Citations

AbstractObjectiveIn this observational study on a cohort of biopsy‐proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early‐active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function.MethodsSeventy‐five patients had at least one early‐active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow‐up was 11 years, median age at biopsy ‐ 41, EDSS ‐ 4.0. At last follow‐up, the median age was 50, EDSS ‐ 3.0. Clinical examination, cognitive assessment (CogState battery), and 3‐Tesla‐MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained.ResultsIP‐I was identified in 14/75 (19%), IP‐II was identified in 41/75 (56%), and IP‐III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow‐up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing–remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP‐III patients recalling one word less on average.InterpretationIn this study, immunopathological heterogeneity of early‐active MS lesions identified at biopsy does not correlate with different long‐term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.

Abstract Memory CD8+ T cells protect against secondary viral infections. They develop and maintain exclusively in circulation (e.g. central memory - Tcm) or are excluded from re-circulation (resident memory - Trm). Circulating memory CD8+ T cells arises from memory precursors (MPs) which express memory, pro-survival, and pluripotency molecules. Trm generation, in contrast, is still not fully understood. Previous reports suggest that Trm and Tcm have a common precursor present at the early effector phase; yet, the nature of this precursor is elusive. We have found that the extracellular ATP receptor P2RX7 promotes both Tcm and Trm generation. Moreover, P2RX7 is quickly upregulated in some (but not all) early effectors and early P2RX7 ablation hinders both Tcm and Trm generation. Thus, we postulated that P2RX7 in early effectors may mark a Tcm/Trm common precursor. Comparison between high (P2RX7hi) and low (P2RX7lo) P2RX7-expressing CD8+ T cells shows a correlation between memory markers and P2RX7, with CD62L+ Tcm precursors exclusively found in P2RX7hi cells. RNA-seq of P2RX7hi and P2RX7lo early effectors show survival, memory and pluripotency genes and pathways are upregulated in P2RX7hi cells. Conversely, many terminal effector and apoptosis genes are upregulated in P2RX7lo cells. P2RX7lo early effectors and MPs have increased apoptosis. Upon transfer into infection-matched mice, P2RX7hi MPs preferentially survive and form Tcm compared to P2RX7lo MPs. This is even more apparent when P2RX7hi and P2RX7lo early effectors are compared: approximately 100x more P2RX7hi cells form memory when compared to P2RX7lo cells, both Tcm and Trm. Our data suggest that P2RX7 in early effector CD8+ T cells promotes the generation of a common Tcm/Trm precursor.

Abstract Immune-mediated blood brain barrier (BBB) disruption is a prominent feature of various neurological conditions for which an emerging role of CD8 T cells is being realized. Our group has developed a unique model of CD8 T cell-mediated BBB disruption which employs Theiler’s murine encephalomyelitis virus (TMEV) infection. Upon intravenous administration of VP2121–130 viral peptide during the peak antiviral adaptive response, Db:VP2121–130 epitope specific CD8 T cells induce BBB disruption in a perforin dependent manner. In this model, we addressed the role of microglia in relation to antigen specific CD8+ T cells and permeable cerebral vessels. Using real time two-photon in vivo imaging, we demonstrate that microglia adopt distinct morphological features, including enlarged cell body and fewer ramified processes as early as 6 hours post administration of VP2 peptide. Notably, microglial population exhibit robust down-regulation of homeostatic markers including CX3CR1 during BBB disruption. This study demonstrates CD8 T cells can promote microglia activation in a perforin-dependent manner during BBB disruption. Importantly, microglial activation occurs concurrently with the onset of vascular permeability and could serve as a critical cell type in this process.

Background Long-term data helps assess the consistency of efficacy, tolerability, and safety of acute treatment over repeated use for different attacks. Real-world studies help assess tolerability, safety, and efficacy in patients with possibly refractory chronic migraine, more comorbidities, other diseases such as cardiovascular diseases, and polypharmacy. Methods This is a narrative review of the long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine. Both manuscripts and abstracts were reviewed. Results The efficacy and tolerability of lasmiditan, ubrogepant, and rimegepant are maintained over time. No significant cardiovascular adverse events were thought to be related to any of these medications. The rare instances of palpitations and/or tachycardia occurred within 48 hours of lasmiditan. One participant with a history of supraventricular tachycardia had sinus tachycardia thought to be related to ubrogepant which did not recur despite continued use. One case of thrombocytopenia and two cases of increased aspartate aminotransferase and alanine transaminase were thought to be possibly related, but the alanine transaminase and aspartate aminotransferase levels normalized despite continued use of ubrogepant. A case of first-degree atrioventricular block was considered possibly related to rimegepant. Acute use of rimegepant was associated with a decrease in monthly migraine days over time. The three medications were associated with improvement in function and/or productivity. Conclusion Long-term and real-world data of tolerability, safety and efficacy of lasmiditan, ubrogepant, and rimegepant is thus far consistent with prior studies, but more longitudinal data that clarifies long-term safety as well as consistency and predictors of response is needed.

Abstract Objective COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs); however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. Methods The first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups. Results We analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26; 95% CI: 0.24, 0.30, P < 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6; 95% CI: 2.9, 4.6, P < 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8; 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4; 95% CI: 1.9, 8.1, P < 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs – OR: 1.9; 95% CI: 1.2, 2.9, P = 0.001; IIMs vs HCs – OR: 5.4 95% CI: 3, 9.6, P < 0.001). Caucasians [OR 4.2 (1.7–10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8–0.97)]. Conclusion Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.

Introduction: The long-term effects of interventional treatment (with surgery, stereotactic radiosurgery, or endovascular embolization) for unruptured brain arteriovenous malformations (uBAVM) are uncertain. We address this in a large multi-center international cohort study comparing risk of intracranial hemorrhage (ICH) in the treated and untreated course of uBAVM patients. Methods: We pooled individual patient data (n=3,291) from 10 cohorts and imputed missing data. Survival analysis was performed from time of uBAVM diagnosis to intracranial hemorrhage (ICH) using Cox models, stratified by cohort, censoring at death or last follow-up, and including BAVM interventional treatment as a time-varying covariate. We tested for an interaction of treatment with follow-up time, then estimated the association of interventional treatment with ICH, adjusting for propensity quintile. Individual treatment propensity scores were calculated using logistic regression with Spetzler-Martin grade, sex, diagnosis age and year, cohort, and presence of presenting symptoms (seizures, headaches, and/or deficits). Results: Median cohort age was 36 years, 48% were female, and 77% received ≥1 treatment modality for uBAVM during follow-up. 373 ICH occurred during 32,054 person-years of follow-up (median=6.6y), for an ICH rate of 1.16 per 100 P-Y. Overall, treatment was not associated with risk of ICH (HR=1.12, 95% CI=0.89-1.51, p=0.33). However, we observed a strong interaction between treatment and follow-up time (p<0.001): between 0-1 year, treatment was associated with higher risk of ICH (HR=3.48, 95% CI: 2.26-5.37, p<0.001); between 1-10 years, we found no association between treatment and risk of ICH (HR=1.02, 95% CI: 0.73-1.45, p=0.87); after 10 years, treatment was associated with a lower risk of ICH (HR=0.46, 95% CI: 0.30-0.70, p<0.001). Survival curves for untreated and treated courses crossed around 17 years. Conclusion: After accounting for treatment propensity for uBAVM, we found an initial increased risk of ICH in the treated relative to untreated course, which continually declined over time with survival curves crossing around 17 years. These results require confirmation in a randomized controlled trial of uBAVM with long-term follow-up.

Abstract Background Histological remission (HR) is an achievable therapeutic target in ulcerative colitis (UC), however there is limited data on the association of HR with long-term clinical outcomes. We evaluated the association between HR and a composite outcome of colectomy, UC-related hospitalization, or intravenous (IV) corticosteroid use in patients with UC. Methods This was a multi-national retrospective study of adult patients with UC treated with a biologic or small molecule drug between 09/01/2005 and 06/30/2019 in Canada, Italy, Netherlands and United States. The study included biologic-naïve (bio-naïve) and biologic-experienced (bio-exp) patients. Biopsies taken during routine practice were procured and re-assessed for histological activity by blinded gastrointestinal pathologists in a central laboratory. HR was defined as the absence of neutrophilic inflammation (Nancy Histological Index ≤1 or Robarts Histological Index ≤3 plus Geboes subgrades 2B.0/3.0) at the most recent endoscopic evaluation within 3 to 9 months after treatment initiation. Cumulative risk of time-to-event outcome over 12 months from treatment initiation was evaluated using Kaplan-Meier (KM) methods and Cox proportional hazard analysis. Statistical significance was set as p-value &lt;0.05. Results We included 227 patients with UC (bio-naïve and bio-exp) (Table 1); of whom, 132 (58%) were bio-naïve (Table 2). Of the bio-naïve patients, 62 (47%) achieved HR and 70 (53%) had histologic activity; 9 (6.8%) underwent colectomy, 16 (12.1%) had UC-related hospitalizations, and 8 (6.1%) received IV corticosteroid. Unadjusted time-to-event for the composite outcome was significantly greater in bio-naïve patients who achieved HR compared to those who did not (p=0.0023; Figure 1A). In multivariable analysis, the association of HR on the composite outcome in bio-naïve patients was not statistically significant (adjusted hazard ratio [aHR], 0.26; 95% CI, 0.02-4.42). In the overall patients (bio-naïve and bio-exp), unadjusted (p&lt;0.001; Figure 1B) and multivariable (aHR, 0.32; 95% CI, 0.06-1.75) associations of HR and the composite outcome were similar to the bio-naïve patients. Conclusion We used central reading to evaluate the association of HR and clinical outcomes in patients with UC. While unadjusted KM curves showed that HR was associated with decreased risk of the composite outcome, the association was no longer significant after adjustment for covariates. The target sample size for this study was not achieved and the number of events was small, resulting in reduced statistical power. Future studies are warranted to explore the association further.

Abstract Background Ustekinumab (UST) is an approved treatment for adults with inflammatory bowel disease (IBD: Crohn’s disease [CD] and ulcerative colitis [UC]), psoriasis (PsO), and psoriatic arthritis (PsA). Here, we present pooled safety analyses in these approved indications of patients (pts) with active tuberculosis (TB) and opportunistic infections (OIs) through 5 years (yrs) of UST treatment. Methods Pooled data included 13 Phase 2/3 UST studies through 5 yrs of CD and PsO, 2 yrs of UC, and 1 yr of PsA. OIs were identified by clinician review. Herpes zoster (HZ) was evaluated separately. Event rates per 100 pt yrs (PYs) are presented. Concomitant immunomodulators/corticosteroids were permitted in IBD and PsA pts. All pts who received ≥1 UST dose were included. In IBD, placebo (PBO) pts included data up to the first UST dose for pts initially treated with PBO, or &gt;16 weeks after the last UST dose for UST pts who switched to PBO. Results Across all approved indications, 19 OIs including TB were reported, with rates in PBO of 0.40 and UST of 0.10 through 5 yrs in 13807 PYs of follow-up (Table 1); rates of HZ were 1.21 and 0.63, respectively. Of 19 OIs, 18 were in IBD pts and 1 in a PsO pt. Overall, 14/16 pts (12/13 UST) with OIs excluding TB were also receiving confounding concomitant medications. A total of 3 active TB cases (2 pts with CD and 1 pt with UC) were reported in PBO (n=2; 1 in a Hungarian CD pt 10 months after receiving last UST dose) and UST (n=1) pts (Table 1). One active TB case was reported in an asymptomatic South African CD pt treated with UST who had a positive QuantiFERON®-TB Gold test on routine screening and bronchial brushings positive for M. tuberculosis. Both CD pts completed TB treatment with disease resolution. The most common OIs were esophageal candidiasis (UST n=3; PBO n=2) and cytomegalovirus colitis (UST n=3; PBO n=1). Conclusion Rates of OIs, including active TB, in UST-treated pts were low across approved indications through up to 5 yrs with 13807 PYs of follow-up and not higher in UST pts vs PBO pts, suggesting no increased risk of OI with long-term UST treatment.

Abstract Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.

Background: The cortical silent period (CSP) and long-interval intracortical inhibition (LICI) are putative markers of γ-aminobutyric acid receptor type B (GABAB)-mediated inhibitory neurotransmission. We aimed to assess the association between LICI and CSP in youths. Methods: We analyzed data from three previous studies of youth who underwent CSP and LICI measurements with transcranial magnetic stimulation and electromyography. We assessed CSP and LICI association using Spearman rank correlation tests and multiple linear regression analyses adjusted for demographic and clinical covariates. Results: The sample included 16 healthy participants and 45 participants with depression. The general mean (SD) age was 15.5 (1.7), 14.3 (1.7) for healthy participants, and 15.9 (1.6) years for participants with depression. Measures were nonnormally distributed (Shapiro–Wilk, p < 0.001). CSP and LICI were not correlated at 100-millisecond (ρ = −0.2421, p = 0.06), 150-millisecond (ρ = −0.1612, p = 0.21), or 200-millisecond (ρ = −0.0507, p = 0.70) interstimulus intervals using Spearman rank correlation test. No correlations were found in the multiple regression analysis (p = 0.35). Conclusions: Although previous studies suggest that cortical silent period and long-interval intracortical inhibition measure GABAB receptor-mediated activity, these biomarkers were not associated in our sample of youths. Future studies should focus on the specific physiologic and pharmacodynamic properties assessed by CSP and LICI in younger populations.