discussion: We found no increased risk of GBS recurrence and a low to negligible risk of worsening of CIDP or MMN-related symptoms after SARS-CoV-2 vaccination. Based on our data, SARS-CoV-2 vaccination in patients with these immune-mediated neuropathies seems to be safe., (© 2022 American Academy of Neurology.)

Ocrelizumab, an anti-CD20 monoclonal antibody, counteracts induction of humoral immune responses after severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccinations in patients with multiple sclerosis (MS). We aimed to assess if serum ocrelizumab concentration measured at the time of vaccination could predict the humoral response after SARS-CoV-2 vaccination. In 52 patients with MS, we found ocrelizumab concentration at the time of vaccination to be a good predictor for SARS-CoV-2 IgG anti-RBD titers after vaccination (comparable to B-cell count). As the course of ocrelizumab concentration may be predicted using pharmacokinetic models, this may be a superior biomarker to guide optimal timing for vaccinations in B-cell depleted patients with MS. ANN NEUROL 2023;93:103-108., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants., Methods: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination., Results: OCR-treated MS patients exhibit a preserved recall response of CD8 + T central memory cells following first vaccination compared to HCs and a similar CD4 + circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4 + and CD8 + T cells., Conclusions: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8 + T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients., Funding: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20&#95;21 L2506), the NHMRC Leadership Investigator Grant (#1173871)., Competing Interests: NV, RH, Jv, LK, CK, TA, LK, MS, MD, Rd, Nd, Cv, AB, EM, KK, Kv, ES, LB, GW, ST, Zv, LW, TK, FE, TR, Sv, At, Cv No competing interests declared, JK has speaking relationships with Merck, Biogen, TEVA, Sanofi, Genzyme, Roche and Novartis. AmsterdamUMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck, Celgene, Biogen, GlaxoSmithKline, Immunic, Roche, Teva, Sanofi, Genzyme, and Novartis, (© 2022, Verstegen et al.)

Introduction: In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN., Methods: In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström's Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN)., Results: NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients., Conclusion: Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up., (© 2022. The Author(s).)

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698). Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an open-label extension phase of 52 weeks. We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

It is unclear whether frequently used cutoff values for outcome measures defining minimal clinically important differences (MCIDs) can accurately identify meaningful deterioration in chronic inflammatory demyelinating polyneuropathy (CIDP). We used data from the immunoglobulin overtreatment in CIDP (IOC) trial, in which 60 clinically stable patients with CIDP were randomized to intravenous immunoglobulin (IVIg) withdrawal or continuation. We calculated change scores of the Inflammatory Rasch-Built Overall Disability Scale (I-RODS), grip strength, and Medical Research Council-sum score (MRC-SS) and classified visits based on a treatment anchor (ie, decision to restart/increase treatment after reaching a predefined early endpoint of deterioration). The variability of scores in patients without deterioration was calculated using the limits of agreement. We defined optimized MCIDs for deterioration and specific combinations of MCIDs from different outcome measures, and subsequently calculated the accuracies of the (combined) MCIDs. Substantial variability was found in scores of the I-RODS, grip strength and MRC-SS in patients without deterioration over time, and most MCIDs were within the limits of the variability observed in patients without deterioration. Some MCID cut-offs were insensitive but highly specific for detecting deterioration, for example, the MCID-SE of -1.96 of the I-RODS and -2 point on the MRC-SS. Others were sensitive, but less specific, for example, -4 centiles of the I-RODS. Some combined MCIDs resulted in high specificities and moderate sensitivities. Our results suggest that clinically important deterioration cannot be distinguished from variability over time with currently used MCIDs on the individual level. Combinations of MCIDs might improve the accuracy of determining deterioration, but this needs validation., (© 2022 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination., Methods: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513., Findings: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections., Interpretation: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors., Funding: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation., Competing Interests: FE and TWK report (governmental) grants from ZonMw (the Netherlands Organization for Health Research and Development) to study immune responses after SARS-CoV-2 vaccination in autoimmune diseases. FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, and Guillain-Barré Syndrome-Chronic Inflammatory Demyelinating Polyneuropathy (GBS-CIDP) Foundation; consulting fees from UCB Pharma and CSl Behring; and honoraria from Grifols. AJvdK reports grants from CSL Behring and participation on an advisory board for Argen-X. MLö reports a grant from Galapagos NV not related to this study, and honoraria from Bristol Myers Squibb, Pfizer, Takeda, and Tillotts. PIS is involved in clinical trials with Regeneron, Sanofi, Leopharma, Lilly, AbbVie, Boerhinger, Celgene, Janssen, and UCB, which manufacture drugs used for the treatment of conditions, including psoriasis and atopic dermatitis, for which financial compensation is paid to their department or hospital, and is a chief investigator of the TREAT NL registry taskforce and SECURE-AD registry. MWB is a secretary for the Dutch Experimental Dermatology Board; head of the pigmentary disorders group within the Dutch Dermatology Board; and reports honoraria from Pfizer, Sanofi, Novartis, and Fondation René Touraine. JKi has consulting relationships with Merck Serono, Biogen Idec, Teva, Genzyme, Sanofi, Roche, and Novartis; Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck, Celgene, Biogen, GlaxoSmithKline, Immunic, Roche, Teva, Sanofi, Genzyme, and Novartis. BH reports unpaid positions as a medical adviser for several patient groups, a board position for European Reference Network for rare skin diseases (ERN-Skin), and associate editor for The British Journal of Dermatology; reports grants from AbbVIe, Akari Therapeutics, Celgene, and Novartis; consulting fees from UCB Pharma, Novartis, and Janssen; and honoraria from AbbVie. JJGMV reports consulting fees from Argen-X, Alexion, and NMD Pharma, and is a co-inventor on a patent applications based on MuSK-related research (patent number 9574015). DJH reports grants from AbbVie, AstraZeneca, Janssen, LEO Pharma, and UCB; honoraria from AbbVie, Galderma, Janssen, Lilly, Pfizer, Sanofi, and UCB; and a paid position on an advisory board for Biomarkers in Atopic Dermatitis and Psoriasis (BIOMAP IMI). PAvD has participated on an advisory board for Octapharma. PvP reports grants from Alexion Pharma and GSK, and participation on advisory boards for GSK and Vifor Pharma. GRAMD reports consulting fees from AbbVie, Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GSK, Gossamerbio, Pfizer, Immunic, Johnson & Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist; honoraria from AbbVie, Arena, Galapagos NV, Gilead, Pfizer, Bristol Myers Squibb, and Takeda; and participation on advisory boards for AbbVie, Seres Health, Galapagos NV, and AstraZeneca. RBT reports honoraria from Sobi and Norgine and participation on an advisory board for Norgine. HSG is a board member of the Dutch Society of Clinical Neurophysiology (unpaid), reports grants from Prinses Beatrix Spierfonds, and has received speaker fees from Shire/Takeda. KAHZ reports paid data safety monitoring board positions for Torrent and Foresee. All other authors declare no competing interests., (© 2022 Published by Elsevier Ltd.)

Objectives: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod., Methods: This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2-specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated., Results: In ocrelizumab-treated patients (N = 24), IFN-γ-producing SARS-CoV-2-specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2-specific T cells were detected after second (N = 12) and third (N = 9) vaccinations., Discussion: In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)