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BACKGROUND: Depression is more common in people with multiple sclerosis (MS) compared to the general population. While many interventions are available for treating depressive symptoms in people with MS, it is unclear how different intervention modalities compare. This systematic review aimed to compare the reported effectiveness, safety, and tolerability of interventions for treating depressive symptoms in people with MS. METHODS: We systematically searched 7 databases for randomised controlled trials (RCTs) of pharmaceutical, psychological, physical, and electromagnetic stimulation interventions which aimed to reduce depressive symptoms amongst adults with MS. Screening, data extraction and risk of bias assessment were completed by at least two independent researchers. We planned to synthesise the data using network meta-analysis, however the high risk of bias of the included trials resulted in synthesis without meta-analysis. RESULTS: Of 1,949 citations, 31 trials (21 psychological, seven physical activity, two pharmaceutical, and one combination) were included, comprising 2,289 participants. Of the 31 eligible trials 24 were at high and six at moderate risk of bias, which precluded meta-analysis. Twenty-six trials reported on efficacy and only 16/31 reported safety and/or tolerability, using inconsistent methods. CONCLUSIONS: The current strength of the evidence for treating depressive symptoms in MS is low, therefore, we are not able to summarise or make comparisons between the treatment modalities. There is an urgent need for high-quality and diverse trials investigating treatment options for depression in people with MS. This can only be achieved if the conduct and reporting of RCTs are improved.
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Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is diagnosed by serum MOG-immunoglobulin G (MOG-IgG) in association with typical demyelination. 111/1127 patients with paired CSF/serum samples were seropositive for MOG-IgG. Only 7/1016 (0.7%) seronegative patients had CSF-restricted MOG-IgG. While 3/7 patients had longitudinally extensive transverse myelitis, four had a confirmed alternate diagnosis (three multiple sclerosis, one CNS vasculitis). In a national referral setting, CSF-restricted MOG-IgG had a low sensitivity (2.63%, 95%CI 0.55-7.50%) and low positive predictive value (1.97%, 95%CI 0.45-8.13%). We strongly recommend serum as the preferred diagnostic biospecimen, and urge caution in the interpretation of CSF-restricted MOG-IgG in patients without clinico-radiological features consistent with MOGAD.
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BACKGROUND: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. METHODS: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. RESULTS: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]. CONCLUSIONS: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.
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BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS), autoimmune inflammatory diseases of the central nervous system, affect the optic nerve and brain. A lumbar puncture to obtain biomarkers is highly invasive. Serum biomarkers and optical coherence tomography angiography (OCTA) are more accessible and less expensive than magnetic resonance imaging and provide reliable, reproducible measures of neuroaxonal damage. This study investigated the association between serum neurofilament light chain (sNfL), serum glial fibrillary acidic protein (sGFAP), and OCTA metrics. Serum sNfL and sGFAP levels, OCTA values, and clinical characteristics were compared among 91 patients with NMOSD, 81 patients with MS, and 34 healthy controls (HCs) at baseline and 1-year follow-up. RESULTS: sNfL and sGFAP levels were higher while the sGFAP/sNfL quotients were significantly lower in NMOSD and MS patients than those in HCs. At baseline, the average thicknesses of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGC-IPL) were significantly smaller in NMOSD and MS patients than those in HCs (pRNFL: MS 92.0 [80.2; 101] µm, NMOSD 80.0 [59.0; 95.8] µm, vs HC 99.0 [92.0; 104] µm, p < 0.001; mGC-IPL: MS 74.5 [64.2; 81.0] µm, NMOSD 68.0 [56.0; 81.0] µm, vs HC 83.5 [78.0; 88.0] µm, p < 0.001). The vessel density (VD) and perfusion density (PD) were increased in MS patients without optic neuritis compared to HCs (VD: MS 16.7 [15.6; 17.9] HC 15.3 [13.4; 16.9], p = 0.008; PD: MS 0.41 [0.38; 0.43], HC 0.37 [0.32; 0.41], p = 0.017). In NMOSD patients without optic neuritis, sNfL was significantly associated with PD at baseline (r = 0.329, q = 0.041). The baseline and follow-up values of the sNfL level and average pRNFL and mGC-IPL thicknesses in MS patients showed significant differences. NMOSD patients showed significant differences between baseline and follow-up sNfL and sGFAP levels but not OCTA metrics. CONCLUSION: Changes in retinal microvasculature might occur earlier than those in retinal structure and may therefore serve as a promising diagnostic marker for early NMOSD. The combination of serum markers and OCTA metrics could be used to evaluate and differentiate between MS and NMOSD.
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Biomarcadores , Proteína Glial Fibrilar Ácida , Esclerose Múltipla , Proteínas de Neurofilamentos , Neuromielite Óptica , Tomografia de Coerência Óptica , Humanos , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/sangue , Feminino , Masculino , Adulto , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Biomarcadores/sangue , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Proteína Glial Fibrilar Ácida/sangueRESUMO
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.
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Autoanticorpos , Imunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Recidiva , Humanos , Glicoproteína Mielina-Oligodendrócito/imunologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Autoanticorpos/sangue , Autoanticorpos/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Epitopos/imunologia , Biomarcadores/sangue , Neurite Óptica/imunologia , Neurite Óptica/sangueRESUMO
Fingolimod is a multiple sclerosis disease-modifying therapy which sequestrates lymphocytes in the lymph nodes, thereby reducing peripheral blood lymphocytes. Cryptococcal infection is an important adverse effect which should be recognised. We report a case of cutaneous and central nervous system infection who presented with isolated cutaneous symptoms in the absence of neurological or systemic manifestations.
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BACKGROUND: Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes in the cerebrospinal fluid (CSF). This study aimed to investigate the possible association between routine CSF findings, especially CSF chloride, at the time of the first lumbar puncture and the relapse risk and disability progression of relapsing-remitting MS (RRMS). METHODS: This retrospective study included 77 patients with RRMS at the MS Center of our institution from January 2012 to December 2020. The Anderson and Gill (AG) model and Spearman correlation analysis were used to explore predictors of relapse and disability during follow-up. RESULTS: In the multivariate AG model, patients with elevated CSF chloride level (hazard ratio [HR], 1.1; 95% confidence interval [CI]: 1.06-1.22; p = 0.001) had a high risk of MS relapse. Using median values of CSF chloride (123.2 mmol/L) as a cut-off, patients with CSF chloride level ≥ 123.2 mmol/L had a 120% increased relapse risk compared with those with CSF chloride level < 123.2 mmol/L (HR = 2.20; 95% CI: 1.19-4.05; p = 0.012). CONCLUSIONS: Elevated CSF chloride levels might be a biologically unfavorable predictive factor for disease relapse in RRMS.
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Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab. Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Results: Among 66â¯840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.
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Cloridrato de Fingolimode , Esclerose Múltipla Recidivante-Remitente , Humanos , Feminino , Adulto , Cloridrato de Fingolimode/uso terapêutico , Natalizumab/efeitos adversos , Fumarato de Dimetilo/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Imunossupressores/efeitos adversos , Fatores Imunológicos/efeitos adversos , RecidivaRESUMO
BACKGROUND: In 2019 and 2020, over 17 million hectares of Australia burned, and half of the Australian population was affected by toxic bushfire smoke. Then in 2020, restrictions designed to curtail the spread of COVID-19 resulted in significant changes to healthcare access. There is no Australian emergency management standard for persons with disabilities, including those with multiple sclerosis (MS). Persons with MS often require multidisciplinary and complex care, with continuity of treatment essential to prevent disease progression. OBJECTIVE: To identify limitations in access to healthcare from the perspective of persons with MS as well as MS care providers during recent crises and make recommendations for policy to improve MS healthcare access during a crisis. METHOD: In mid-2020, we undertook online surveys and interviews with persons with MS, their carers, healthcare professionals and staff of MS service providers (i.e., care providers). We used descriptive analysis for quantitative, and a general inductive approach for qualitative data. RESULTS: One-hundred and thirteen persons with MS and a total of 63 MS care providers, who were close carers, healthcare professionals and service providers provided survey responses. For participants with MS, limited access to general practitioners and medical tests were of the most significant concern during the bushfires and the pandemic. In contrast, during the pandemic accessing physiotherapy was another top concern. Twenty-nine people participated in in-depth interviews, revealing that reduced healthcare access during the bushfire and the pandemic caused concern. The use of telehealth received both positive and negative reviews. All participants indicated a need for preparation and planning for healthcare access before a crisis. Persons with MS recommended centralised information sources, prioritised access to healthcare and increased levels of MS nurses and other allied healthcare. Care providers recommended centralised information sources, more nursing and mental health care access, and increased opportunities for multidisciplinary telehealth delivery. CONCLUSIONS: We recommend the involvement of the MS community in creating and designing disaster preparation plans, which should cater to a range of disaster types, to improve disaster preparedness in a community that is vulnerable to increasingly common community crises.
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COVID-19 , Esclerose Múltipla , Humanos , Esclerose Múltipla/terapia , Austrália , Pessoal de Saúde , Acessibilidade aos Serviços de SaúdeRESUMO
PURPOSE: The Australian multiple sclerosis (MS) community experienced two recent major crises, widespread bushfires and the COVID 19 pandemic. We aimed to understand the needs of persons with MS during times of crisis. MATERIALS AND METHODS: A consumer-directed mixed-method study. We included an online survey, semi-structured interviews, and a workshop with persons with MS, carers, healthcare professionals, and disability advocates. Data were collected via: (1) 176 people completing online surveys to identify crisis concerns and communications, (2) 29 people completing online interviews on bushfire and pandemic impact, and (3) 13 people participating in a crises-priorities workshop. Descriptive data were calculated for survey response, and a general inductive analytical approach was taken with interview and workshop responses. RESULTS: The most significant concerns were bushfire smoke exposure and disease-modifying-medication and susceptibility to COVID-19 (66% and 63% mean concern score, respectively). Interviews indicated crises experiences from the bushfires, and the pandemic overlapped respective of changes in mood and symptom stability. For bushfires, a need for future preparations, and for the pandemic, the benefits of social restrictions, disclosing personal health information and increased care burden were important. CONCLUSIONS: Multiple crises challenged the MS community but offered lessons for healthcare in future crises. Continued progress in centralised crisis information, with considered use of telehealth and rural healthcare support, is needed.Implications for rehabilitationThe MS community showed high concerns for the effect of toxic smoke from the 2019/2020 Australian bushfires and, separately, for the disease-modifying-medication and susceptibility to COVID-19.The MS community placed priority on a crisis management plan for individuals.Reduced social activity due to restrictions was beneficial for MS symptom self-awareness and may help overall fatigue management.Healthcare system preparation must prepare to alleviate increased carer workload at times of crisis.
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COVID-19 , Esclerose Múltipla , Humanos , Pandemias , Austrália , FumaçaRESUMO
BACKGROUND: Familial clustering of neuromyelitis optica spectrum disorder (NMOSD) was present in Chinese. This study was to investigate the clinical characteristics and genetic background of familial NMOSD. METHODS: Through questionnaires in four medical centres in 2016-2020, we identified 10 families with NMOSD aggregation. The statistical differences of clinical characteristics between familial and sporadic NMOSD (22 cases and 459 cases) were summarised. The whole-exome sequencing (WES) for seven families (13 cases and 13 controls) was analysed, compared with our previous WES data for sporadic NMOSD (228 cases and 1 400 controls). The family-based and population-based association and linkage analysis were conducted to identify the pathogenetic genes, the variant impacts were predicted. RESULTS: The familial occurrence was 0.87% in Chinese. Familial patients had higher expanded disability status scale score than sporadic patients (p=0.03). The single-nucleotide polymorphism (SNP) rs2252257 in the promoter and enhancer of ubiquitin-specific peptidase USP18 was linked to familial NMOSD (p=7.8E-05, logarithm of the odds (LOD)=3.1), SNPs rs361553, rs2252257 and rs5746523 were related to sporadic NMOSD (p=1.29E-10, 3.45E-07 and 2.01E-09, respectively). Patients with the SNP rs361553 T/T genotype had higher recurrence rate than C/T or C/C genotype (1.22±0.85 vs 0.69±0.57 and 0.81±0.65, p=0.003 and 0.001, respectively). SNPs rs361553 and rs2252257 altered USP18 expression in brain and nerve tissues. CONCLUSION: Most clinical characteristics of familial NMOSD were indistinguishable from sporadic NMOSD except for the worst episodes severity. USP18 with impaired intronic regulatory function contributed to the pathogenesis of NMOSD.
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Neuromielite Óptica , Humanos , Neuromielite Óptica/patologia , Proteases Específicas de Ubiquitina/genética , Povo Asiático/genética , Polimorfismo de Nucleotídeo Único/genética , China , Ubiquitina Tiolesterase/genéticaRESUMO
BACKGROUND: Comorbid depression is prevalent in people with multiple sclerosis (MS). Depression is commonly untreated or undertreated, thus, there is a need for effective and safe interventions and current guidelines recommend psychological and pharmaceutical interventions for people with MS. However, research suggests that other interventions, such as exercise, could also be effective. The comparative efficacy and safety of intervention modalities have not been quantified.We plan to conduct a systematic review and network meta-analysis to compare efficacy and safety of psychological, pharmaceutical, physical and magnetic stimulation interventions for depression in people with MS. METHODS AND ANALYSIS: We will search EMBASE, Medline, Cochrane CENTRAL, APA PsycINFO, Web of Science, CINAHL and PEDro from inception to 31 December 2021. Search terms will stem from three concepts: MS, depression and randomised controlled trials. Included studies will be randomised controlled trials, where participants are people with MS randomised to receive one of the aforementioned intervention types, and depression or depressive symptoms is the primary outcome, only outcome or secondary outcome with an a priori power calculation. Screening, data extraction and risk of bias assessment (using the Risk of Bias 2 tool) will be conducted independently by two reviewers. If possible, we will synthesise the evidence by fitting a frequentist network meta-analysis model with multivariate random effects, or a pairwise random-effects meta-analysis model. For each model, efficacy will be measured using a standardised mean difference, and safety using an OR. We plan to provide summary measures including forest plots, a geometry of the network, surface under the cumulative ranking curve, and a league table, and perform subgroup analyses. Otherwise, a narrative review will be provided. ETHICS AND DISSEMINATION: Ethics is not required for a systematic review and network meta-analysis. Results will be published in a peer reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020209803.
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Depressão , Esclerose Múltipla , Comorbidade , Depressão/terapia , Humanos , Metanálise como Assunto , Esclerose Múltipla/complicações , Metanálise em Rede , Preparações Farmacêuticas , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND AND PURPOSE: Preventing relapse by immunosuppressants (ISs) is critical for the prognosis of neuromyelitis optica spectrum disorder (NMOSD); however, the optimal duration of IS treatment is still under discussion. The objective was to explore the optimal duration of IS treatment and the risk of IS discontinuation for NMOSD. METHOD: This cohort study was conducted at a major neurological center that housed the largest NMOSD database in South China. Eligible participants were patients with NMOSD undergoing IS treatment. The main outcome measures were changes in relapse risk based on IS treatment duration, clinical outcomes and predictors of relapse following IS discontinuation. RESULTS: In total, 343 patients were included in this study. The duration of IS treatment was strongly associated with a decrease in relapse risk (hazard ratio [HR] 0.53, p < 0.001). Continuous IS treatment resulted in decreased relapse HRs within 5 years of receiving IS medication, with a mild rebound starting at 5 years. Rituximab reduced the risk of NMOSD relapse to approximately zero within 3 years. The rate of relapse after IS withdrawal was high (77.5%). As opposed to other ISs, a delayed relapse following rituximab withdrawal was observed in this study. Longitudinal extensive transverse myelitis (HR = 2.023, p = 0.006) was associated with a higher risk of relapse after IS discontinuation. CONCLUSIONS: Long-term IS medication for NMOSD is generally suitable. Patients with longitudinal extensive transverse myelitis had a higher risk of relapse after IS discontinuation. Future studies should explore individualized strategies of rituximab maintenance treatment.
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Mielite Transversa , Neuromielite Óptica , Aquaporina 4 , Estudos de Coortes , Duração da Terapia , Humanos , Imunossupressores/uso terapêutico , Recidiva Local de Neoplasia , Neuromielite Óptica/tratamento farmacológico , Estudos Retrospectivos , Rituximab/uso terapêuticoRESUMO
Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system that results in demyelination of axons, inefficient signal transmission and reduced muscular mobility. Recent findings suggest that B cells play a significant role in disease development and pathology. To further explore this, B cell profiles in peripheral blood from 28 treatment-naive patients with early MS were assessed using flow cytometry and compared to 17 healthy controls. Conventional and algorithm-based analysis revealed a significant increase in MS patients of IgA+ memory B cells (MBC) including CD27+, CD27- and Tbet+ subsets. Screening circulating B cells for markers associated with B cell function revealed a significantly decreased expression of the B cell activation factor receptor (BAFF-R) in MS patients compared to controls. In healthy controls, BAFF-R expression was inversely associated with abundance of differentiated MBC but this was not observed in MS. Instead in MS patients, decreased BAFF-R expression correlated with increased production of proinflammatory TNF following B cell stimulation. Finally, we demonstrated that reactivation of Epstein Barr Virus (EBV) in MS patients was associated with several phenotypic changes amongst MBCs, particularly increased expression of HLA-DR molecules and markers of a T-bet+ differentiation pathway in IgM+ MBCs. Together, these data suggest that the B cell compartment is dysregulated in MS regarding aberrant MBC homeostasis, driven by reduced BAFF-R expression and EBV reactivation. This study adds further insights into the contribution of B cells to the pathological mechanisms of MS, as well as the complex role of BAFF/BAFF-R signalling in MS.
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Receptor do Fator Ativador de Células B , Infecções por Vírus Epstein-Barr , Células B de Memória , Esclerose Múltipla , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4 , Humanos , Imunoglobulina A , Imunoglobulina M , Células B de Memória/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismoRESUMO
Background: Ocrelizumab is a monoclonal antibody targeting CD20-expressing B cells used in the treatment of multiple sclerosis (MS). Currently, there is limited safety data in pregnancy. Objectives: To report the pregnancy outcome following exposure to ocrelizumab in MS. Methods: We retrospectively identified 14 pregnancies of 12 MS patients who had been exposed to ocrelizumab within 6 months prior to conception or during pregnancy from a specialty clinic in Western Australia. Results: 13 of 14 pregnancies resulted in live births. One pregnancy was electively terminated following detection of a chromosomal defect. One pregnancy was complicated with placental insufficiency and the infant developed hyaline membrane disease which was complicated by sepsis. There were no observed major congenital anomalies, preterm births, stillbirths or low birthweight. We did not observe any serious maternal infections. All patients were relapse-free despite a mean ocrelizumab-free interval of 65.1 weeks. Conclusions: We did not identify any major safety signals among the patients who received ocrelizumab prior to conception or during the first trimester of pregnancy. Our patients appeared to have a stable disease course despite a prolonged period of treatment interruption during pregnancy.
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From the perspective of the role of T follicular helper (Tfh) cells in the destruction of tolerance in disease progression, more attention has been paid to their role in autoimmunity. To address the role of Tfh cells in neuromyelitis optica spectrum disorder (NMOSD) recurrence, serum C-X-C motif ligand 13 (CXCL13) levels reflect the effects of the Tfh cells on B-cell-mediated humoral immunity. We evaluated the immunobiology of the CXCR5+CD4+ Tfh cells in 46 patients with NMOSD, including 37 patients with NMOSD with an annual recurrence rate (ARR) of<1 and 9 patients with NMOSD with an ARR of ≥1. Herein, we reported several key observations. First, there was a lower frequency of circulating Tfh cells in patients with an ARR of<1 than in those with an ARR of ≥1 (P< 0.05). Second, the serum CXCL13 levels were downregulated in individuals with an ARR<1 (P< 0.05), processing the ability to promote Tfh maturation and chemotaxis. Third, the level of the primary bile acid, glycoursodeoxycholic acid (GUDCA), was higher in patients with NMOSD with an ARR of<1 than in those with NMOSD with an ARR of ≥1, which was positively correlated with CXCL13. Lastly, the frequency of the Tfh precursor cells decreased in the spleen of keyhole limpet haemocyanin-stimulated animals following GUDCA intervention. These findings significantly broaden our understanding of Tfh cells and CXCL13 in NMOSD. Our data also reveal the potential mechanism of intestinal microbiota and metabolites involved in NMOSD recurrence.
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Ácidos e Sais Biliares/metabolismo , Quimiocina CXCL13/sangue , Microbioma Gastrointestinal/fisiologia , Neuromielite Óptica/imunologia , Células T Auxiliares Foliculares/imunologia , Adulto , Animais , Autoimunidade , Biomarcadores/sangue , Antígenos CD4/metabolismo , Fezes/microbiologia , Feminino , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Receptores CXCR5/metabolismo , Recidiva , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.
Assuntos
Neuromielite Óptica , Aquaporina 4 , Humanos , Imunossupressores/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Estudos Retrospectivos , Rituximab/uso terapêuticoRESUMO
BACKGROUND: An association between tumour necrosis factor alpha (TNF-α) inhibitors exposure and central nervous system (CNS) demyelinating disorders has been postulated but is poorly understood. OBJECTIVES: Describe the clinical spectrum and progress of a cohort of patients who developed demyelinating disorder following exposure to TNF-α inhibitor. METHODS: Retrospective chart review of patients who presented to a single neurologist in Western Australia between May 2003 and July 2020. RESULTS: 7 patients (6 females and 1 male) were identified. Mean age was 49.1 years. Mean follow-up time was 2.9 years. Mean interval between commencement of TNF-α inhibitor and onset of demyelinating event was 3 years. The spectrum of demyelinating events included transverse myelitis (N = 3), acute brainstem syndrome (N = 1) and optic neuritis (N = 1). 2 patients had an atypical presentation but had MRI findings which unequivocally showed demyelinating changes. 2 patients had a monophasic event while the other 5 patients were diagnosed to have multiple sclerosis. All symptomatic patients with multiple sclerosis were started on disease modifying therapy and remained relapse free during follow-up. CONCLUSION: Exposure to TNF-α inhibitor appears to increase the risk of demyelinating event. Whether TNFα inhibition directly results in CNS demyelination or trigger demyelination in susceptible individuals requires further research.
RESUMO
Posterior reversible encephalopathy syndrome (PRES) may present with diverse clinical symptoms including visual disturbance, headache, seizures and impaired consciousness. MRI shows oedema, usually involving the posterior subcortical regions. Triggering factors include hypertension, pre-eclampsia/eclampsia, renal failure, cytotoxic agents and autoimmune conditions. The mechanism underlying PRES is not certain, but endothelial dysfunction is implicated. Treatment is supportive and involves correcting the underlying cause and managing associated complications, such as seizures. Although most patients recover, PRES is not always reversible and may be associated with considerable morbidity and even mortality.
Assuntos
Hipertensão , Síndrome da Leucoencefalopatia Posterior , Feminino , Cefaleia/complicações , Humanos , Imageamento por Ressonância Magnética/efeitos adversos , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/etiologia , Gravidez , Convulsões/complicaçõesRESUMO
INTRODUCTION: Neurofilament light chains (NfL) have been reported as potential markers for neuronal-axonal injury in neuroinflammatory diseases. In the current study, we describe serum NfL levels as a prognostic marker for anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). METHODS: Serum levels of NfL of 64 patients with anti-NMDARE and 84 healthy controls were measured by Simoa. The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score, Modified Rankin Scale (mRS) scores, and clinical and cerebrospinal fluid parameters were evaluated in patients with anti-NMDARE. Meanwhile, we performed a receiver-operator characteristic analysis to assess the power of the serum NFL in predicting the 1-year functional status. RESULTS: Serum NfL levels were significantly elevated in patients with anti-NMDARE compared to healthy controls (p < 0.001, padjusted < 0.001), especially in patients with severe impairments (mRS > 3 vs ≤ 3, p = 0.035) or with limited response to treatment (vs. favorable outcome, p = 0.011). Serum NFL was positively associated with the initial admission mRS (r = 0.23, p = 0.072) and 1-year mRS (r = 0.29, p = 0.018). The AUC of serum NfL and NEOS score for 1-year poor functional status was 0.697 (95% CI 0.527-0.866, p = 0.011), 0.753 (95% CI 0.616-0.890, p = 0.001), respectively. Furthermore, AUC of the combination of serum NfL and NEOS was 0.815 (95% CI 0.680-0.950, p < 0.001). CONCLUSION: Our findings show that serum NfL levels evaluated in anti-NMDAR encephalitis may be a good predictor of the risk of 1-year poor functional status.