RESUMEN
OBJECTIVES: In myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD. METHODS: CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured. RESULTS: CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044). DISCUSSION: The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.
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Acuaporina 4 , Activación de Complemento , Inmunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/líquido cefalorraquídeo , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Acuaporina 4/inmunología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Glicoproteína Mielina-Oligodendrócito/inmunología , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Anciano , Complemento C5a/líquido cefalorraquídeo , Complemento C5a/metabolismo , Complemento C5a/inmunología , Adulto Joven , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Complemento C3a/metabolismo , Complemento C3a/líquido cefalorraquídeo , Complemento C3a/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/líquido cefalorraquídeo , Complejo de Ataque a Membrana del Sistema Complemento/inmunologíaRESUMEN
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.
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Acuaporina 4 , Autoanticuerpos , Diagnóstico Precoz , Neuromielitis Óptica , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Humanos , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Biomarcadores/sangreRESUMEN
OBJECTIVE: To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value. MATERIAL AND METHODS: We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months). RESULTS: During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%. CONCLUSION: The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.
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Acuaporina 4 , Autoanticuerpos , Neuromielitis Óptica , Sensibilidad y Especificidad , Humanos , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/sangre , Neuromielitis Óptica/inmunología , Adulto , Femenino , Persona de Mediana Edad , Masculino , Federación de Rusia , Autoanticuerpos/sangre , Anciano , Adolescente , Acuaporina 4/inmunología , Adulto Joven , Inmunoglobulina G/sangre , Valor Predictivo de las PruebasRESUMEN
OBJECTIVES: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections in patients with Neuromyelitis optica spectrum disorder (NMOSD) remain unclear. The objective of this study was to investigate CMV and EBV infections in patients with NMOSD. METHODS: Serum immunoglobin (Ig) G antibodies against CMV and EBV were measured in patients with NMOSD and healthy controls (HCs), including anti-CMV, anti-EBV nuclear antigen-1 (EBNA-1), anti-EBV virus capsid antigen (VCA), and anti-EBV early antigen (EA) IgGs. The immune status ratio (ISR) was used to evaluate the serum anti-CMV and anti-EBV IgG levels and ISR â§1.10 was defined as seropositivity. RESULTS: In total, 238 serum samples were collected from 94 patients with NMOSD and 144 HCs, and no significant difference of sex and age between NMOSD and HCs. Comparing to the HCs, patients with NMOSD exhibited significantly higher serum anti-CMV IgG level. In contrast, the serum anti-EBNA1 IgG level was significantly lower in patients with NMOSD than in HCs. The serum anti-VCA and anti-EA IgG levels did not differ between the two groups, but the anti-EA seropositivity was significantly higher in NMOSD group than that in HC group. We did not find associations between serum anti-CMV or anti-EBV IgG levels and NMOSD disease stage, immunotherapy, or disability score. CONCLUSIONS: Our findings indicated that increased CMV infection and EBV recent infection, as well as reduced EBV latency infection were associated with the risk of NMOSD. Prospective cohort studies are needed to verify our findings and clarify the correlation between CMV and EBV infections and clinical characteristics of NMOSD.
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Anticuerpos Antivirales , Infecciones por Citomegalovirus , Infecciones por Virus de Epstein-Barr , Inmunoglobulina G , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/inmunología , Femenino , Masculino , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/sangre , Adulto , Persona de Mediana Edad , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/sangre , Anticuerpos Antivirales/sangre , Inmunoglobulina G/sangre , Herpesvirus Humano 4/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/sangre , Anciano , Adulto JovenRESUMEN
Neuromyelitis optica spectrum of disorders is a rare cause of optic neuritis in children. It is a critical diagnosis requiring urgent management, with delays carrying both life- and sight-threatening complications. Most of the published literature on this entity is in adult patients, with only a few case reports to guide management in the paediatric population. The purpose of this article is to shareour experience in the management of this condition in a child, and thus hopefully add to the limited body of knowledge currently available.
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Acuaporina 4 , Biomarcadores , Gastroenteritis , Inmunoglobulina G , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Acuaporina 4/inmunología , Gastroenteritis/complicaciones , Gastroenteritis/diagnóstico , Inmunoglobulina G/sangre , Biomarcadores/sangre , Femenino , Niño , Enfermedad Aguda , Imagen por Resonancia Magnética , Neuritis Óptica/diagnóstico , Neuritis Óptica/inmunología , Ceguera/etiología , MasculinoRESUMEN
BACKGROUND: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data. METHODS: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases. RESULTS: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder. CONCLUSIONS: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy.
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Edad de Inicio , Acuaporina 4 , Autoanticuerpos , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Acuaporina 4/inmunología , Femenino , Masculino , Autoanticuerpos/sangre , Razón de MasculinidadRESUMEN
Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease affecting the central nervous system (CNS). NMOSD pathogenesis involves systemic inflammation. However, a causal relationship between circulating cytokine levels and NMOSD remains unclear. Methods: Mendelian randomization (MR) approaches were used to investigate the potential association between genetically determined circulating 19 inflammatory cytokines and 12 chemokines levels and the risk of developing NMOSD. Results: After Bonferroni correction, the risk of aquaporin 4-antibody (AQP4-ab)-positive NMOSD was suggested to be causally associated with the circulating levels of three cytokines, including interleukin (IL)-4 [odds ratio (OR): 11.01, 95% confidence interval (CI): 1.16-104.56, P = 0.037], IL-24 (OR: 161.37; 95% CI: 2.46-10569.21, P = 0.017), and C-C motif chemokine 19 (CCL19) (OR: 6.87, 95% CI: 1.78-26.93, P = 0.006). Conclusion: These findings suggest that a genetic predisposition to higher levels of IL-4, IL-24, and CCL19 may exert a causal effect on the risk of AQP4-ab-positive NMOSD. Further studies are warranted to clarify how these cytokines affect the development of AQP4-ab-positive NMOSD.
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Citocinas , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Neuromielitis Óptica , Neuromielitis Óptica/sangre , Neuromielitis Óptica/genética , Neuromielitis Óptica/inmunología , Humanos , Citocinas/sangre , Acuaporina 4/inmunología , Acuaporina 4/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Autoanticuerpos/sangre , Autoanticuerpos/inmunologíaRESUMEN
There is debate on the role of glial fibrillary acidic protein (GFAP) as a reliable biomarker in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), and its potential to reflect disease progression. This review aimed to investigate the role of GFAP in MS and NMOSD. A systematic search of electronic databases, including PubMed, Embase, Scopus, and Web of Sciences, was conducted up to 20 December 2023 to identify studies that measured GFAP levels in people with MS (PwMS) and people with NMOSD (PwNMOSD). R software version 4.3.3. with the random-effect model was used to pool the effect size with its 95% confidence interval (CI). Of 4109 studies, 49 studies met our inclusion criteria encompassing 3491 PwMS, 849 PwNMOSD, and 1046 healthy controls (HCs). The analyses indicated that the cerebrospinal fluid level of GFAP (cGFAP) and serum level of GFAP (sGFAP) were significantly higher in PwMS than HCs (SMD = 0.7, 95% CI: 0.54 to 0.86, p < 0.001, I2 = 29%, and SMD = 0.54, 95% CI: 0.1 to 0.99, p = 0.02, I2 = 90%, respectively). The sGFAP was significantly higher in PwNMOSD than in HCs (SMD = 0.9, 95% CI: 0.73 to 1.07, p < 0.001, I2 = 10%). Among PwMS, the Expanded Disability Status Scale (EDSS) exhibited significant correlations with cGFAP (r = 0.43, 95% CI: 0.26 to 0.59, p < 0.001, I2 = 91%) and sGFAP (r = 0.36, 95% CI: 0.23 to 0.49, p < 0.001, I2 = 78%). Regarding that GFAP is increased in MS and NMOSD and has correlations with disease features, it can be a potential biomarker in MS and NMOSD and indicate the disease progression and disability in these disorders.
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Biomarcadores , Proteína Ácida Fibrilar de la Glía , Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/fisiopatología , Neuromielitis Óptica/diagnóstico , Proteína Ácida Fibrilar de la Glía/sangre , Proteína Ácida Fibrilar de la Glía/análisis , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Esclerosis Múltiple/sangre , Esclerosis Múltiple/fisiopatología , Biomarcadores/sangre , Biomarcadores/análisis , Progresión de la EnfermedadRESUMEN
Background: Optic neuritis, myelitis, and neuromyelitis optica spectrum disorder (NMOSD) have been associated with antibodies against myelin oligodendrocyte glycoprotein-immunoglobulin G (anti-MOG-IgG). Furthermore, patients with radiological and demographic features atypical for multiple sclerosis (MS) with optic neuritis and myelitis also demonstrate antibodies against aquaporin-4 and anti-MOG-IgG. However, data on the diagnosis, treatment, follow-up, and prognosis in patients with anti-MOG-IgG are limited. Aims: To evaluate the clinical, radiological, and demographic characteristics of patients with anti-MOG-IgG. Study Design: Multicenter, retrospective, observational study. Methods: Patients with blood samples demonstrating anti-MOG-IgG that had been evaluated at the Neuroimmunology laboratory at Ondokuz Mayis University's Faculty of Medicine were included in the study. Results: Of the 104 patients with anti-MOG-IgG, 56.7% were women and 43.3% were men. Approximately 2.4% of the patients were diagnosed with MS, 15.8% with acute disseminated encephalomyelitis (ADEM), 39.4% with NMOSD, 31.3% with isolated optic neuritis, and 11.1% with isolated myelitis. Approximately 53.1% of patients with spinal involvement at clinical onset demonstrated a clinical course of NMOSD. Thereafter, 8.8% of these patients demonstrated a clinical course similar to MS and ADEM, and 28.1% demonstrated a clinical course of isolated myelitis. The response to acute attack treatment was lower and the disability was higher in patients aged > 40 years than patients aged < 40 years at clinical onset. Oligoclonal band was detected in 15.5% of the patients. Conclusion: For patients with NMOSD and without anti-NMO antibodies, the diagnosis is supported by the presence of anti-MOG-IgG. Furthermore, advanced age at clinical onset, Expanded Disability Status Scale (EDSS) score at clinical onset, spinal cord involvement, and number of attacks may be negative prognostic factors in patients with anti-MOG-IgG.
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Glicoproteína Mielina-Oligodendrócito , Humanos , Masculino , Femenino , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Neuritis Óptica/sangre , Neuritis Óptica/inmunología , Neuritis Óptica/diagnóstico por imagen , Neuromielitis Óptica/sangre , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/diagnóstico por imagen , Autoanticuerpos/sangre , Autoanticuerpos/análisis , Anciano , Adolescente , Inmunoglobulina G/sangre , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunologíaRESUMEN
Neuromyelitis optica spectrum disorder is an autoimmune disease, causing severe disability due to relapses, but recent mortality data are limited. Among 396 patients seropositive for anti-aquaporin-4 antibody from 2014 to 2020 in the United Kingdom, 39 deaths occurred: 19 (48.7%) were unrelated to disease; 14 (35.9%) were severe disability- or relapse-related; and 4 (10.3%) were attributed to malignancy/infection. Mean annual mortality was 1.92% versus 0.63% in the matched population. The standardized mortality ratio was 3.04 (95% confidence interval 1.67-5.30) with 1.29% excess mortality per year in patients. Median Expanded Disability Status Scale before death was 7.0. Results highlight the importance of preventing relapses that drive disability.
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Acuaporina 4 , Autoanticuerpos , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/mortalidad , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Acuaporina 4/inmunología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Autoanticuerpos/sangre , Reino Unido/epidemiología , Anciano , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement. METHODS: Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL). RESULTS: This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL (p < 0.001) and GCIPL (p = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL (p = 0.027) and GCIPL (p = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses. DISCUSSION: DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.
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Acuaporina 4 , Neuromielitis Óptica , Tomografía de Coherencia Óptica , Humanos , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/sangre , Femenino , Masculino , Adulto , Estudios Transversales , Persona de Mediana Edad , Acuaporina 4/inmunología , Estudios Retrospectivos , Autoanticuerpos/sangre , Retina/diagnóstico por imagen , Retina/patología , Retina/inmunologíaRESUMEN
BACKGROUND: To date, most existing models for predicting neuromyelitis optica spectrum disorder (NMOSD) are based primarily on clinical characteristics. Blood-based NMOSD severity and prognostic predictive immune- and inflammation-related biomarkers are needed. We aimed to investigate the associations between plasma inflammatory biomarkers and relapse and attack severity in NMOSD. METHODS: This two-step, single-center prospective cohort study included discovery and validation cohorts. We quantified 92 plasma inflammatory proteins by using Olink's proximity extension assay and identified differentially expressed proteins in the relapse group (relapse within 1 year of follow-up) and severe attack group. To define a new molecular prognostic model, we calculated the risk score of each patient based on the key protein signatures and validated the results in the validation cohort. RESULTS: The relapse prediction model, including FGF-23, DNER, GDNF, and SLAMF1, predicted the 1-year relapse risk. The severe attack prediction model, including PD-L1 and MCP-2, predicted the severe clinical attack risk. Both the relapse and severe attack prediction models demonstrated good discriminative ability and high accuracy in the validation cohort. CONCLUSIONS: Our discovered biomarker signature and prediction models may complement current clinical risk stratification approaches. These inflammatory biomarkers could contribute to the discovery of therapeutic interventions and prevent NMOSD progression.
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Biomarcadores , Neuromielitis Óptica , Recurrencia , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/diagnóstico , Femenino , Biomarcadores/sangre , Masculino , Adulto , Estudios Prospectivos , Persona de Mediana Edad , Estudios de Cohortes , Índice de Severidad de la Enfermedad , Inflamación/sangre , Inflamación/diagnóstico , PronósticoRESUMEN
BACKGROUND AND OBJECTIVES: AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons. METHODS: In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients. RESULTS: In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD. DISCUSSION: Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.
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Linfocitos B , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica , Proteómica , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Femenino , Persona de Mediana Edad , Masculino , Adulto , Estudios Retrospectivos , Linfocitos B/inmunología , Acuaporina 4/inmunología , Autoanticuerpos/sangre , AncianoRESUMEN
ABSTRACT: This is a case description of a patient with bipolar disorder undergoing lithium therapy who received plasmapheresis for neuromyelitis optica spectrum disorder. Plasmapheresis resulted in lower and subtherapeutic serum lithium levels. Using therapeutic drug monitoring, a dose escalation of 80% was necessary to maintain therapeutic serum lithium levels. This underscores the importance of individualized therapy through therapeutic drug monitoring.
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Trastorno Bipolar , Monitoreo de Drogas , Neuromielitis Óptica , Plasmaféresis , Humanos , Antimaníacos/uso terapéutico , Antimaníacos/sangre , Trastorno Bipolar/terapia , Trastorno Bipolar/sangre , Monitoreo de Drogas/métodos , Unidades de Cuidados Intensivos , Litio/sangre , Litio/uso terapéutico , Neuromielitis Óptica/terapia , Neuromielitis Óptica/sangre , Plasmaféresis/métodosRESUMEN
BACKGROUND AND OBJECTIVES: Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC). METHODS: We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission. RESULTS: Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p < 0.001) and compared to all other groups (p < 0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups. DISCUSSION: Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities.
Asunto(s)
Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica , Humanos , Niño , Glicoproteína Mielina-Oligodendrócito/inmunología , Femenino , Masculino , Adolescente , Neuromielitis Óptica/sangre , Neuromielitis Óptica/inmunología , Autoanticuerpos/sangre , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Preescolar , Acuaporina 4/inmunología , Acuaporina 4/sangre , Proteína C-Reactiva/análisis , Encefalomielitis Aguda Diseminada/sangre , Encefalomielitis Aguda Diseminada/inmunología , Encefalomielitis Aguda Diseminada/diagnósticoRESUMEN
Aquaporin 4-immunoglobulin G (AQP4-IgG) specifically targets aquaporin 4 in approximately 80% of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases. NMOSD is presently categorized as anti-AQP4-antibody (Ab) positive or negative based on AQP4-Ab presence. The association between antibody titers and patient prognosis remains unclear. Therefore, the present study explores the correlation between severe attacks and serum AQP4 Ab titers in patients with neuromyelitis optica spectrum disorder. Data were gathered retrospectively from 546 patients with NMOSD between September 1, 2009, and December 1, 2021. Patients were categorized based on their AQP4-Ab titers: AQP4 titer ≥ 1:320 were classified as the high-titer group, AQP4 (+ +), and AQP4 titer of ≤ 1:100 were classified as the low-titer group, AQP4 ( +). Clinical characteristics and prognoses between the two groups were compared. Patients with AQP4 ( +) exhibited few severe optic neuritis (SON) attacks (false discovery rate [FDR] corrected p < 0.001), a reduced percentage experiencing SON attacks, and a lower incidence of visual disability than patients with AQP4 (+ +). Patients with AQP4 (+ +) and AQP4 ( +) NMOSD exhibited significant difference in annual recurrence rate (ARR) (FDR-corrected p < 0.001). The lower AQP4 Ab titer group demonstrated reduced susceptibility to severe relapse with conventional immunosuppressive agents and rituximab (RTX) than the higher titer group. No significant differences in sex, age at onset, coexisting connective tissue diseases, motor disability, or mortality rates were observed between the two groups. Higher AQP4 Ab titers correlated with increased disease severity and visual disability in patients with NMOSD.
Asunto(s)
Acuaporina 4 , Autoanticuerpos , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/inmunología , Acuaporina 4/inmunología , Acuaporina 4/sangre , Femenino , Masculino , Adulto , Persona de Mediana Edad , Autoanticuerpos/sangre , Estudios Retrospectivos , Adulto Joven , Índice de Severidad de la Enfermedad , Anciano , AdolescenteRESUMEN
BACKGROUND: Sphingolipids are signaling molecules and structural components of the axolemma and myelin sheath. Plasma sphingolipid levels may reflect disease status of neuromyelitis optica spectrum disorder (NMOSD). We aimed to examine plasma sphingolipids as disease severity biomarkers for NMOSD and compare their characteristics with those of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). METHODS: We measured plasma sphingolipids, sNfL, and sGFAP levels in NMOSD cases with anti-aquaporin-4-antibody. An unbiased approach, partial least square discriminant analysis (PLS-DA), was utilized to determine whether sphingolipid profiles differ according to the disease state of NMOSD (presence, moderate-to-severe disability [Expanded Disease Severity Scale, (EDSS) > 3.0], and relapses). RESULTS: We investigated 81 patients and 10 controls. PLS-DA models utilizing sphingolipids successfully differentiated patients with EDSS > 3.0, but failed to identify the presence of disease and relapses. Ceramide-C14-a significant contributor to differentiating EDSS > 3.0-positively correlated with EDSS, while its levels were independent of age and the presence of relapses. This characteristic was unique from those of sNfL and sGFAP, which were affected by age and relapses as well as EDSS. CONCLUSION: Plasma sphingolipids may be useful NMOSD biomarkers for disability with distinct characteristics compared to sNfL and sGFAP.
Asunto(s)
Biomarcadores , Proteínas de Neurofilamentos , Neuromielitis Óptica , Esfingolípidos , Humanos , Neuromielitis Óptica/sangre , Neuromielitis Óptica/diagnóstico , Biomarcadores/sangre , Femenino , Esfingolípidos/sangre , Adulto , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Índice de Severidad de la Enfermedad , Acuaporina 4/sangre , Acuaporina 4/inmunologíaRESUMEN
BACKGROUND: Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear. METHODS: Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels. RESULTS: PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females. CONCLUSION: Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.