Objectives
We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) ...and transition to secondary progression (SP) in relapsing multiple sclerosis (MS).
Methods
Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively.
Results
Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (
p
< 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120–0.577,
p
= 0.003).
Discussion
In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.
Chronic neuroinflammation is a key pathological hallmark of multiple sclerosis (MS) that suggests that resolution of inflammation by specialized proresolving molecules is dysregulated in the disease. ...Annexin A1 (ANXA1) is a protein induced by glucocorticoids that facilitates resolution of inflammation through several mechanisms that include an inhibition of leukocyte recruitment and activation. In this study, we investigated the ability of ANXA1 to influence T cell effector function in relapsing/remitting MS (RRMS), an autoimmune disease sustained by proinflammatory Th1/Th17 cells. Circulating expression levels of ANXA1 in naive-to-treatment RRMS subjects inversely correlated with disease score and progression. At the cellular level, there was an impaired ANXA1 production by CD4
CD25
conventional T and CD4
RORγt
T (Th17) cells from RRMS subjects that associated with an increased migratory capacity in an in vitro model of blood brain barrier. Mechanistically, ANXA1 impaired monocyte maturation secondarily to STAT3 hyperactivation and potently reduced T cell activation, proliferation, and glycolysis. Together, these findings identify impaired disease resolution pathways in RRMS caused by dysregulated ANXA1 expression that could represent new potential therapeutic targets in RRMS.
Objective
This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset ...pediatric multiple sclerosis.
Methods
Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease‐modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated.
Results
A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease‐modifying treatment exposure were independent predictors for long‐term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long‐term disability.
Interpretation
These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022;91:483–495
•We studied 56 patients with AQP4-IgG+NMOSD (n = 26) or MOGAD (n = 30) who received at least one dose of SARS-CoV-2 vaccination (mRNA-based).•Disease relapses within 1 month of vaccination occurred ...in only one patient with AQP4-IgG+NMOSD (4%).•The frequency of disease relapses was higher in patients who contracted SARS-CoV-2 infection before the vaccine (20%; 1/5).•In patients with AQP4-IgG+NMOSD or MOGAD the benefits of SARS-CoV-2 vaccination outweigh the risk of potential disease reactivation.
Post-vaccination disease relapses have been reported in patients with MOGAD and AQP4-IgG+NMOSD. In this retrospective multicenter Italian study we assessed the frequency of relapses after SARS-CoV-2 vaccination. We included 56 cases: MOGAD, 30; AQP4-IgG+NMOSD, 26. Vaccines received were BNT162b2-Pfizer-BioNTech in 42 patients and mRNA-1273-Moderna in 14 patients. Six patients had a history of SARS-CoV-2 infection; two of them experienced a post-infection disease relapse (MOGAD). The frequency of relapses within one month of SARS-CoV-2 vaccination was 4% (1/26) in the AQP4-IgG+NMOSD group and 0% in the MOGAD group. In these patients the potential benefits of vaccination overcome the risk of relapses.
Objectives:
Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of ...switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity.
Methods:
We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models.
Results:
We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse.
Discussion and Conclusion:
This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.
Introduction
Neurological disorders are considered rare complications of immune-checkpoint inhibitor.
Case description
We report a 63-year-old man with recurrence of melanoma who presented epilepsy, ...limbic encephalitis, cerebellar ataxia, and stiff person syndrome soon after treatment with nivolumab, an immune-checkpoint inhibitor. On autoimmune screening, serum and CSF GAD65 were detected. Significant response to steroids and intravenous immunoglobulins were observed, but cancer recurred after nivolumab discontinuation in parallel with epileptic seizure and worsening of cognitive impairment and the patient died.
Discussion
This case expands the spectrum of GAD65-associated conditions induced by immune-checkpoint inhibitor and underlines treatment complexity when both neurological complications and tumour recurrence occur.
Background and purpose
Real‐world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease‐modifying therapies (DMTs). Our aim was to provide real‐world ...data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab.
Methods
Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation.
Results
We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow‐up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first‐line oral agents (56), first‐line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty‐five patients were treatment‐naïve. The pre‐alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous‐year relapses was associated with alemtuzumab ARR (adjusted risk ratio RR 1.38, p = 0.009). Progression‐free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re‐baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years.
Conclusions
Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.
Alemtuzumab decreases annualized relapse independent of previous therapy, including in patients with disease activity during natalizumab treatment. Overall, 90% of patients show no disease progression, and 20% an improvement after 2 years of alemtuzumab. Re‐baselining patients after 6 months, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years.
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