RESUMO
Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab's clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.
Assuntos
Aquaporina 4 , Centro Germinativo , Fatores Imunológicos , Neuromielite Óptica , Rituximab , Aquaporina 4/efeitos dos fármacos , Aquaporina 4/metabolismo , Autoanticorpos , Centro Germinativo/patologia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Linfonodos/metabolismo , Neuromielite Óptica/tratamento farmacológico , Rituximab/farmacologia , Rituximab/uso terapêuticoRESUMO
OBJECTIVE: CHAMPION-NMOSD (NCT04201262) is a phase 3, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half-life, enabling an extended dosing interval (8 vs 2 weeks). METHODS: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION-NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight-based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on-trial relapse. RESULTS: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient-years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient-years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%-100.0%, p < 0.0001). Median (range) study period follow-up time was 73.5 (11.0-117.7) weeks for ravulizumab. Most treatment-emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. INTERPRETATION: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053-1068.
Assuntos
Neuromielite Óptica , Adulto , Humanos , Neuromielite Óptica/tratamento farmacológico , Aquaporina 4 , Inativadores do Complemento/uso terapêutico , RecidivaRESUMO
BACKGROUND: Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4Ab+NMOSD) is an inflammatory disorder of the central nervous system with relapse-dependent progression. Few studies have reported the effects of prednisolone and biologics on disability progression in AQP4Ab+NMOSD, although it is established that they prevent clinical relapses. This retrospective study investigated long-term disability progression and the effects of therapeutic interventions on disability progression in AQP4Ab+NMOSD. METHODS: This study included a total of 101 patients with AQP4Ab+NMOSD. Disease progression was investigated in the following two cohorts: (1) duration from disease onset to Expanded Disability Status Scale (EDSS) 3.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 3.0 and (2) duration from disease onset to EDSS 6.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 6.0. RESULTS: Approximately half of the untreated patients reached EDSS 3.0 and 6.0 at 10 and 46 months after disease onset, respectively. In addition, 88% and 71% of the untreated patients reached EDSS 3.0 and 6.0 within 10 years after disease onset, respectively. Disability progression, clinical relapses and attack severity were suppressed by prednisolone and biologics. CONCLUSIONS: AQP4Ab+NMOSD is a severely disabling disease. Treatment interventions using prednisolone and biologics are useful in suppressing disability progression in AQP4Ab+NMOSD.
Assuntos
Aquaporina 4 , Autoanticorpos , Progressão da Doença , Neuromielite Óptica , Prednisolona , Humanos , Neuromielite Óptica/imunologia , Neuromielite Óptica/tratamento farmacológico , Aquaporina 4/imunologia , Feminino , Masculino , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Autoanticorpos/sangue , Avaliação da Deficiência , Adulto Jovem , Idoso , Produtos Biológicos/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: The association between onset age and sex with relapse risk in neuromyelitis optica spectrum disorder (NMOSD) remains inconclusive. We aimed to describe the clinical features of patients with NMOSD in different age groups and sexes and to analyse relapse characteristics pre- and post-immunosuppressive therapy (IST). METHODS: Patients with NMOSD were retrospectively reviewed from our clinical centre's database. Demographic and clinical data, attack presentation, and disease course pre- and post-IST were investigated. We also analysed the effect of onset age on the annualized relapse rate and relapse risk according to sex and IST status. Interactions on the additive scale between onset age and sex were analysed. A restricted cubic spline was used to analyse potential nonlinear correlations. Longitudinal changes in the Expanded Disability Status Scale score across NMOSD attacks were analysed using linear mixed-effect models. RESULTS: In total, 533 patients experienced 1394 attacks pre-IST and 753 relapses post-IST. Older age at onset was correlated with more myelitis attacks but fewer optic neuritis attacks, with no sex-related differences in attack presentation. Pre-IST, relapse risk increased with age at onset in women, while a U-shaped correlation between onset age and relapse risk was found in men. Post-IST, an inverted U-shaped association between the predicted relapse risk and onset age was observed in women. Conversely, a negative correlation between the predicted relapse risk and onset age was found in men. Overall, a higher ratio of myelitis attacks was found post-IST. CONCLUSIONS: Patients of different onset ages and sexes had different relapse patterns before and after IST.
Assuntos
Mielite , Neuromielite Óptica , Masculino , Humanos , Feminino , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/epidemiologia , Estudos Retrospectivos , Aquaporina 4 , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , RecidivaRESUMO
BACKGROUND: Pure red cell aplasia (PRCA) in neuromyelitis optica spectrum disorder (NMOSD) has not been reported before. This study presents a patient with NMOSD who developed PRCA. CASE PRESENTATION: A 54-year-old female was admitted in January 2023 for dysuria and progressive numbness and weakness of lower limbs. She had difficulty standing and walking in a straight line. Both lower limbs were positive for the Babinski and Chaddock signs. MRI showed abnormal signals in the spinal cord. Aquaporin-4-IgG (AQP-4-IgG) was positive (1:320), and NMOSD was confirmed. Intravenous immunoglobulin and methylprednisolone were given, and the symptoms improved. She received maintenance treatment with methylprednisolone tablets, and the dosage was gradually reduced. She was readmitted for fatigue, palpitations, and shortness of breath in May 2023. Bone marrow aspiration and biopsy showed elevated erythroid precursors and erythroid hypoplasia, with normal megakaryocytes and myeloid precursors. Chest CT showed no mediastinal lymph node enlargement or thymoma. PRCA secondary to NMOSD was diagnosed. Recombinant human erythropoietin was given. Her condition improved after 1.5 months, as indicated by blood cell count and imaging. CONCLUSIONS: This case suggests that PRCA can be secondary to NMOSD. A comprehensive immune function and bone marrow evaluation might be necessary if abnormal blood cells are found while managing NMOSD.
Assuntos
Neuromielite Óptica , Aplasia Pura de Série Vermelha , Humanos , Feminino , Neuromielite Óptica/complicações , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/diagnóstico por imagem , Pessoa de Meia-Idade , Aplasia Pura de Série Vermelha/complicações , Aplasia Pura de Série Vermelha/diagnóstico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Aquaporina 4/imunologiaRESUMO
Neuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory disorders of central nervous system characterized by immune-mediated demyelination and axonal damage, predominantly affecting spinal cord and optic nerves. This case report describes a 47-year-old woman with an aggressive form of seropositive NMOSD who had previously been treated with corticosteroids, plasma exchange, and cyclophosphamide. She experienced a life-threatening relapse that did not respond to conventional treatment, but ultimately showed a positive response to eculizumab. Furthermore, we describe the role of sNfL.
Assuntos
Neuromielite Óptica , Feminino , Humanos , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Medula Espinal , Recidiva , Doença Crônica , Aquaporina 4RESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)-derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO-IgG-induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO-IgG-treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.
Assuntos
Neuromielite Óptica , Remielinização , Animais , Camundongos , Remielinização/fisiologia , Neuromielite Óptica/tratamento farmacológico , Edaravone/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Diferenciação Celular/fisiologia , Transdução de Sinais , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Imunoglobulina GRESUMO
OBJECTIVE: Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb). METHODS: Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa-mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa-signaling in macrophages. RESULTS: In both NMO rats and an NMO-autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa-mAb treatment. RGMa-mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin-expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa-mAb treatment effectively ameliorated the severity of neuropathic pain. INTERPRETATION: RGMa signaling in infiltrated macrophages is a critical driver of neutrophil-related astrocytopathy in NMO lesions, and RGMa-mAb may provide an efficient therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532-547.
Assuntos
Neuralgia , Neuromielite Óptica , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Aquaporina 4 , Proteínas Ligadas por GPI , Humanos , Imunoglobulina G , Interleucina-8 , Macrófagos , Proteínas de Membrana , Proteínas do Tecido Nervoso , Neuromielite Óptica/tratamento farmacológico , Neutrófilos , RatosRESUMO
BACKGROUND: Rituximab (RTX) efficacy in patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorders (MOGADs) is still poorly understood, though it appears to be lower than in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSDs). The aim of this systematic review and meta-analysis is to assess the efficacy and safety profile of RTX in patients with MOGAD and to compare RTX efficacy between MOGAD and AQP4-IgG+NMOSD. METHODS: We searched original English-language articles published between 2012 and 2021 in MEDLINE, Cochrane, Central Register of Controlled Trials and clinicaltrials.gov, reporting data on RTX efficacy in patients with MOGAD. The main outcome measures were annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score mean differences (MDs) after RTX. The meta-analysis was performed with a random effects model. Covariates associated with the outcome measures were analysed with a linear meta-regression. RESULTS: The systematic review included 315 patients (138 women, mean onset age 26.8 years) from 32 studies. Nineteen studies (282 patients) were included in the meta-analysis. After RTX, a significant decrease of ARR was found (MD: -0.92, 95% CI -1.24 to -0.60, p<0.001), markedly different from the AQP4-IgG+NMOSD (MD: -1.73 vs MOGAD -0.92, subgroup difference testing: Q=9.09, p=0.002). However, when controlling for the mean ARR pre-RTX, this difference was not significant. After RTX, the EDSS score decreased significantly (MD: -0.84, 95% CI -1.41 to -0.26, p=0.004). The frequency of RTX-related adverse events was 18.8% (36/192) and overall RTX-related mortality 0.5% (1/192). CONCLUSIONS: RTX showed effective in MOGAD, although to a lesser extent than in AQP4-IgG+NMOSD, while the safety profile warrants some caution in its prescription. Randomised-controlled trials are needed to confirm these findings and provide robust evidence to improve treatment strategies in patients with MOGAD. PROSPERO REGISTRATION NUMBER: CRD42020175439.
Assuntos
Neuromielite Óptica , Feminino , Humanos , Neuromielite Óptica/tratamento farmacológico , Rituximab/efeitos adversos , Glicoproteína Mielina-Oligodendrócito , Aquaporina 4 , Recidiva , Imunoglobulina G , AutoanticorposRESUMO
OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.
Assuntos
Neuromielite Óptica , Humanos , Neuromielite Óptica/sangue , Neuromielite Óptica/tratamento farmacológico , Biomarcadores , Anticorpos Monoclonais Humanizados/uso terapêutico , Método Duplo-CegoRESUMO
MECP2 and its product methyl-CpG binding protein 2 (MeCP2) are associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), which are inflammatory, autoimmune, and demyelinating disorders of the central nervous system (CNS). However, the mechanisms and pathways regulated by MeCP2 in immune activation in favor of MS and NMOSD are not fully understood. We summarize findings that use the binding properties of MeCP2 to identify its targets, particularly the genes recognized by MeCP2 and associated with several neurological disorders. MeCP2 regulates gene expression in neurons, immune cells and during development by modulating various mechanisms and pathways. Dysregulation of the MeCP2 signaling pathway has been associated with several disorders, including neurological and autoimmune diseases. A thorough understanding of the molecular mechanisms underlying MeCP2 function can provide new therapeutic strategies for these conditions. The nervous system is the primary system affected in MeCP2-associated disorders, and other systems may also contribute to MeCP2 action through its target genes. MeCP2 signaling pathways provide promise as potential therapeutic targets in progressive MS and NMOSD. MeCP2 not only increases susceptibility and induces anti-inflammatory responses in immune sites but also leads to a chronic increase in pro-inflammatory cytokines gene expression (IFN-γ, TNF-α, and IL-1ß) and downregulates the genes involved in immune regulation (IL-10, FoxP3, and CX3CR1). MeCP2 may modulate similar mechanisms in different pathologies and suggest that treatments for MS and NMOSD disorders may be effective in treating related disorders. MeCP2 regulates gene expression in MS and NMOSD. However, dysregulation of the MeCP2 signaling pathway is implicated in these disorders. MeCP2 plays a role as a therapeutic target for MS and NMOSD and provides pathways and mechanisms that are modulated by MeCP2 in the regulation of gene expression.
Assuntos
Doenças Autoimunes , Esclerose Múltipla , Neuromielite Óptica , Humanos , Esclerose Múltipla/complicações , Neuromielite Óptica/genética , Neuromielite Óptica/tratamento farmacológico , Proteína 2 de Ligação a Metil-CpG/genética , Doenças Autoimunes/complicações , CitocinasRESUMO
BACKGROUND: Recently, satralizumab (interleukin-6 receptor blocker) was approved for seropositive neuromyelitis optica spectrum disorder (NMOSD) patients. In SAkuraSky trial, mild neutropenia was reported in 15% of patients under satralizumab. Most neutropenias were transient; grade 3-4 was not related to serious infections. So far, no severe neutropenia (<100 cell/mm3) has been reported worldwide. METHODS: We present an aquaporin-4-antibody-positive NMOSD patient who developed severe febrile neutropenia 2 weeks after adding satralizumab to her azathioprine treatment. CONCLUSION: Analytic control for satralizumab is recommended at 4 weeks. However, we recommend this control at week 2, in order to closely monitor neutrophil count and prevent further complications.
Assuntos
Neutropenia Febril , Neuromielite Óptica , Humanos , Feminino , Neuromielite Óptica/complicações , Neuromielite Óptica/tratamento farmacológico , Aquaporina 4 , Anticorpos Monoclonais Humanizados , Autoanticorpos , Neutropenia Febril/induzido quimicamenteRESUMO
BACKGROUND: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum. METHODS: Adults (n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed. RESULTS: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks. CONCLUSION: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.
Assuntos
Anticorpos Monoclonais Humanizados , Neuromielite Óptica , Neuromielite Óptica/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , Biomarcadores/sangue , Proteína Glial Fibrilar Ácida/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos RetrospectivosRESUMO
ABP 959 is being developed as a biosimilar to Soliris® (eculizumab) reference product (RP), which was approved under orphan designation for a group of rare diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). Development of biosimilars for therapeutics approved for rare disease indications must provide scientific rationale based on the totality of evidence (TOE). To support the TOE and the scientific justification for extrapolation to all approved indications for eculizumab RP, including but not limited to aHUS and NMOSD, we utilized simulated ex-vivo pharmacodynamic (PD) assessments to compare the complement component 5 (C5) inhibitory activity of ABP 959 and the RP. Hemolysis activity of CH50 and AH50, and Wieslab CP, AP, and LP endpoints represent the three complement activation pathways (classical, alternative, and lectin), all of which share the terminal pathway and require C5 for activity. These endpoints were evaluated in normal serum, simulated aHUS serum, and simulated NMOSD serum to provide a robust comparison. The results support the conclusion that ABP 959 and eculizumab RP exhibit highly similar inhibition of C5 function regardless of the type of serum used. This work presents a full comparison of the effect of C5 inhibition across five complement functional assays. Using this approach to confirm functional similarity of ABP 959 with eculizumab RP contributes to the TOE for biosimilarity and provides support for extrapolation based on inhibition of C5 function to other rare disease indications approved for eculizumab RP.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Medicamentos Biossimilares , Neuromielite Óptica , Humanos , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Neuromielite Óptica/tratamento farmacológico , Doenças RarasRESUMO
BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin-4 antibodies (AQP4-IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed. METHODS: In an open-label, dose-escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end-points were safety and tolerability. Secondary end-points included pharmacodynamics and efficacy, with key efficacy assessment at week 4. RESULTS: In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add-on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4-IgG was undetectable in six of seven subjects whose baseline AQP4-IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0). CONCLUSIONS: Batoclimab add-on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.
Assuntos
Mielite , Neuromielite Óptica , Neurite Óptica , Recém-Nascido , Humanos , Neuromielite Óptica/tratamento farmacológico , Aquaporina 4 , Autoanticorpos , Neurite Óptica/tratamento farmacológico , Metilprednisolona/uso terapêutico , Imunoglobulina G/uso terapêutico , Anticorpos Monoclonais/uso terapêuticoRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD. METHODS: A total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients. RESULTS: Purine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p < 0.05). Additionally, the richness and microbial diversity of gut microbiota was found to be similar between EG and LEG patients. However, LEG patients had increased presence of Clostridium and Synergistes but decreased abundance of the Coprococcus genus. CONCLUSIONS: The PSP metabolites and composition of the gut microbiota were changed between patients with or without optimal clinical response after MMF treatment. This may help us to understand the pharmacodynamics of MMF in NMOSD.
Assuntos
Microbioma Gastrointestinal , Neuromielite Óptica , Humanos , Ácido Micofenólico/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , RNA Ribossômico 16S , Resultado do Tratamento , Azatioprina/uso terapêutico , RecidivaRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory disorders of the CNS in which patients have severe relapses of optic neuritis and myelitis. Aquaporin-4 antibody (AQP4-IgG) positive NMOSD has not been reported in members of the same family in Sub Saharan Africa. We report the uncommon scenario in which both a Ugandan HIV positive woman and her HIV negative daughter were diagnosed with AQP4-IgG positive NMOSD. We discuss pathogenic mechanisms that may underlie familial presentation of AQP4-IgG positive NMOSD. CASE PRESENTATION: Case 1, a 54-year-old female teacher with a 20-year history of HIV infection and virally suppressed on Tenofovir, Lamivudine and Dolutegravir HAART regimen, presented with 8 months of progressive quadriparesis and urinary incontinence with a T6 sensory level. She had gadolinium enhancing longitudinally extensive transverse myelitis on MRI and was AQP4-IgG positive on serum studies. She received IV Methylprednisone 1 g daily for 3 days as a pulse and was continued on tapering doses of oral Prednisone with maintenance doses of Azathioprine. She showed slow improvements in limb motor function. Her daughter, case 2, is a 35-year-old HIV negative nutritionist, independently ambulant, with no known comorbidities or precedent autoimmune disease. She presented 1 year before her mother's AQP4-IgG positive NMOSD diagnosis with 7 months history of bilateral visual loss of rapid onset, with gadolinium-enhancing optic nerves on Brain and orbit MRI, in keeping with bilateral optic neuritis. She was AQP4-IgG positive on serum studies. She stabilized on tapered doses of oral Prednisone and continues daily oral Azathioprine with moderate improvement in her vision and no further relapses as yet. CONCLUSIONS: We add to existing literature and hypothesize that NMOSD appears to show a complex genetic background. To our knowledge, this is the first report in Sub-Saharan Africa, of familial AQP4-IgG positive NMOSD presenting with clinical heterogeneity between first degree relatives. A better understanding of the pathogenic mechanisms involved, including genome wide studies for particular risk loci for familial NMOSD, will be pivotal for future preventative and therapeutic strategies.
Assuntos
Doenças Autoimunes , Infecções por HIV , Mielite Transversa , Neuromielite Óptica , Neurite Óptica , Feminino , Humanos , Azatioprina , Gadolínio , Imunoglobulina G , Recidiva Local de Neoplasia , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Prednisona , Adulto , Pessoa de Meia-IdadeRESUMO
PURPOSE OF REVIEW: Neuromyelitis optica spectrum disorder (NMOSD) is a rare but highly disabling disease of the central nervous system. Unlike multiple sclerosis, disability in NMOSD occurs secondary to relapses that, not uncommonly, lead to blindness, paralysis, and death. Recently, newer, targeted immunotherapies have been trialed and are now in the treatment arsenal. We have endeavoured to evaluate the current state of NMOSD therapeutics. RECENT FINDINGS: This review provides a pragmatic evaluation of recent clinical trials and post-marketing data for rituximab, inebilizumab, satralizumab, eculizumab, and ravalizumab, contrasted to older agents. We also review contemporary issues such as treatment in the context of SARS-CoV2 infection and pregnancy. There has been a dramatic shift in NMOSD morbidity and mortality with earlier and improved disease recognition, diagnostic accuracy, and the advent of more effective, targeted therapies. Choosing a maintenance therapy remains nuanced depending on patient factors and accessibility. With over 100 putative agents in trials, disease-free survival is now a realistic goal for NMOSD patients.
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COVID-19 , Neuromielite Óptica , Humanos , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/tratamento farmacológico , RNA Viral/uso terapêutico , COVID-19/complicações , SARS-CoV-2 , Imunoterapia , Aquaporina 4RESUMO
INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a group of antibody-mediated inflammatory demyelinating central nervous system diseases. T lymphocytes participate in NMOSD pathogenesis, with regulatory T cells (Treg) being the core in maintaining immune homeostasis. Studies have revealed that different Treg subsets play different roles in autoimmune diseases. The distribution of LAP+ or GARP+ Treg subsets in NMOSD may help us deeply understand their immune mechanism. METHODS: This study reviewed 22 NMOSD patients and 20 normal controls. Flow cytometric analysis was utilized to detect subsets of Treg cells expressing Foxp3, Helios, LAP, or GARP in peripheral blood. ELISA was used to detect plasma TGF-ß1 and IL-10. In addition, changes in the proportion of Treg cell subsets before and after glucocorticoid treatment in 10 patients were analyzed. RESULTS: Compared with healthy controls, LAP and GARP expressions were significantly downregulated in the peripheral blood of NMOSD patients. TGF-ß1 expression in NMOSD patients was lower and was positively correlated with the ratio of CD4+GARP+ Treg cells. After treatment with glucocorticoid, LAP and GARP expressions in the peripheral blood of NMOSD patients were upregulated. CONCLUSIONS: The proportion of Treg cells expressing LAP and GARP is downregulated, implying that Treg cells with the best inhibitory function are insufficient to maintain autoimmune homeostasis in NMOSD patients. Upregulation of Treg cells expressing LAP and GARP in NMOSD patients may be one of the mechanisms of glucocorticoid treatment.
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Proteínas de Membrana , Neuromielite Óptica , Linfócitos T Reguladores , Fator de Crescimento Transformador beta1 , Humanos , Glucocorticoides/uso terapêutico , Proteínas de Membrana/imunologia , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/imunologiaRESUMO
INTRODUCTION: Vaccination against the coronavirus disease 2019 (COVID-19) is recommended for patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, vaccine safety in these patients taking immunotherapeutic agents is unclear as they were not included in the vaccine trials. OBJECTIVES: To evaluate the safety of COVID-19 vaccines in patients with MS, NMOSD, and MOGAD. METHODS: We reviewed the medical records of MS, NMOSD, and MOGAD patients at the Keimyung University Dongsan Hospital. Information regarding vaccination schedules and adverse events was collected. RESULTS: A total of 56 patients (19, 22, and 15 patients with MS, NMOSD, and MOGAD, respectively) with a median age of 48.18 ± 15.72 years (range, 16-81 years) were included. Of them, 42 (75.0%) were female. In total, 76.8% (43/56) of all patients were vaccinated, and the vaccination rate was the highest for NMOSD patients (81.8%) and the lowest for MS patients (68.4%). All vaccinated patients were administered mRNA vaccines at least once in single or multiple vaccination doses. Only 3 of 43 (7.0%) vaccinated patients experienced clinical relapse following vaccination. Facial sensory changes with a brainstem lesion developed in an MS patient taking dimethyl fumarate, while myelitis occurred in a MOGAD patient receiving azathioprine maintenance therapy. The first episode of optic neuritis occurred in a patient who was later diagnosed with MOGAD. CONCLUSIONS: Our study demonstrated a favorable safety profile with no serious adverse events associated with COVID-19 vaccines in patients with MS, NMOSD, and MOGAD.