BACKGROUND AND AIMS:Rituximab has been proposed as a potential treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but formal evidence regarding its clinical effectiveness is weak. The CIDPRIT trial found no clinical benefit in comparison with placebo, but secondary analyses suggested some beneficial effect. Analysis of serum neurofilament light chain (sNfL) may provide evidence to support rituximab's effect on CIDP patients. METHODS:We performed a post hoc analysis of sNfL levels from the CIDPRIT trial participants. Blood samples were collected at baseline, month 6, and 12. sNfL was measured using Simoa technology. Geometric means and z-scores were compared across groups. Linear mixed-effects models and survival analyses were used to evaluate treatment effects and clinical correlations. RESULTS:33 participants were included (18 rituximab, 15 placebo). Baseline sNfL was significantly higher in the rituximab group (11.51 vs. 6.67 pg/mL, p = 0.019). While between-group differences over time were not statistically significant, rituximab-treated patients showed stable sNfL levels at month 6 and a slight decrease at month 12, contrasting with modest increases in the placebo group. Among rituximab-treated patients who remained clinically stable at month 12, sNfL showed a non-significant decline by 31%. No significant associations were found between baseline sNfL and clinical worsening. NfL levels correlated with neurophysiological parameters of axonal damage. INTERPRETATION:The analysis did not demonstrate biomarker-based evidence of rituximab efficacy in CIDP. However, observed trends suggest a possible biological effect in reducing axonal injury in a subset of patients. Further studies are needed to clarify the role of sNfL in treatment monitoring and patient stratification.

ABSTRACT INTRODUCTION Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer’s disease (AD), and healthy controls (HC). METHODS Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain–Barré syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot–Marie–Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

Pompe disease is a rare genetic neuromuscular condition produced by pathogenic variants in the GAA gene. In recent years gene therapy using AAV has been tested in clinical trials. Our aim is to describe a late onset Pompe disease patient who developed sensory neuronopathy after initiating gene therapy with AT845 in a clinical trial. We describe the clinical, electrophysiological and response to treatment features of a 49-year-old woman with Pompe disease who developed a sensory neuronopathy after receiving AT845, an investigational adeno-associated virus (AAV) gene replacement therapy designed to deliver a functional human acid alpha-glucosidase gene. The patient started with progressive sensory symptoms affecting distal regions of the four limbs associated with gait ataxia two months after receiving intravenous infusion of AT845. A pure sensory axonal neuropathy was documented through neurophysiological studies and therefore a sensory neuronopathy was considered. Complementary studies were all negative. Sensory symptoms gradually improved after treatment with intravenous methylprednisolone and oral prednisone, although symptoms have not completely resolved after one year. Injury to dorsal root ganglion neurons has been reported in animal models treated with gene therapy using recombinant AAV, but there are limited reports of AAV-mediated sensory neuronopathy in clinical trials. This case illustrates the need of careful review of neurological symptoms and clinical signs in patients treated systemically with AAV, and of repeated neurophysiological studies.

Abstract Background and Objectives Patients with peripheral neuropathies (PN) commonly exhibit balance impairment. In clinical practice, balance is typically assessed using the Romberg’s test and ataxia scales, which rely on examiner interpretation, while objective biomarkers for quantifying balance remain lacking. Wearable sensors are valuable tools for objectively quantifying gait abnormalities in PN patients and may capture clinically meaningful changes over time. By integrating these parameters, artificial intelligence (AI) can assist in generating a digital score that enables easy, objective, and reproducible monitoring of patients’ postural balance. This study aims to generate and assess an AI-generated digital Romberg’s test to quantify balance impairments in a cohort of PN patients. Methods PN patients were assessed in a longitudinal study using a wearable system composed of inertial sensors placed on the trunk and plantar pressure sensors integrated in insoles. Patients performed the Romberg’s test under both eyes-open and eyes-closed conditions and were classified according to ataxia severity (mild, moderate, or severe) following the score obtained in item 1 of MICARS and SARA scales. Results We included 97 patients with PN (including autoimmune and hereditary polyneuropathies), and 117 healthy controls (HC). Significant differences in trunk sway and center of pressure (COP) were observed between groups, particularly with eyes closed. Using wearable sensor parameters, we developed an AI digital Romberg’s test, which correlated with clinician-rated Romberg’s test performance and distinguished patients with and without ataxia (AUC=0.632) and across different PN pathologies. Longitudinally, digital Romberg’s test and iRODS showed concordant trajectories. Also, changes ≥25% in the score were associated with clinical changes in ataxia severity measured by an increase in MICARS-SARA score (+1.42 points), whereas improvement was associated with a decrease (−0.20 points) in the scale. Discussion This study demonstrates that wearable sensors are useful to detect and quantify balance impairment. The AI-generated Romberg’s test is an objective and reproducible tool for postural balance assessment, with robust discriminatory performance across clinical ataxia severity in PN. Score’s longitudinal changes aligned with clinical severity, supporting its potential for monitoring disease progression and treatment response. Its strong association with balance measures reinforces its role as a quantitative biomarker of postural control in ataxia patients.

What is this summary about? This is a plain language summary of an article published in The Lancet Neurology in 2024. The article describes the results of the ADHERE clinical study, which involved people with chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP for short. CIDP is a rare autoimmune disease that affects nerves in the arms and legs. There is a need for new treatment options for CIDP that reduce symptoms, are convenient to take, and have manageable side effects. What happened in this study? In this study, researchers looked at how well efgartigimod worked in people with CIDP and the side effects people had during the study. Stage A of the study aimed to find people who had signs of reduced symptoms and disability after receiving efgartigimod. People received weekly injections of efgartigimod under the skin (subcutaneous). Stage B compared efgartigimod with a placebo treatment to find out how well efgartigimod worked and the side effects that people had. What were the results? Overall, 66% of all participants in ADHERE showed signs of clinical improvement after receiving efgartigimod. Half of these people had first signs of clinical improvement in about 22 days. Compared to a placebo, people who received efgartigimod had a reduced risk of CIDP symptoms getting worse or returning (relapsing). More people who received efgartigimod were able to carry out their daily activities and maintained grip strength than those who took a placebo. Most side effects that people developed during the study were mild or moderate. What do the results mean? In this study, people who received efgartigimod had stable or improving symptoms for up to 48 weeks, while more people who received a placebo had worsening strength, disability, and quality of life. Subcutaneous injections of efgartigimod may offer a more convenient option for people with CIDP compared with current treatments.

The evolving landscape of generalised myasthenia gravis (gMG) treatment with new targeted immunotherapy options presents challenges for neurologists and potentially leads to therapeutic inertia (TI), the failure to initiate or intensify treatment when therapeutic goals are not met. This study aimed to assess neurologists' therapeutic decision-making process in gMG and its influencing factors. A cross-sectional, web-based study was conducted, involving 149 neurologists (mean age [standard deviation]: 39.0 [9.4] years; 54.4% male; median MG experience [interquartile range]: 7 [3-15] years). Participants responded to 8 simulated case scenarios, 7 of which assessed TI. Overall, 79.9% of neurologists (n = 119/149) exhibited TI in at least 2 of the 7 scenarios. Multivariate analysis revealed that lower organisational support (odd ratio [OR] = 0.308, 95%CI:0.109-0.870, p = 0.0262) and greater reluctance to adopt new treatments (OR = 0.015, 95%CI:0.001-0.739, p = 0.0347) were significant predictors of TI. Understanding these factors is crucial for optimising gMG treatment decisions, underscoring the importance of updated guidelines and continued professional education.

BACKGROUND/OBJECTIVES:Immunoglobulin (Ig) therapy is the first-line treatment and often the single option for a substantial number of diseases. Still, Ig supply and use have experienced restrictions, aggravated during the COVID-19 pandemic. This study assessed the clinical and economic implications of Ig use under restrictive conditions in neurological diseases and immunodeficiencies in Spain. METHODS:Hospitalization cases in neurological disorders and immunodeficiencies in which Ig is the main therapeutic option, identified by ICD-10 codes, were retrieved from the Spanish Minimum Basic Data Set for 2019 and 2022. Comorbidities and outcomes were analyzed along with hospitalization rates and characteristics, like the length of stay (LoS) and costs, among others. Therapeutic plasma exchange (TPE) use was evaluated as the alternative treatment of choice in the conditions analyzed. RESULTS:In 2022 compared to 2019, hospitalizations due to relapses remained stable in patients with neurological conditions. Comorbidity and complications increased significantly in this group, as well as LoS, mofrtality (p < 0.05 for all), and TPE rates (p = 0.003). These changes were not identified for immunodeficiencies, which only experienced a decrease in hospitalization rates (p < 0.001). Hospital costs increased in both groups (7.97% in neurological conditions and 2.41% in immunodeficiencies). CONCLUSIONS:In a period in which access to Ig may have been limited, neurological patients, but not patients with immunodeficiencies, show an increase in LoS and mortality, as well as an increased TPE. These results suggest that modifying the management strategy of patients with neurological disorders requiring Ig due to restrictive conditions could have negatively impacted their clinical outcomes.

Autoimmune nodopathies (AINs) are rare acquired autoimmune neuropathies with distinct clinical features and circulating autoantibodies, often of the immunoglobulin G4 (IgG4) subclass, targeting proteins at the node of Ranvier. Defects in B cell tolerance checkpoints have been implicated in several autoimmune diseases, including MuSK-positive myasthenia gravis, another IgG4 autoantibody-mediated disease. Here, we investigated whether tolerance defects exist in neurofascin-155-mediated AIN (NF155-AIN), using a well-established assay, by generating recombinant antibodies from new emigrant (NE) and mature naive (MN) B cells from three NF155-AIN patients, and tested them for polyreactivity and autoreactivity. Additionally, we analyzed the transcriptome of peripheral blood mononuclear cells, with a particular focus on naive B cells and CD4+ T cells at the single-cell level, and characterized cell-cell interactions. NF155-AIN patients have an elevated frequency of polyreactive B cells in the NE (37.4% compared to 9.7% in healthy controls (HCs), P = 0.03) and MN (31.5% compared to 10.5% in HCs, P = 0.03) compartments, consistent with a breach in early B cell tolerance checkpoints. In this unbiased exploratory transcriptomics analysis, we observed potentially abnormal B cell receptor (BCR) signaling characterized by low CD79B, CSK, BLNK, and BTK expression, and possible impaired CD4+ T cell regulatory function. Moreover, comparison with chronic inflammatory demyelinating polyneuropathy, a related autoimmune neuropathy, suggested that these differences are specific to NF155-AIN. A breach in early B cell tolerance checkpoints, with defective BCR signaling, and disrupted T cell-B cell interactions in NF155-AIN, may contribute to the development of pathogenic autoreactivity.

Guillain-Barré syndrome (GBS) is an acute immune-mediated neuropathy triggered by infections, with poorly understood pathophysiological diversity. COVID-19-associated GBS (COVID-GBS) is a rare but severe post-infectious condition, and its immune mechanisms remain unclear. We profiled immune mediators in cerebrospinal fluid (CSF) and serum from COVID-GBS patients, comparing them to non-COVID GBS (Control-GBS), COVID-19 patients without neurological complications (COVID-no-GBS) and non-inflammatory neuropathy controls (Neuropathy-no-GBS). To gain mechanistic insights, we integrated publicly available single-nucleus transcriptomic data from sural nerve biopsies of neuropathy patients. IL-8 was confirmed as a key cytokine in GBS. Analysis of publicly available single-nucleus transcriptomic data from non-GBS sural nerve biopsies suggested myeloid cells as potential sources of IL-8, with evidence of autocrine signaling capacity. LIF and CD8A emerged as novel biomarkers, with this transcriptomic analysis indicating that LIF receptor components are expressed on endothelial and stromal cells, suggesting these as potential cellular targets. COVID-GBS patients exhibited unique CSF alterations and distinct serum profiles marked by altered NK cell activity, cytotoxic T-cell responses, and myeloid differentiation. Moreover, associations between inflammatory, extracellular matrix, and regulatory markers with clinical disability differed between COVID-GBS and Control-GBS, pointing to divergent immune mechanisms. Our findings suggest that GBS involves myeloid-driven cytokine responses and local LIF signaling. Analysis of publicly available transcriptomic data from non-GBS sural nerve biopsies suggests potential cellular sources and targets, though validation in GBS-affected tissue is needed. COVID-GBS features a distinct immune signature involving localized and systemic inflammation. These insights deepen our understanding of GBS pathogenesis and nominate candidate biomarkers for further validation and potential therapeutic targeting. CSF proteomics confirm elevated IL-8 and newly identify increased leukemia inhibitory factor (LIF) in Guillain-Barré Syndrome (GBS). Integration of public transcriptomic nerve biopsy data sets suggests myeloid cells as source of IL-8 and maps LIF receptor (LIFR) to nerve endothelial cells. COVID-associated GBS has a distinct immune profile compared to pre-pandemic GBS. Serum proteins OPG and MMP-10 correlate with clinical disability in COVID-associated GBS.

BACKGROUND AND AIMS:In ADHERE, subcutaneous efgartigimod PH20 (1000 mg once weekly) was effective and well tolerated in participants with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). ADHERE+ is an open-label extension of ADHERE assessing long-term safety and efficacy. METHODS:Eligible participants from ADHERE run-in period (prior CIDP treatments discontinued), stage A (open-label efgartigimod), and stage B (stage A responders randomized to placebo or efgartigimod) could roll over to ADHERE+ and receive efgartigimod. The primary outcome was to assess long-term safety and tolerability. Efficacy outcomes evaluated adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score, Inflammatory Rasch-built Overall Disability Scale (I-RODS) score, and mean grip strength (GS) from ADHERE run-in baseline through ADHERE+ week 36. RESULTS:At interim data cut-off (February 16, 2024), 228/229 eligible participants advanced to ADHERE+. Prolonged efgartigimod exposure did not increase the incidence (n = 171/228 [75.0%]) or severity of TEAEs (grade ≥ 3 TEAEs, n = 41/228 [18.0%]); regardless of immunoglobulin G level, there was a low incidence of infections. Stage A responders reported long-term clinically meaningful improvements in mean aINCAT (decreased by 1.2 points), I-RODS centile metric (increase of 8.8 points), and GS scores (increase of 17.5 kPa) from run-in baseline to ADHERE+ week 36, irrespective of stage B treatment. INTERPRETATION:Interim results from ADHERE+ indicate long-term efgartigimod PH20 treatment in participants with CIDP was well tolerated (maximum exposure = 187.3 weeks; mean (SD) treatment duration = 58.0 [33.8] weeks). Clinically meaningful improvements in disability and strength were observed across assessments, regardless of stage B treatment or prior treatment status, with greater improvements seen over time.

BACKGROUND AND OBJECTIVES:Key terms describing the activity status and clinical outcomes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) lack standardized definitions. To address the need for uniform definitions, we sought to develop formal consensus-based terminology to define key aspects pertinent to the management of CIDP. METHODS:In April 2025, the GBS|CIDP Foundation International convened a Task Force of 17 international CIDP experts, 2 guest experts from related specialties, and 3 patient representatives. Task Force panels iteratively reviewed, discussed, and voted on proposed definitions for No Evidence of Disease Activity, Relapse, Response, Refractory, Remission, and Residual Symptoms. Relevant literature was reviewed to inform each definition. A modified Delphi approach was used to achieve consensus, defined as a median rating ≥7 on a 9-point scale with ≥80% agreement. Voting included 17 content experts and 3 patient representatives. Guest experts provided nonvoting input. RESULTS:Composite metrics incorporating disability, strength impairment, and patient perception were determined to provide the most sensitive and specific assessment of clinical change in CIDP. Using commonly used clinical outcome measures, including minimally clinically important differences where available, unique definitions were developed for each clinical term. Definitions for No Evidence of Disease Activity, Relapse, Response (minimal, partial, and optimal), Refractory, Remission, and Residual Symptoms were iteratively refined to integrate patient-reported experiences, standardized disability scores, and objective measures of strength impairment, ensuring that each term captured a multidimensional view of disease status. DISCUSSION:The development of consensus-based definitions for key clinical terms in CIDP addresses a longstanding gap in standardizing the assessment of disease activity and treatment outcomes. By combining patient-reported experiences with objective disability and strength measures, the Task Force created comprehensive definitions reflecting the patient experience. The iterative Delphi process ensured broad expert agreement while allowing patient perspectives to inform the terminology. These standardized definitions may improve consistent evaluations in clinical practice, facilitate communication among healthcare providers, and support more robust design and interpretation of clinical trials. Furthermore, the incorporation of composite metrics sensitive to meaningful clinical changes may enhance the ability to detect treatment effects and disease progression, ultimately promoting more precise and patient-centered management of CIDP.

BACKGROUND AND OBJECTIVES:Anti-IgLON5 disease is characterized by substantial clinical heterogeneity and variable outcomes. We investigated the associations of clinical features as well as serum neurofilament light chain (NfL), phosphorylated tau (p-tau), IgG4 levels, and the HLA-DRB110:01∼DQB105:01 haplotype with disease presentation and outcome. METHODS:This is a retrospective observational study of patients with anti-IgLON5 disease diagnosed in our laboratory with adequate clinical information and follow-up. Neurologic disability was evaluated with the modified Rankin Scale (mRS) and the anti-IgLON5 composite score (ICS). Serum NfL and p-tau181 levels were measured using a commercial single-molecule array (Simoa) assay and IgG4 levels by flow cytometry. Associations between biomarkers and baseline clinical features were assessed using Spearman rank correlation and linear regression analyses. Prognostic variables were evaluated using binary logistic and Cox proportional hazards regression models. RESULTS:We included 78 patients (median age 66 years, 55% male). Higher serum NfL levels correlated with clinical severity at diagnosis, as measured with the mRS (r = 0.438; p = 0.002) and ICS (r = 0.30; p = 0.029). Patients with the HLA-DRB1*10:01∼DQB1*05:01 haplotype more frequently presented with the bulbar or sleep phenotypes (24/41; 58%) compared with those without the haplotype (4/28; 14%; p = <0.001). Sixty-six patients received immunotherapy, and 14 (21%) showed clinical improvement at the last follow-up. In the multivariate Cox regression model, the neuromuscular phenotype was the only independent predictor of good outcome (mRS: 0-3; HR: 10.8; 95% CI 2.48-47.1; p = 0.002). Among the 30 patients who died (42%), the strongest independent predictor of mortality was the bulbar phenotype (HR: 2.59; 95% CI 1.08-6.21; p = 0.033), while serum NfL levels showed a significant but limited association (HR: 1.02; 95% CI 1.00-1.04; p = 0.02). DISCUSSION:Serum NfL levels correlate with neurologic disability, whereas the bulbar phenotype was the main risk factor of mortality, indicating that these patients should be closely monitored and considered for early interventions (i.e., tracheostomy) that may modify an otherwise poor prognosis.

Background and Objectives This study describes the human leukocyte antigen (HLA) Class II allele frequencies in patients with anti-CNTN1+ and anti-Caspr1+ autoimmune nodopathy (AN).Methods Forty-four AN patients and 50 seronegative CIDP patients from 19 different European hospitals were included in the study. Thirty AN patients had anti-contactin 1 (CNTN1) antibodies, 11 anti-contactin-associated protein 1 (Caspr1) antibodies, and 3 had antibodies against both proteins. HLA-DRB1 was genotyped at the 4-digit allele levels, and the percentage of individuals carrying each allele was compared with that of the general population, obtained from the Allele frequencies database.Results HLA-DRB1*11 alleles appeared in higher proportions in anti-CNTN1+ patients than in seronegative CIDP patients and in the general population (46.7% vs 18% vs 28.4%), with an odds ratio of 3.99 (CI = 1.44 to 11.03, p = 0.01) and 2.2 (CI = 1.07 to 4.53, p = 0.04), respectively. HLA-DRB1*03:01 alleles appeared in significantly higher proportions in anti-Caspr1+ patients than in CIDP patients and in the general population (64.3% vs 22% vs 24.2%), with an odds ratio of 6.38 (CI = 1.77 to 22.99, p = 0.007) and 5.64 (CI = 1.876 to 16.96, p = 0.002), respectively. In the anti-Caspr1+ group, we included 3 patients presenting with antibodies against both CNTN1 and Caspr1 proteins in the acute phase, in which the anti-CNTN1 antibodies disappeared in the chronic phase.Discussion HLA-DRB1*11 alleles are associated with the detection of anti-CNTN1 antibodies in AN patients, and HLA-DRB1*03:01 alleles associate with anti-Caspr1 antibodies. In addition, our study suggests that antiparanodal antibodies targeting both Caspr1 and CNTN1 are present in a small number of patients with AN. These data reinforce the idea that these patients represent specific subsets with clinical features and risk factors that differ from seronegative CIDP patients and from other AN patients. However, further studies should address the functional relevance of these associations and their pathophysiologic implications.

Polyneuropathies are common and often require specialist expertise for accurate diagnosis. This study evaluated the diagnostic performance of ChatGPT-4o on real-world polyneuropathy cases, comparing it to peripheral neuropathy specialists and non-specialist neurologists. One hundred cases were selected from two tertiary centers in Milan, Italy. Standardized summaries included clinical, laboratory, and electrophysiological data. ChatGPT-4o was prompted to provide a leading diagnosis, two differentials, and a confirmatory test. Neurologists reviewed the same cases and generated comparable outputs, then could revise their responses after viewing ChatGPT-4o's suggestions. ChatGPT-4o achieved 65.5% leading diagnosis accuracy, comparable to non-specialists (63.0%) but lower than specialists (74.0%, p = 0.002). For differential diagnoses, it outperformed non-specialists (82.0% vs. 77.5%, p = 0.043) and recommended more appropriate tests (68.0% vs. 53.0%, p < 0.001). After reviewing ChatGPT-4o outputs, non-specialists revised their assessments in 21.8% of cases, improving accuracy. ChatGPT-4o shows potential as a diagnostic aid, particularly in non-specialist or resource-limited settings.

Introduction:Natalizumab (NTZ) is a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS) that can be administered intravenously (IV) or subcutaneously (SC). While switching from IV to SC NTZ is increasingly common in clinical practice, evidence on pharmacodynamic stability, particularly under extended interval dosing (6 weeks), remains limited. This study aimed to evaluate CD49d receptor occupancy (RO), serum neurofilament light chain (sNfL) levels, and clinical outcomes in RRMS patients switching from IV to SC NTZ while maintaining either 4- or 6-week dosing intervals. Methods:We conducted a multicenter, ambispective, observational study including RRMS patients who had received IV NTZ for at least 6 months on a 4w or 6w schedule and subsequently switched to SC NTZ while maintaining the same dosing interval. CD49d RO was assessed in CD4+, CD8+, and CD19+ lymphocyte subsets before the first, third, and seventh SC administrations. sNfL levels and clinical outcomes (relapses, MRI activity, EDSS score) were also evaluated. Mixed models for repeated measures were applied. Results:A total of 48 patients were included (4w: n=20; 6w: n=28). CD49d RO remained stable over time within both dosing schedules across all lymphocyte subsets. A significant difference between groups was observed only in CD19+ cells at the third administration (LS mean difference 13.08, SE = 4.10; p=0.028; 95% CI: 4.90-21.26) without clinical correlation. sNfL levels showed no significant differences at any timepoint within or between groups. Clinically, patients remained stable, with no new MRI activity or disability progression during the follow-up. Conclusion:Switching from IV to SC NTZ while maintaining either standard (4w) or extended (6w) dosing intervals preserves pharmacodynamic stability, as reflected by sustained CD49d RO, stable sNfL levels, and consistent clinical outcomes. These findings support SC administration as a reliable alternative to IV NTZ, including in extended interval dosing strategies.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder, which causes peripheral nervous system dysfunction. Guidelines recommend maintenance treatment with intravenous (IVIG) or subcutaneous (SCIG) immunoglobulins. Drawbacks for IVIG include the burden of hospital administration, which is less for SCIG, which allows self- or caregiver-assisted administration at home. However, conventional SCIG (c-SCIG) requires more frequent administration than IVIG. Recently, facilitated-SGIG (f-SCIG) was developed, spacing injections so that administration frequency is analogous to IVIG. The aim of this study was to estimate and compare the costs of IVIG, c-SCIG, and f-SCIG for CIDP maintenance treatment in Spain. A cost-analysis model based on a decision tree was developed to evaluate the annual cost per patient treated with each immunoglobulin from a societal perspective. Costs considered included direct health costs (pharmaceutical acquisition and administration), non-health costs (transport to hospital), and indirect costs related to labor productivity. All costs were valued in 2024 euros. The annual cost for a patient with CIDP receiving maintenance treatment was €109,212.67 with IVIG, €98,161.97 with c-SCIG, and €98,191.37 with f-SCIG. Across all treatments, direct healthcare costs were the highest. The main driver of the difference between SCIG and IVIG cost was treatment administration (−€10,705.78). Sensitivity analyses were generally consistent with the base case results. Overall, the findings of this analysis suggest that SCIG may be a cost-saving alternative to IVIG for patients with CIDP requiring maintenance treatment in Spain, with a similar cost between c-SCIG and f-SCIG.

Abstract Guillain-Barré syndrome is an acute immune-mediated polyradiculoneuropathy with heterogeneous outcomes and limited molecular biomarkers for diagnosis, disease monitoring, and prognosis. To elucidate the circulating proteomic profile of this disorder and identify candidate biomarkers associated with disease activity and recovery, we measured over 6,500 proteins using an aptamer-based proteomic platform. We analysed paired, longitudinal sera from 20 patients at disease onset and one-year follow-up, alongside 15 healthy controls. Unbiased differential protein abundance and gene-set enrichment analyses were performed. Candidate proteins were validated using conventional immunoassays in a cohort including healthy and disease controls. We identified 39 differentially abundant proteins between the acute and recovery phases and 248 proteins altered in acute Guillain-Barré syndrome compared to controls. The acute phase was characterised by a marked enrichment in systemic immune cascades and muscle sarcomere proteins, alongside a significant depletion of axonal adhesion molecules. Serum amyloid A1 (SAA1) emerged as the most strongly increased protein in the acute phase. Validation through independent immunoassays confirmed robust serum amyloid A elevations at disease onset relative to the one-year recovery phase, healthy controls, and relevant post-infectious and neuromuscular disease controls (acute disseminated encephalomyelitis and myasthenia gravis), underscoring a peripheral nerve-specific inflammatory response. Furthermore, unexpected elevations of cardiac troponin T (cTnT) were observed at disease onset. Clinical validation using high-sensitivity assays demonstrated that cTnT exceeded the diagnostic 99 th percentile upper reference limit in 25.5% of acute Guillain-Barré syndrome patients. A similarly high frequency of elevation in the myasthenia gravis disease control group (42.1%) suggests these increases predominantly reflect neuromuscular damage rather than myocardial injury. Finally, Mendelian randomisation provided causal genetic evidence linking specific systemic proteins to disease susceptibility, identifying robust roles for SERPING1 (plasma protease C1 inhibitor), CNDP1 (an antioxidant protein), and CRISPLD2 (a lipopolysaccharide-binding protein that regulates endotoxin function). Together, this comprehensive proteomic characterisation reveals distinct, stage-specific molecular signatures in Guillain-Barré syndrome. Importantly, it suggests SAA1 as a robust marker of acute peripheral nerve inflammation and challenges the conventional interpretation of elevated cTnT in severe neuropathies and neuromuscular disorders. Furthermore, this work provides a novel dataset to explore future targeted therapeutic development in Guillain-Barré syndrome.

BACKGROUND AND PURPOSE:Autoimmune nodopathies (AN) are a group of rare disorders caused by autoantibodies targeting cell-adhesion molecules located at the node of Ranvier. Reliable and efficient antibody testing for AN has become essential for optimal care of autoimmune neuropathies. In this study, we developed a multiplex flow cytometry (FCM) assay capable of simultaneously detecting four major AN antibodies and validated its diagnostic performance through inter-laboratory collaboration. METHODS:Multiplex FCM assay was established using live cell lines stably expressing each of the four AN targets-neurofascin-155 (NF155), contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1), and NF186. Using this assay, we tested 87 serum samples (46 AN, 39 disease controls, and 2 healthy controls) and compared the results with those obtained by enzyme linked immunosorbent assay (ELISA), fixed and/or live cell-based assay (CBA) conducted at an independent laboratory. IgG4 subclass positivity and autoantibody titers were also analyzed and compared between multiplex FCM assay and ELISA. RESULTS:Multiplex FCM assay demonstrated excellent diagnostic performance, with overall sensitivity of 95.1%, specificity of 97.8%, and accuracy of 99.6%. IgG4 subclass was detected in approximately 80% of AN sera, showing high concordance with ELISA. Antibody titers showed positive correlations between ELISA end-point titers and FCM-derived fluorescence intensity values. CONCLUSIONS:This multiplex FCM assay enables rapid, objective, and quantitative detection of AN autoantibodies and the presence of IgG4 subclass using minimal sample volume. High sensitivity and specificity support its potential utility for routine serological testing for AN.