Treatment strategies and treatment-related adverse events in MG according to the age of onset.

Introduction: Early-onset (EOMG) and late-onset (LOMG) are distinct groups of MG patients. It is unclear if treatment strategies and treatment-related adverse events may differ according to the age of MG onset. Methods: This single-center retrospective study includes all MG patients followed at a tertiary center since 2007. We reviewed the electronic clinical records. Results: In total, 212 patients were identified, 142 (67.0%) females, with a median disease duration of 10 years. The median age of symptom onset was 42.0 (26.0-64.5) years, with 130 (61.3%) EOMG cases and 82 (38.7%) LOMG. EOMG were more frequently female, had longer disease duration and often more generalized MG (p < 0.001). Comorbidities were significantly more frequent in LOMG (67.1%) compared to EOMG (53.1%) (p = 0.002). Steroid-related adverse effects motivating the switch to steroid-sparing agents (82.0%) were different between groups, with hypertension, hypercholesterolemia, diabetes mellitus and malignancies being more common in LOMG. At the same time, osteoporosis and dyspepsia were more frequent in EOMG (p < 0.001). The most common first-line choice was azathioprine (45.8%), and rituximab was used in 4 patients (1.9%). Conclusion: Our study shows that treatment modalities are similar between EOMG and LOMG, while steroid-related adverse events appear to be distinct.

Role of NLRP3 inflammasome and oxidative stress in hepatic insulin resistance and the ameliorative effect of phytochemical intervention.

NLRP3 inflammasome has a key role in chronic low-grade metabolic inflammation, and its excessive activation may contribute to the beginning and progression of several diseases, including hepatic insulin resistance (hIR). Thus, this review aims to highlight the role of NLRP3 inflammasome and oxidative stress in the development of hIR and evidence related to phytochemical intervention in this context. In this review, we will address the hIR pathogenesis related to reactive oxygen species (ROS) production mechanisms, involving oxidized mitochondrial DNA (ox-mtDNA) and thioredoxin interacting protein (TXNIP) induction in the NLRP3 inflammasome activation. Moreover, we discuss the inhibitory effect of bioactive compounds on the insulin signaling pathway, and the role of microRNAs (miRNAs) in the phytochemical target mechanism in ameliorating hIR. Although most of the research in the field has been focused on evaluating the inhibitory effect of phytochemicals on the NLRP3 inflammasome pathway, further investigation and clinical studies are required to provide insights into the mechanisms of action, and, thus, encourage the use of these bioactive compounds as an additional therapeutic strategy to improve hIR and correlated conditions.

Consensus for the Early Identification of Secondary Progressive Multiple Sclerosis in Portugal: a Delphi Panel.

INTRODUCTION: Multiple sclerosis is a disease with a heterogeneous evolution. The early identification of secondary progressive multiple sclerosis is a clinical challenge, which would benefit from the definition of biomarkers and diagnostic tools applicable in the transition phase from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis. We aimed to reach a Portuguese national consensus on the monitoring of patients with multiple sclerosis and on the more relevant clinical variables for the early identification of its progression. MATERIAL AND METHODS: A Delphi panel which included eleven Portuguese Neurologists participated in two rounds of questions between July and August of 2021. In the first round, 39 questions which belonged to the functional, cognitive, imaging, biomarkers and additional evaluations were included. Questions for which no consensus was obtained in the first round (less than 80% of agreement), were appraised by the panel during the second round. RESULTS: The response rate was 100% in both rounds and consensus was reached for a total of 33 questions (84.6%). Consensus was reached for monitoring time, evaluation scales and clinical variables such as the degree of brain atrophy and mobility reduction, changes suggestive of secondary progressive multiple sclerosis. Additionally, digital devices were considered tools with potential to identify disease progression. Most questions for which no consensus was obtained referred to the cognitive assessment and the remaining referred to both functional and imaging domains. CONCLUSION: Consensus was obtained for the determination of the monitorization interval and for most of the clinical variables. Most questions that did not reach consensus were related with the confirmation of progression taking into account only one test/domain, reinforcing the multifactorial nature of multiple sclerosis.

REALMS study: real-world effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis in Portugal.

BACKGROUND: Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal. METHODS: Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected. RESULTS: Two-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study. CONCLUSIONS: Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.

Discordance between patient and physician global assessment of disease activity in Behçet's syndrome: a multicenter study cohort.

BACKGROUND: To compare the patients' and physician's global assessment of disease activity in Behçet's syndrome (BS) and investigate the frequency, magnitude, and determinants of potential discordance. METHODS: A total of 226 adult BS patients with a median (IQR) age of 46.9 (35.6-55.2) years were enrolled across Italy, Greece, Portugal, and Spain. Demographic, clinical, and therapeutic variables, as well as the patient reported outcomes, were collected at the recruitment visit. The physical (PCS) and mental (MCS) component summary scores of the Short Form Questionnaire 36 (SF-36) and the Behçet's syndrome Overall Damage Index (BODI) were calculated. Disease activity was assessed by the patients' (PtGA) and physician's global assessment (PGA) in a 10-cm visual analog scale, as well as the Behçet Disease Current Activity Form (BDCAF). Discordance (∆) was calculated by subtracting the PGA from the PtGA and defined as positive (PtGA>PGA) and negative (PtGA 80%) of disagreements were due to patients rating higher their disease activity. Higher values of BDCAF were associated to increased rate of positive discordance. When BDCAF = 0, the median (IQR) values of PtGA and PGA were 0.2 (0-2) and 0 (0-1), respectively. PCS (adjusted odds ratio (adjOR) 0.96 per unit, 95% CI 0.93-0.98, p = 0.006) and MCS (adjOR 0.96 per unit, 95% CI 0.93-0.99, p = 0.003) were independently associated with positive discordance using both cutoffs. Active ocular involvement emerged as a potential determinant of negative discordance (adjOR 5.88, 95% CI 1.48-23.30, p = 0.012). CONCLUSIONS: PtGA and PGA should be considered as complementary measures in BS, as patients and physicians may be influenced by different factors when assessing active disease manifestations. Particularly, PtGA may be a useful tool in the assessment of BS disease activity, as it carries a low risk to misclassify an inactive disease, and may allow to capture aspects of the patient's health that negatively affect his well-being and the treatment.

Development and preliminary validation of the Behçet's syndrome Overall Damage Index (BODI).

OBJECTIVE: To develop and validate the evidence-based and consensus-based Behçet's Syndrome Overall Damage Index (BODI). METHODS: Starting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet's syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet's Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility. RESULTS: The final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen's k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0-14). The BODI significantly correlated with the VDI (r=0.693, p<0.001), demonstrating to effectively measure damage (construct validity), but had greater sensitivity in identifying major organ damage and did not correlate with disease activity measures (ie, BDCAF: p=0.807, PGA: p=0.820, PtGA: p=0.794) discriminating damage from the major confounding factor. The instrument was deemed credible (face validity), complete (content validity) and feasible by an independent group of clinicians. CONCLUSIONS: Pending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.

Concurrent autoimmune hepatitis in multiple sclerosis.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare and chronic inflammatory disorder associated with extrahepatic autoimmune diseases, including, infrequently, multiple sclerosis (MS). Short Reports: We report five cases of MS and AIH association. One patient developed AIH while under interferon beta-1b and the remaining while off disease-modifying therapy, although after methylprednisolone bolus in three. All presented a liver biopsy compatible with AIH. Hepatitis resolution was achieved with immunosuppressive treatment, but one patient died after a fulminant hepatitis requiring liver transplant. DISCUSSION: A thorough review of published cases supports this clear, although rare, association and a liver biopsy should be considered in AIH suspected cases.

Frequent involvement of central nervous system in primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the salivary and tear glands, and autoantibody secretion, in the absence of other systemic autoimmune disorder. Among autoimmune diseases, it is a relatively common disease, but the burden of central nervous system (CNS) involvement is controversial. This retrospective study evaluates the prevalence, clinical patterns and outcomes of CNS involvement in a cohort of patients with primary Sjögren syndrome. We evaluated 93 patients with pSS diagnosed according to American-European Consensus Group criteria. Fourteen patients (15.1 %) had CNS involvement. All were women with an average age of onset of the disease of 42.1 ± 14.7 years (average ± SD) and an average age of onset of neurological involvement of 47.29 ± 16 years. Three had parkinsonian syndrome, two epilepsy, two motor and sensory deficits, two headache with brain magnetic resonance abnormalities, two neuromyelitis optica, two chronic progressive myelitis and one aseptic meningitis. Neurological involvement preceded Sjögren syndrome diagnosis in nine of the patients (64 %), and neurological outcome was good in 11 patients (78.6 %). Central nervous involvement was not as rare as expected, and the frequency was similar to the frequency of peripheral nervous system involvement. In half of the patients, this was the first symptom of the disease, emphasizing the importance of considering this diagnosis, especially in young female with neurological symptoms without other evident cause.

Estudio retrospectivo de la eficacia y seguridad del natalizumab en el tratamiento de la esclerosis múltiple en Portugal / The efficacy and safety of natalizumab for the treatment of multiple sclerosis in Portugal: a retrospective study

Introducción. Los estudios han demostrado que el natalizumab constituye un tratamiento eficaz contra la esclerosis múltiple remitente recurrente (EMRR). Hasta la fecha, no había datos de pacientes portugueses. Objetivo. Determinar la eficacia y la seguridad del natalizumab en pacientes con EMRR atendidos en la práctica clínica ordinaria en Portugal. Pacientes y métodos. Los datos clínicos de adultos con EMRR tratados con natalizumab en centros especializados de neurología en Portugal se introdujeron de forma retrospectiva en una base de datos para llevar a cabo un análisis entre octubre de 2010 y febrero de 2012. Se analizó el cambio en la tasa anualizada de brotes (TAB), en las puntuaciones de la escala ampliada de discapacidad (EDSS) y en el estado de discapacidad. Resultados. Se admitió un total de 383 pacientes atendidos en 20 centros. Antes de iniciar el tratamiento con natalizumab, la mediana inicial de la EDSS era de 4,0 y la TAB media, de 1,64. La mayor parte de los pacientes ya había recibido tratamiento contra la esclerosis múltiple (93,0%). La duración media del tratamiento con natalizumab era de 12 meses. El tratamiento propicio reducciones significativas (p < 0,001) de los valores iniciales de la TAB media y de las puntuaciones EDSS en los tratados con el anticuerpo durante ≥ 12 meses (n = 288) y durante ≥ 24 meses (n = 160). El natalizumab resulto mas eficaz en los pacientes que presentaban un menor grado de discapacidad (EDSS < 3,0) y en los que no habían recibido ningún tratamiento modificador de la enfermedad. Se notificaron dos casos de leuco encefalopatía multifocal progresiva. No hubo efectos adversos inesperados. Conclusión. El natalizumab presenta una tolerabilidad satisfactoria y se muestra eficaz en la reducción de las recidivas y la estabilización de la EMRR en el marco de la practica clínica ordinaria en Portugal. Conserva su eficacia con el tratamiento continuado y podría ser eficaz especialmente en los pacientes con menos discapacidad y en aquellos que no han recibido ningún tratamiento modificador de la enfermedad hasta el momento (AU)

Introduction. Studies have shown that natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). To date, no data are available in Portuguese patients. Aim. To determine the efficacy and safety of natalizumab in patients with RRMS in routine clinical practice in Portugal. Patients and methods. Clinical data for adult patients with RRMS treated with natalizumab at specialist neurology centres in Portugal were entered retrospectively into a database for analysis between October 2010 and February 2012. Changes in annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) scores and disability status were analysed. Results. A total of 383 patients from 20 centres were included. Prior to starting natalizumab, the baseline median EDSS score was 4 and the mean ARR was 1.64. Most patients had previously received multiple sclerosis treatment (93.0%). Median natalizumab treatment duration was 12 months. Natalizumab treatment was associated with significant (p < 0.001) reductions from baseline in the mean ARR and EDSS scores in patients treated with natalizumab for ≥ 12 months (n = 288) and for ≥ 24 months (n = 160). Natalizumab was more effective in patients with less disability (EDSS < 3) and in those who had not previously received disease-modifying treatments. Two cases of progressive multifocal leukoencephalopathy were reported. No new unexpected adverse events occurred. Conclusion. Natalizumab is well tolerated, and is effective in reducing relapse rate and stabilising disease in patients with RRMS in the clinical practice setting in Portugal. Its efficacy persists with continued treatment, and it may be particularly effective in patients with less disability and without prior disease modifying therapy (AU)

CC chemokine receptor polymorphism CCR5Δ32 in Portuguese Behçet's disease patients.

OBJECTIVES: To investigate whether CCR5 deletion is associated with susceptibility to Behçet's disease (BD) in a Portuguese population. METHODS: A total of 122 BD patients and 227 ethnically-matched controls were studied. Genotyping of the CCR5Δ32 polymorphisms was performed using polymerase chain reaction product sizing. RESULTS: No significant differences were observed in the allelic frequencies of CCR532 between patients and controls (OR=0.820; p=0.512). Stratification for gender and for the presence of HLA-B*51 did not reveal any significant differences. CONCLUSIONS: These results indicate that CCR5Δ32 is unlikely to contribute to susceptibility to BD in Portuguese patients. This may be explained by the known functional redundancy of this signalling system.

The STAR Study: a real-world, international, observational study of the safety and tolerability of, and adherence to, serum-free subcutaneous interferon ß-1a in patients with relapsing multiple sclerosis.

BACKGROUND: Adverse reactions, particularly injection site reactions (ISRs), are common reasons for nonadherence to injectable multiple sclerosis (MS) treatments. Adherence to MS treatment is important to ensure good treatment outcomes. OBJECTIVE: The aim of this study was to assess the local tolerability of subcutaneous (SC) serum-free interferon (IFN) ß-1a in patients with relapsing MS over 1 year in a real-life, international setting. The study also assessed safety, disease activity, and adherence. METHODS: This was a prospective, international, multicenter, observational study of 251 patients with relapsing-remitting MS treated with SC serum-free IFN ß-1a 44 µg or 22 µg 3 times weekly for 12 months or until early discontinuation. The primary end point was the proportion of patients with ISRs. Secondary end points included proportion of patients with adverse events (AEs); annualized relapse rate (ARR); proportion of patients remaining relapse-free; and adherence to treatment. RESULTS: During the observation period, 27.5% (69 of 251) of patients experienced nonserious ISRs, which was consistent with the incidence reported in clinical studies. Five patients discontinued treatment and 2 patients suspended treatment because of ISRs. Mean age was 35.8 years; patients were predominantly white (94.8%), and two thirds (66.1%) were female. The overall incidence of AEs was 63.7% (160 of 251), and overall safety and tolerability were assessed as excellent, very good, or good in >85% of patients. More than 70% of patients remained relapse-free, and the mean ARR was 0.4. More than 90% of patients had very good or good adherence to treatment; a significantly greater proportion of these were relapse-free at 12 months compared with those with fair or poor adherence (77.6% vs 50.0%; P = 0.0107), and their ARR was significantly lower (0.3 vs 0.9; P = 0.0055). Patients with fair or poor adherence had 4.6 times higher odds of experiencing a relapse than those with very good or good adherence. CONCLUSIONS: The incidence of ISRs and the overall safety profile in this observational study, in an international population in a real-life setting, confirm the good local tolerability of SC serum-free IFN ß-1a reported in clinical studies. The association between good adherence and a lower ARR underlines the importance of good adherence. The good local and general tolerability of SC IFN ß-1a may help ensure a high level of adherence, which is associated with better clinical outcomes. ClinicalTrials.gov identifier: NCT01080027.

Different Frontal Involvement in ALS and PLS Revealed by Stroop Event-Related Potentials and Reaction Times.

BACKGROUND: A growing body of evidence suggests a link between cognitive and pathological changes in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobar degeneration (FTLD). Cognitive deficits have been investigated much less extensively in primary lateral sclerosis (PLS) than in ALS. OBJECTIVE: To investigate bioelectrical activity to Stroop test, assessing frontal function, in ALS, PLS, and control groups. METHODS: Thirty-two non-demented ALS patients, 10 non-demented PLS patients, and 27 healthy subjects were included. Twenty-nine electroencephalography channels with binaural reference were recorded during covert Stroop task performance, involving mental discrimination of the stimuli and not vocal or motor response. Group effects on event-related potentials (ERPs) latency were analyzed using statistical multivariate analysis. Topographic analysis was performed using low-resolution brain electromagnetic tomography (LORETA). RESULTS: Amyotrophic lateral sclerosis patients committed more errors in the execution of the task but they were not slower, whereas PLS patients did not show reduced accuracy, despite a slowing of reaction times (RTs). The main ERP components were delayed in ALS, but not in PLS, compared with controls. Moreover, RTs speed but not ERP latency correlated with clinical scores. ALS had decreased frontotemporal activity in the P2, P3, and N4 time windows compared to controls. CONCLUSION: These findings suggest a different pattern of psychophysiological involvement in ALS compared with PLS. The former is increasingly recognized to be a multisystems disorder, with a spectrum of executive and behavioral impairments reflecting frontotemporal dysfunction. The latter seems to mainly involve the motor system, with largely spared cognitive functions. Moreover, our results suggest that the covert version of the Stroop task used in the present study, may be useful to assess cognitive state in the very advanced stage of the disease, when other cognitive tasks are not applicable.