BACKGROUND AND OBJECTIVES:It is currently difficult to accurately predict who, after the index event of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), will develop relapsing disease (R-MOGAD). Several clinical features have been reported as possibly predictive, but none have been validated in clinical practice. We used a prospectively designed analysis to assess a combined model of reported clinical prognosticators for developing R-MOGAD in 101 patients with MOGAD (86% with onset in adulthood) from 3 UK specialist centers. METHODS:A multivariable binary logistic regression model using variables identified from a scoping literature review was fitted in a retrospective clinical data set of patients with MOGAD (Nottingham MS & Neuroinflammation Centre [NUH]), with validation analysis in 2 independent data sets (Walton NMOSD Specialist Centre [WSC]; Imperial College London [ICL]). Secondary analysis investigated time to first relapse using Cox proportional hazards on the combined cohort. Results from the significant variables from the initial analysis were further examined in a meta-analysis of relevant literature studies. RESULTS:In the Neuroinflammation - Nottingham University Hospitals NHS Trust data set (n = 33), treatment with steroids ≥10 mg for ≥ 3 months after the index event was significantly associated with a lower likelihood of developing R-MOGAD (p = 0.006) with sensitivity 83% (95% CI 59-96) and specificity 73% (95% CI 45-92). A persistently positive MOG-IgG status, age at onset, optic neuritis at onset, and sex were not significant predictors of developing R-MOGAD. To assess generalizability, this predictor was tested in 2 independent data sets. In Walton Centre Liverpool (n = 39), not receiving prednisolone ≥10 mg ≥ 3 months was associated with R-MOGAD (OR = 9.7; 95% CI 2.1-45.4; sensitivity 63%; 95% CI 38-84; specificity 85%; 95% CI 62-97). In ICL (n = 29), the association was directionally consistent but inconclusive, with wide confidence intervals crossing unity (OR = 2.7; 95% CI 0.5-13.4; sensitivity 73%; 95% CI 39-94; specificity 50%; 95% CI 26-74). For the combined cohort (n = 101), not receiving prednisolone ≥ 10 mg for ≥3 months was associated with increased odds of developing R-MOGAD (OR = 6.2; 95% CI 2.6-14.8; p < 0.0001). Conversely, prednisolone ≥10 mg ≥ 3 months was associated with a lower hazard of relapse (HR = 0.47; 95% CI 0.24-0.91; p = 0.024). Median follow-up for monophasic patients was 42 months (IQR: 17.5-64.5). DISCUSSION:Prednisolone ≥10 mg for ≥ 3 months after the index event was associated with a lower likelihood of relapsing MOGAD. This association was supported in first external cohort and directionally consistent but inconclusive in a second, smaller cohort. Further prospective multicenter studies are required to assess the reproducibility and clinical utility of this association.
BACKGROUND AND OBJECTIVES:Although anti-CD20 monoclonal antibodies (anti-CD20s) theoretically represent an ideal treatment option for women with multiple sclerosis (wwMS) planning a pregnancy, the paucity of real-world data still limits their use in this context. Through our Italian registry "CD20-PREGNANCY," we aim to report pregnancy, infant, and maternal outcomes in wwMS treated with anti-CD20s. METHODS:In this observational study, wwMS having received rituximab (RTX), ocrelizumab (OCR), or ofatumumab (OFA) before and/or during pregnancy (≤12 months for RTX/OCR, ≤6 months for OFA) were included. Considering drug pharmacokinetics and timings of immunoglobulin placental transfer, pregnancies were classified as "exposed" (last administration pre-pregnancy ≤2.3 months for RTX, ≤3 for OCR, ≤1.8 for OFA) and "not-exposed" (last administration beyond these intervals) for comparative analysis. RESULTS:A total of 153 pregnancies (85 "not-exposed," 68 "exposed") across 27 Italian MS centers were collected. The median age at conception was 33.9 years (interquartile range 30.0-37.6) with 39.9% of women older than 35 years. Most pregnancies occurred in patients treated with OCR (77.1%). 80.4% of pregnancies ended in livebirth and 13.1% in spontaneous abortions (SA), without stillbirths/neonatal deaths. There was a significantly higher percentage of SA in "exposed" pregnancies than "not-exposed" (20.6% vs 7.1%, p = 0.014), but with values similar to those reported in general population. One serious perinatal infection ("exposed" group) and 2 major congenital anomalies (MCA) (one per group) were reported. Compared with the 12 months pre-pregnancy, annualized relapse rate remained stable during pregnancy but slightly increased postpregnancy (0.00 vs +0.09) in "not-exposed." Conversely, it decreased in both periods (-0.02 vs -0.13) among "exposed". Compared with pre-pregnancy, postpregnancy combined unique active lesions decreased in both groups (-0.15 in "not-exposed", -0.38 in "exposed"), while 2 confirmed disability worsening were observed ("not-exposed"). DISCUSSION:In conclusion, a good control of disease activity was observed without an increased risk of MCA or perinatal infections. Percentages of SA were overall in line with those of general population, although with a higher proportion in the "exposed" group. These findings support the use of anti-CD20 therapies in wwMS planning pregnancy, although further data are needed to better define their safety profile in this setting.
BACKGROUND AND OBJECTIVES:Fc gamma receptor 3A (FCGR3A) V158F polymorphism has been shown to modify the response to anti-CD20 therapy across several autoimmune diseases. Ocrelizumab (OCR), an anti-CD20 agent, suppresses inflammatory activity in multiple sclerosis (MS), yet whether FCGR3A V158F polymorphism affects its efficacy in MS remains unclear. Here, we tested whether this genetic variant influences B-cell repopulation and disease activity in MS participants treated with OCR and assessed genotype-dependent differences in OCR binding to FcγRIIIa-expressing natural killer (NK) cells. METHODS:In this observational cohort study, we enrolled people with MS treated with OCR consecutively between May 2022 and August 2025. FCGR3A V158F genotyping was performed by pyrosequencing. The primary outcome was preinfusion CD19+ B-cell repopulation, defined as CD19+ B cells ≥1%. Secondary outcomes included clinical and MRI inflammatory activity and composite disease activity/disability-worsening measures. In a parallel mechanistic ex vivo substudy, OCR or rituximab (RTX) binding to NK cells was evaluated in genotype-selected donors by flow cytometry. Cycle-based repeated measures were analyzed using mixed-effects logistic regression. RESULTS:In 101 participants, 500 interinfusion intervals were analyzed. The odds of B-cell repopulation decreased with higher cycle number (odds ratio [OR] per cycle 0.77; 95% CI 0.65-0.91; p = 0.002) and increased with longer infusion intervals (OR per +30 days, 2.02; 95% CI 1.27-3.21; p = 0.0029). FCGR3A F-carrier status significantly modified the effect of interval length (interaction OR, 2.47; 95% CI 1.04-5.89; p = 0.042). Specifically, the odds of B-cell repopulation increased with longer intervals in MS participants carrying the FCGR3A-F allele (OR, 3.67; 95% CI 1.84-7.34; p = 0.00023) but not in FCGR3A-VV individuals (OR, 1.49; 95% CI 0.87-2.54; p = 0.146). FCGR3A genotype was not associated with clinical or MRI activity outcomes. In ex vivo assays, NK cells from FCGR3A-FF donors exhibited significantly lower binding of OCR (p = 4.34 × 10-4) and RTX (p = 0.00172) as compared with VV donors. DISCUSSION:Longer OCR infusion intervals were associated with higher odds of B-cell repopulation. The FCGR3A V158F polymorphism modified this interval-dependent repopulation, possibly by affecting OCR binding to NK cells. Prospective studies are needed to determine whether FCGR3A V158F polymorphism and B-cell repletion kinetics can inform optimized interval-based OCR dosing in MS.
Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are inflammatory disorders of the CNS with distinct immunopathologic mechanisms and treatment responses and partially overlapping clinical phenotypes. The identification of aquaporin-4 (AQP4)-IgG and MOG-IgG has transformed disease classification and diagnosis, enabled a classification of antibody-defined subgroups, and facilitated the development of targeted therapies. However, optimal use of these biomarkers in clinical practice requires careful interpretation within the appropriate clinical and radiologic context. This review synthesizes current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility. We review antibody detection using cell-based assays, highlighting differences between live and fixed platforms and the impact of antigen conformation on sensitivity and specificity, particularly for MOG-IgG. Common causes of false-positive and false-negative results are discussed, including low-titer reactivity, testing in low pretest probability populations, treatment-related antibody titer reduction, and assay-specific limitations. The diagnostic challenges posed by indiscriminate testing in adult cohorts with multiple sclerosis, in whom disease prevalence markedly exceeds that of MOGAD, are emphasized. We also discuss the role of repeat testing during acute attacks and paired serum-CSF analysis in improving diagnostic confidence when results are equivocal or discordant. Beyond disease-defining antibodies, we examine biomarkers of tissue injury and immune activation. Serum and CSF neurofilament light chain and glial fibrillary acidic protein provide complementary measures of neuroaxonal and astrocytic damage and show associations with attack severity, disease activity, relapse risk, and long-term disability. Cytokines, chemokines, and complement components reflect inflammatory pathways, including IL-6-driven immune activation in NMOSD and MOGAD and complement-mediated astrocytopathy in NMOSD, and may support mechanistic stratification and treatment monitoring in both conditions. We further review the contribution of CSF analysis, neuropathology, genetics, and antigen discovery platforms to refine disease classification, particularly in seronegative or atypical presentations. Finally, we outline priorities for future research, including assay harmonization, standardized sampling protocols, longitudinal biomarker profiling, and integrative multiomic approaches. Collectively, advances in biomarker science have the potential to improve diagnostic precision, guide individualized therapeutic strategies, and support de-escalation decisions in NMOSD and MOGAD.
OBJECTIVES:Immune checkpoint inhibitor (ICI)-related parkinsonism is an exceedingly rare neurologic immune-related adverse event (irAE). METHODS:We reviewed retrospectively the French Pharmacovigilance Agency and French National Center for Autoimmune Encephalitis and Paraneoplastic Neurologic Syndromes Lyon databases (2015-2025) following identification of index case. RESULTS:We identified 4 male and one female patient, with a median age of 67 years (range 34-75), who developed acute-to-subacute parkinsonism after a median of 4 ICI cycles (range 1-12). The predominant phenotype was bilateral akinetic-rigid syndrome (rigidity n = 5, bradykinesia n = 4, tremor n = 3); the median modified Rankin Scale score at onset was 3. CSF analysis showed pleocytosis in 2/4 tested patients and elevated protein in 4/4 tested patients. Dopamine transporter imaging demonstrated bilateral dopaminergic denervation in both patients tested (n = 2), with documented reversibility in one. ICI discontinuation alone (n = 1/2) or combined with immunomodulatory therapy (n = 3) yielded clinical improvement over a median follow-up of 15 months (range 3-30). Levodopa/carbidopa supplementation was required in 2 patients. DISCUSSION:Post-ICI-related parkinsonism is a rare but potentially reversible irAE. Early recognition and prompt ICI discontinuation may favor significant clinical recovery. Immunosuppressive therapy should be considered for severe cases or those not improving after ICI discontinuation alone.
BACKGROUND AND OBJECTIVES:Reliable biomarkers for autoimmune encephalitis (AE) are limited, and emerging CSF markers are not incorporated into current diagnostic criteria. Prognostic tools remain insufficient, highlighting the need for biomarkers that support both early diagnosis and assessment of disease severity and prognosis. METHODS:In this multicenter prospective cohort study, we analyzed clinical data and paired CSF-serum samples from adults with definite AE enrolled in the German Network for Research on Autoimmune Encephalitis registry and the CSF biobank of Hannover Medical School. Of 2,330 screened individuals, 92 patients with anti-N-methyl-d-aspartate receptor (NMDAR, n = 53), anti-leucine-rich glioma-inactivated 1 (LGI1, n = 20), or anti-contactin-associated protein-like 2 (CASPR2, n = 19) encephalitis were included and followed longitudinally for a median of 38 months. Control groups comprised patients with relapsing multiple sclerosis, varicella-zoster virus encephalitis, and noninflammatory neurologic conditions (each n = 30), as well as antibody-positive patients without AE (n = 15), with the groups frequency-matched for age and sex. Kappa free light chain (KFLC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokines were measured in paired CSF-serum samples obtained at baseline and during follow-up. Disease severity and disability were assessed using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score and the modified Rankin Scale (mRS). RESULTS:Intrathecal synthesis of KFLC was detected in 94% of anti-NMDAR, 50% of anti-LGI1, and 53% of anti-CASPR2 encephalitis cases, demonstrating higher diagnostic sensitivity than CSF-restricted oligoclonal bands or pleocytosis. Diagnostic specificity across pooled control groups was moderate at 44% but reached 90% when compared with noninflammatory neurologic controls. CSF NfL z-score levels were strongly associated with baseline disease severity, with each 1-standard deviation increase corresponding to an approximately 10-point higher CASE score, independent of clinical covariates (β = 0.61). Longitudinal changes in NfL concentrations in CSF and serum were associated with disease severity and neurologic disability at follow-up (CASE score: adjusted R2 = 0.401; mRS score: adjusted R2 = 0.203). GFAP and cytokines showed limited diagnostic or prognostic utility. DISCUSSION:Intrathecal KFLC synthesis represents a highly sensitive CSF marker that supports early suspicion of autoimmune encephalitis and prompts antibody testing. NfL provides robust biochemical information on baseline disease severity and longitudinal changes that may aid prognostic assessment across AE subtypes.
BACKGROUND AND OBJECTIVES:Bispecific antibodies (BisAbs) have transformed the management of relapsed and refractory multiple myeloma (MM), achieving high response rates in heavily pretreated patients. However, these therapies induce profound immune perturbation, including plasma cell aplasia, hypogammaglobulinemia, and T-cell exhaustion, predisposing patients to serious infections. Progressive multifocal leukoencephalopathy (PML) has rarely been reported in this setting. METHODS:We report on 5 patients with MM who developed PML following BisAbs therapy. Clinical presentation, prior treatments, imaging, CSF studies, pathology, and outcomes were reviewed. In addition, T-cell immunophenotyping and antiviral T-cell responses were evaluated. RESULTS:Five patients (median age 63 years; range 60-77; 3 male) developed PML after treatment with elranatamab (1) or teclistamab (4), with (3) or without (1) talquetamab (1). All patients were under BCMA-directed BisAbs treatment at the time of PML diagnosis. Patients had received a median of 5 prior treatment lines (range 2-7) and 4 had undergone autologous stem cell transplantation. All demonstrated significant immune compromise. Median time from BisAbs initiation to PML diagnosis was 12 months (range 6-24; mean 15.4 months). One patient developed PML after only 2 prior therapies. Three of 5 patients had positive PCR for JC virus (JCV) in the CSF, while the other 2 were positive for JCV on brain biopsy. Clinical manifestations included dysarthria, ataxia, cognitive decline, and focal weakness. Although all patients demonstrated significant immune compromise (lymphopenia and hypogammaglobulinemia), 2 of 4 tested, showed specific anti-JCV/BKV T-cell response. DISCUSSION:PML represents a rare but serious, life-threatening complication of BisAbs therapy in MM. Although most patients were heavily pretreated, occurrence after limited prior therapies and the presence of specific anti-JCV T cells in 2 patients suggests BisAbs-related immune modulation may contribute independently to the risk. Duration of exposure may also be relevant. Given emerging therapeutic options such as immune check point inhibitors and anti-JCV-specific T-cell therapies, early recognition is critical. PML should be considered in patients receiving BisAbs therapy who develop new neurologic symptoms, and prompt evaluation is warranted.
BACKGROUND AND OBJECTIVES:Neuromyelitis optica spectrum disorder (NMOSD) is a severe condition usually associated with aquaporin-4 (AQP4) antibodies. A clinical presentation suggestive of NMOSD can also be associated with myelin oligodendrocyte glycoprotein (MOG) antibodies (MOGAD). NMOSD can be diagnosed in the absence of autoantibodies (double-negative NMOSD [DN-NMOSD]), but this subgroup has been poorly investigated. We conducted a systematic review and meta-analysis to define the clinical spectrum, prognosis, and treatment response in DN-NMOSD vs AQP4-NMOSD/MOGAD. METHODS:We searched on PubMed, Scopus, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov databases of studies on patients fulfilling inclusion criteria. Patient characteristics, outcome measures, and treatment regimens were extracted. RESULTS:We included 41 of 1,027 articles screened and analyzed 671 patients with DN-NMOSD (median age 38.6 years [range IQR: 32.5-42.85]; female-to-male ratio 1.5:1; median follow-up 44.4 months [range 1-600]), 73.6% of which relapsed. In the meta-analysis, mean annualized relapse rate (ARR) was higher, albeit not significantly, in DN-NMOSD (1.08; 95% CI 0.73-1.43) vs AQP4-NMOSD (0.84; 95% CI 0.45-1.23) and MOGAD (0.61; 95% CI 0.39-0.83, p = 0.08). Administration of maintenance immunosuppression in DN-NMOSD led to a significant ARR reduction (pooled rate ratio 0.19, 95% CI 0.07-0.49; p = 0.001), with high heterogeneity (I2 = 90%, p < 0.0001). In meta-regression, no covariates were associated with ARR reduction, including the administration of specific drugs (rituximab, p = 0.288; azathioprine, p = 0.291; mycophenolate, p = 0.918). The pooled mean difference in pre‑ and post‑maintenance treatment Expanded Disability Status Scale values indicated a significant change in disability in MOGAD (-0.93, 95% CI -1.67 to -0.19, p = 0.02) but not in AQP4-NMOSD (-0.62, 95% CI -1.85 to 0.61, p = 0.27) or DN-NMOSD (-0.52 (95% CI -1.30 to 0.25, p = 0.16). DISCUSSION:DN-NMOSD is a heterogenous, severe and highly relapsing disease, where attacks lead to irreversible dysfunction. The administration of maintenance immunotherapy reduces the relapse risk and should be considered early to prevent further disability.
BACKGROUND AND OBJECTIVES:Pediatric-onset opsoclonus-myoclonus-ataxia syndrome (POOMAS) is a rare, neuroinflammatory syndrome that targets the cerebellum and can cause irreversible cerebellar structural changes, namely cerebellar atrophy. We investigated the frequency of cerebellar atrophy, as well as associated risk factors and functional outcome measures, using the largest active POOMAS registry. METHODS:This was a retrospective observational study of participants with POOMAS with disease onset from 1995 to 2025 using data from the multinational, multicenter POOMAS registry. Variables were compared between the cerebellar atrophy subgroups using the Fisher exact test or Wilcoxon rank-sum test. RESULTS:Of participants with follow-up imaging, cerebellar atrophy developed in 9.5% (6/63) of those with an MRI scan obtained at least 6 months after disease onset and 12.5% (3/24) with an MRI scan obtained at least 48 months after disease onset. Half of the participants who developed cerebellar atrophy (3/6) were identified more than 48 months after disease onset. Cerebellar atrophy was associated with older age at diagnosis (p = 0.023), but not with other demographic or clinical characteristics. There were no statistically significant differences in functional outcome measures or educational setting. DISCUSSION:The overall frequency of cerebellar atrophy was likely underestimated in this study because of the lack of standardized MRI timing and the large number of patients without MRI scans beyond 48 months.
BACKGROUND AND OBJECTIVES:CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform-capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes-could validate previously proposed biomarkers and identify additional candidates relevant to ALS. METHODS:Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls. RESULTS:The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases-particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature. DISCUSSION:Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.
Over the past decade, therapeutic paradigms in multiple sclerosis have shifted toward a "hit-hard-and-early" approach to suppress inflammatory activity and delay progression. However, adverse events, safety concerns, aging, comorbidities, and life circumstances frequently necessitate treatment transitions during the patient journey. Sequencing decisions generally arise from 3 scenarios: insufficient efficacy, tolerability or safety issues, and conceptual considerations such as family planning or exit strategies for discontinuation. Discontinuation or de-escalation of therapy is associated with a significant risk of disease reactivation, particularly after lymphocyte-trafficking inhibitors, underscoring the importance of proactive transition planning to maintain disease control. Evidence suggests that treatment-specific immunologic effects strongly influence optimal sequencing. This narrative review synthesizes mechanistic insights and real-world clinical evidence to guide sequencing strategies for disease-modifying therapies (DMTs) in multiple sclerosis (MS), an increasingly relevant challenge in the era of early high-efficacy treatment. Following natalizumab, anti-CD20 monoclonal antibodies demonstrate superior control of relapse and MRI activity compared with sphingosine-1-phosphate receptor modulators (S1PRMs). Short transition intervals (<30 days) may minimize risk of rebound activity. After S1PRMs, rapid initiation of anti-CD20 therapies or cladribine seems effective, whereas prolonged washout periods increase relapse risk. Anti-CD20 therapies provide sustained suppression of inflammatory activity but are associated with long-term risks, including hypogammaglobulinemia and infections; cladribine may represent a viable exit strategy by enabling durable immune reconstitution. Platform therapies permit straightforward escalation without major rebound concerns, although lymphopenia must be considered when switching from dimethyl fumarate. Emerging Bruton tyrosine kinase inhibitors may further reshape sequencing paradigms, potentially functioning as maintenance therapies targeting compartmentalized inflammation after initial immune-depleting treatment. Future strategies will likely rely on close clinical and biomarker-based monitoring to individualize transitions and identify therapeutic windows. Overall, pragmatic sequencing that anticipates future switches and balances rebound risk against cumulative immunosuppression is essential for optimizing long-term outcomes in MS.
BACKGROUND AND OBJECTIVES:Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a novel and potentially treatable entity. Therefore, it is important to recognize all clinical symptoms and diagnostic clues. We specifically investigated neuromuscular signs and symptoms and muscle biopsy pathology, providing a link between IgLON5 and clinical features of myopathy. METHODS:All patients diagnosed with anti-IgLON5 disease in the Netherlands between 2016 and 2023 were included. Serum and CSF samples were tested with immunohistochemistry on rat brain and in-house cell-based assay using live cells. Biopsies of the vastus lateralis muscle were performed in patients with neuromuscular signs and symptoms and analyzed in Vienna together with 3 biopsies of non-Dutch patients sent to Vienna for second opinion. RESULTS:Twenty patients with anti-IgLON5 disease were included (10 male, 50%). The median age at onset was 61.5 years (range 45-85), and the median time from onset to diagnosis was 30 months (range 3-280). Neuromuscular symptoms were present in over half of the patients (11/20), including proximal limb weakness (n = 11), axial weakness (n = 1), muscle atrophy (n = 6), and fasciculations (n = 5). All 12 muscle biopsies (9 from the Dutch cohort, 3 external) showed mild myopathic alterations, 2 additionally presented target fibers and fiber type grouping (compatible with neurogenic myopathy), and 3 patients showed immune cell infiltration. We found a strong upregulation of IgLON5 expression in muscle fibers in all patients and also in different muscle disease controls, while immunoreactivity in healthy control muscle was faint/absent. DISCUSSION:Our data support that IgLON5 might play a role in muscle regeneration, which might result in proximal myopathy as a prominent clinical feature in anti-IgLON5 disease. This finding broadens the clinical phenotype of anti-IgLON5 disease and can be an important clue for earlier diagnosis and start of immunotherapy.
BACKGROUND AND OBJECTIVES:Ravulizumab, a complement component 5 inhibitor, was approved for the treatment of adults with anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) based on results of the primary treatment period (PTP) of CHAMPION-NMOSD, a phase 3, open-label, external placebo-controlled trial. Here, we report the final efficacy and safety results of CHAMPION-NMOSD (PTP and the long-term extension [LTE]). METHODS:Adult patients with AQP4-Ab+ NMOSD received an IV, weight-based loading dose of ravulizumab on day 1 and a maintenance dose on day 15 and every 8 weeks thereafter. After completion of the PTP (up to 2.5 years), patients could enter the LTE. The primary endpoint was time to first adjudicated on-trial relapse. The placebo group of the eculizumab phase 3 trial PREVENT was used as an external comparator because eculizumab availability at CHAMPION-NMOSD initiation precluded the use of concurrent placebo control. RESULTS:Of 58 patients enrolled in the trial, 56 entered and 55 completed the LTE. The overall median (range) follow-up was 170.3 (11.0-243.0) weeks, with 100.8 (53-137) weeks during the LTE. No patient receiving ravulizumab had an adjudicated on-trial relapse throughout the PTP (84.0 patient-years) and LTE (105.7 patient-years); relative reduction in risk of relapse vs placebo (n = 47) was 98.9% (95% CI 91.8-100; p < 0.0001). Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 94.8% and 27.6% of patients, respectively, during the PTP and LTE. Most TEAEs were grade 1 and unrelated to ravulizumab. One patient discontinued ravulizumab because of TEAEs. Two cases of meningococcal infection occurred during the PTP; none occurred in the LTE. One death due to hypertensive heart disease (unrelated to ravulizumab) occurred during the LTE. DISCUSSION:Long-term ravulizumab treatment (median follow-up, >3 years) continued to show significant relapse risk reduction in patients with AQP4-Ab+ NMOSD, and the safety profile was consistent with the known safety profile for ravulizumab. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov, NCT04201262; EudraCT: 2019-003352-37. Submitted December 11, 2019. First patient enrolled: December 13, 2019. clinicaltrials.gov/study/NCT04201262. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that long-term ravulizumab treatment, as compared with placebo, decreases the probability of clinical relapse in patients with AQP4-Ab+ NMOSD.
BACKGROUND AND OBJECTIVES:Compartmentalized CNS inflammation involving B cells is implicated in gray matter injury and disease progression in multiple sclerosis (MS). Products secreted by B cells of patients with MS can kill oligodendrocytes and neurons, a cytotoxicity conferred by their exosome-enriched extracellular vesicle (Ex En) fraction. METHODS:To explore the potential molecular mediators of this cytotoxicity, we profiled proteomic and transcriptomic cargo of Ex En isolated from B cells of patients with treatment-naive MS and matched healthy controls. RESULTS:MS B-cell-derived Ex En appeared enriched in cell-death-associated proteins (including fibrinogen, complement C9, APP, and SPARC) and deficient in cell-survival-associated proteins (such as galectin-3). Abnormal enrichment for cell-death proteins was supported by gene set enrichment analysis. Protein pathway analysis revealed densely connected prodeath modules in the MS B-cell-derived Ex En, contrasting with homeostatic signatures in controls. Transcriptomic analysis further revealed that Ex En of MS B cells appeared to carry reduced levels of miRNAs (miR-182, miR-212, and miR-1270) known to inhibit apoptosis. DISCUSSION:Our findings indicate that B-cell-derived Ex En of patients with MS, previously shown to impair neuronal and glial survival, harbor an abnormal cytotoxic molecular profile that may contribute to CNS-compartmentalized injury and progressive MS biology.
Subacute cognitive decline and imbalance in aquaporin-4-antibody-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD) treated with mycophenolate has a broad differential diagnosis, including cerebral involvement of AQP4+NMOSD, infections, or other complications of immunosuppression. In this article, we highlight the diagnostic and treatment approach in a patient with AQP4+NMOSD who developed multifocal brain lesions.
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.
BACKGROUND AND OBJECTIVES:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder that overlaps clinically with multiple sclerosis (MS) but immunopathologically distinct. Although often considered an acute inflammatory disease, recurrent attacks in MOGAD can lead to demyelination, axonal injury, and secondary neurodegeneration. Reliable biomarkers associated with relapse risk and disease subphenotypes, including optic neuritis, remain limited. Here, we aimed to define molecular and cellular signatures that distinguish MOGAD from MS as a prototypical neuroinflammatory disease and from Alzheimer disease (AD) as a proxy of neurodegeneration and to identify candidate immune-proteomic features associated with relapse frequency and clinical phenotype in MOGAD. METHODS:CSF, serum, and whole-blood samples from patients with MOGAD (n = 67), MS (n = 49), and AD (n = 36) were profiled using NULISAseq™ CSF proteomics, Olink Explore 3072 CSF and serum proteomics, and high-dimensional mass cytometry for immune cell characterization. In MOGAD, longitudinal clinical data, including total attack counts from the earliest documented attack through follow-up, were integrated with immune and proteomic profiles to assess associations with disease course and clinical phenotype. RESULTS:CSF and blood proteomic profiling revealed distinct inflammatory and cardiometabolic proteomic profiles in MOGAD, differentiating it from both MS and AD. Compared with MS, MOGAD showed relative reductions in lymphocyte populations with regulatory phenotypes. Within MOGAD, relapsing disease was associated with reduced frequencies of CD8+CCR7+CD31+CTLA4+ T cells and concurrent expansion of double-negative γδ T-cell subsets. IL-13 correlated positively with relapse frequency and inversely with circulating regulatory T cells, whereas IL-32 and CASP4 showed opposite associations, correlating negatively with relapse count and positively with Treg frequency. IL-13 was also inversely associated with CD31-expressing CD8+ T cells. Phenotype-stratified analyses suggested that these immune-proteomic relationships differed according to clinical presentation, including optic neuritis vs nonoptic neuritis phenotypes. DISCUSSION:This integrative immune-proteomic analysis identifies cellular and molecular features associated with relapsing vs monophasic MOGAD, suggesting a model of impaired peripheral immune regulation in relapsing disease. While exploratory, these findings generate a concrete hypothesis for future longitudinal and functional studies aimed at refining biomarker-based monitoring and informing individualized therapeutic strategies in MOGAD.
Objectives Ma/Ma2-associated neurologic autoimmunity is characterized by CNS involvement. However, isolated peripheral nervous system (PNS) presentations have been rarely reported. We aimed to describe the frequency and syndromes of patients with Ma/Ma2 antibodies and isolated PNS involvement.Methods We performed a nested case series within multicenter cohorts of patients with Ma/Ma2-associated neurologic syndromes, confirmed by tissue-based assay and line-blot. Patients with isolated PNS presentations were included.Results Among 212 patients with Ma/Ma2 antibody-associated neurologic syndromes, 7 (3%) presented with isolated PNS involvement (median age, 68 years; 4/7 female). PNS syndromes included sensory neuronopathy (3 patients), myeloradiculopathy (1), radiculoplexopathy (1), motor neuronopathy (1), and multiple mononeuropathy. All patients were anti-Ma2-positive, whereas Ma antibodies (reactive against Ma1 and Ma2 proteins) were detected in 2 (33%)/6 tested patients. An associated cancer was identified in 6 (86%)/7 patients: pleural mesothelioma; oral squamous cell; testicular, lung, and breast cancer; and B-cell lymphoma. Five patients received immunotherapy, cancer treatment, or both. After a median follow-up of 23 months, symptoms improved or stabilized in 3 patients and progressed in 4.Discussion Isolated PNS involvement is a rare manifestation of Ma/Ma2 associated autoimmunity. Ma/Ma2 antibody testing should be considered in neuronopathies and unexplained non-length-dependent neuropathies.
Background and Objectives Neuromyelitis optica spectrum disorders (NMOSDs) comprise rare autoimmune diseases of the CNS in which disabilities accrue with relapses. The ability to predict and prevent relapses could dramatically improve clinical outcomes, potentially reducing morbidity and quality-of-life declines. This proteomic study aimed to identify individual and composite candidate serum biomarkers predictive of NMOSD relapse.Methods Patients with NMOSD previously enrolled in the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) cohort were selected based on documented relapses simultaneous with retrievable banked cryopreserved serum. Longitudinal serum proteomic profiles were characterized using high-resolution mass spectrometry. We used linear models with logistic regression, Cox proportional hazards models with fixed-time intervals, and time-dependent Cox proportional hazards models to analyze individual proteins and proteomic profiles for their association with future relapses factoring demographics, clinical phenotype/course, and treatments.Results We characterized a total of 305 longitudinally collected serum samples (N = 126), using high-resolution mass spectrometry, and identified 265 proteins overall. There was a 10-protein signature with the highest average association coefficient consistently across at least 4 of the 6 modeling analyses, including factor XI, surfactant protein B, C1RL, filamin A, cholesteryl ester transfer protein, cathelicidin antimicrobial peptide, C4A, transferrin receptor, for consistency immunoglobulin kappa constant, and serum amyloid A2 protein. This signature could significantly stratify patients with higher vs lower risk of subsequent relapse. These proteins differed in their increasing or decreasing abundance trajectories in advance of relapse. Most belong to pathways plausibly related to the immunopathology of NMOSD.Discussion Collectively, these findings provide a basis for novel biomarker development to predict NMOSD relapses sufficiently in advance to enable preventive treatment.
BACKGROUND AND OBJECTIVES:Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction most commonly associated with acetylcholine receptor (AChR) antibodies (AChR-Abs), detected in up to 80% of patients. The emergence of targeted therapies, such as neonatal Fc receptor (FcRn) inhibitors, highlights the need for standardized functional assays capable of dissecting AChR-Ab pathogenic mechanisms. By selectively reducing circulating IgG through FcRn blockade, these agents differ fundamentally from conventional immunosuppressants, emphasizing the need to characterize antibody-mediated AChR dysfunction and complement activation as potential markers of therapeutic response. However, current functional assays often rely on transiently transfected or heterogeneous cell systems, limiting reproducibility and scalability. A stably transfected human cell line expressing physiologically clustered adult AChRs could fill this methodological gap and enable standardized, quantitative evaluation of antibody effector functions. METHODS:We generated a stable rhabdomyosarcoma (RD) cell line expressing clustered human adult AChRs (hAChR-RDcl) using the PiggyBac transposon system for genomic integration of AChR subunit genes. The hAChR-RDcl line was applied to functional cell-based assays using serum samples from 30 patients with AChR-MG before and after one treatment cycle with efgartigimod. Clinical efficacy was assessed by Quantitative Myasthenia Gravis (QMG) and MG Activities of Daily Living (MG-ADL) scores. RESULTS:The hAChR-RDcl cell line showed stable transcription and surface expression of adult AChR subunits, confirmed by RT-qPCR, α-bungarotoxin binding, and antibody-specific reactivity (mAb637 and patient serum samples). Baseline functional assays identified blocking antibodies in 15 of 30 (50%), internalizing antibodies in 20 of 30 (66.7%), and complement-activating antibodies in 14 of 30 (46.6%) samples. After efgartigimod treatment, all 3 antibody-mediated mechanisms were significantly reduced. Patients with persistent complement activity after treatment experienced more severe symptoms (higher QMG scores) compared with those showing other antibody-mediated pathogenetic mechanisms or complete suppression of antibody effector functions. DISCUSSION:The hAChR-RDcl cell line represents a reliable and scalable platform for standardized functional profiling of AChR-Abs. Functional characterization of AChR-Abs provides a translational approach to monitor therapeutic responses and elucidate the mechanisms underlying FcRn inhibitor efficacy in MG.
