When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Addressing dispersion in mis-measured multivariate binomial outcomes: A novel statistical approach for detecting differentially methylated regions in bisulfite sequencing data.

Motivated by a DNA methylation application, this article addresses the problem of fitting and inferring a multivariate binomial regression model for outcomes that are contaminated by errors and exhibit extra-parametric variations, also known as dispersion. While dispersion in univariate binomial regression has been extensively studied, addressing dispersion in the context of multivariate outcomes remains a complex and relatively unexplored task. The complexity arises from a noteworthy data characteristic observed in our motivating dataset: non-constant yet correlated dispersion across outcomes. To address this challenge and account for possible measurement error, we propose a novel hierarchical quasi-binomial varying coefficient mixed model, which enables flexible dispersion patterns through a combination of additive and multiplicative dispersion components. To maximize the Laplace-approximated quasi-likelihood of our model, we further develop a specialized two-stage expectation-maximization (EM) algorithm, where a plug-in estimate for the multiplicative scale parameter enhances the speed and stability of the EM iterations. Simulations demonstrated that our approach yields accurate inference for smooth covariate effects and exhibits excellent power in detecting non-zero effects. Additionally, we applied our proposed method to investigate the association between DNA methylation, measured across the genome through targeted custom capture sequencing of whole blood, and levels of anti-citrullinated protein antibodies (ACPA), a preclinical marker for rheumatoid arthritis (RA) risk. Our analysis revealed 23 significant genes that potentially contribute to ACPA-related differential methylation, highlighting the relevance of cell signaling and collagen metabolism in RA. We implemented our method in the R Bioconductor package called "SOMNiBUS."

Understanding COVID-19 Vaccine Confidence in People Living with HIV: A pan-Canadian Survey.

Understanding the roots of Covid-19 vaccine hesitancy in at-risk groups, such as persons living with HIV (PLWH), is of utmost importance. We developed a modified Vaccine Hesitancy Scale (VHS) questionnaire using items from the National Advisory Committee on Immunization Acceptability Matrix. To examine factors associated with receiving COVID-19 vaccine and the link between vaccine attitudes and beliefs with vaccine behavior, PLWH were recruited via social media and community-based organizations (February-May 2022). Descriptive statistics were used to summarize results. Total VHS score was generated by adding Likert scale scores and linear regression models used to compare results between participants who received or did not receive COVID-19 vaccines. Logistic regression models were used to identify factors associated with vaccine uptake. A total of 246 PLWH indicated whether they received a COVID-19 vaccine. 89% received ≥ 1 dose. Mean total VHS(SD) for persons having received ≥ 1 COVID-19 vaccine was 17.8(6.2) vs. 35.4(9.4) for participants not having received any COVID-19 vaccine. Persons who received ≥ 1 dose were significantly older than those who had not received any (48.4 ± 13.8 vs. 34.0 ± 7.7 years, p < 0.0001). The majority of participants considered COVID-19 vaccination important for their health(81.3%) and the health of others(84.4%). Multivariate logistic regression revealed the odds of taking ≥ 1dose were increased 2.4-fold [95% CI 1.6, 3.5] with each increase in age of 10 years (p < 0.0001). Sex and ethnicity were not different between groups. In conclusion, PLWH accept COVID-19 vaccines for both altruistic and individual reasons. With evolving recommendations and increasing numbers of booster vaccines, we must re-examine the needs of PLWH regularly.

Preexisting autoimmune disease and immune-related adverse events associated with anti-PD-1 cancer immunotherapy: a national case series from the Canadian Research Group of Rheumatology in Immuno-Oncology.

BACKGROUND: Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). METHODS: Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. RESULTS: Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0-17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. CONCLUSION: PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy.

Barriers and facilitators to influenza and pneumococcal vaccine hesitancy in rheumatoid arthritis: a qualitative study.

OBJECTIVES: Immunization is an essential component of RA care. Nevertheless, vaccine coverage in RA is suboptimal. Contextual, individual and vaccine-related factors influence vaccine acceptance. However, barriers and facilitators of vaccination in RA are not well defined. The aim of this study was to assess perspectives of RA patients and healthcare professionals (HCPs) involved in RA care of barriers and facilitators regarding influenza and pneumococcal vaccines. METHODS: Eight focus groups (four with RA patients and four with HCPs) and eight semi-structured open-ended individual interviews with vaccine-hesitant RA patients were conducted. Data were audio recorded, transcribed verbatim and imported to MAXQDA software. Analysis using the framework of vaccine hesitancy proposed by the Strategic Advisory Group of Experts on Immunization was conducted. RESULTS: RA patients and HCPs reported common and specific barriers and facilitators to influenza vaccination that included contextual, individual and/or group and vaccine- and/or vaccination-specific factors. A key contextual influence on vaccination was patients' perception of the media, pharmaceutical industry, authorities, scientists and the medical community at large. Among the individual-related influences, experiences with vaccination, knowledge/awareness and beliefs about health and disease prevention were considered to impact vaccine acceptance. Vaccine-related factors including concerns about vaccine side effects such as RA flares, the safety of new formulations, the mechanism of action, access to vaccines and costs associated with vaccination were identified as actionable barriers. CONCLUSION: Acknowledging RA patients' perceived barriers to influenza and pneumococcal vaccination and implementing specific strategies to address them might increase vaccination coverage in this population.

A novel statistical method for modeling covariate effects in bisulfite sequencing derived measures of DNA methylation.

Identifying disease-associated changes in DNA methylation can help us gain a better understanding of disease etiology. Bisulfite sequencing allows the generation of high-throughput methylation profiles at single-base resolution of DNA. However, optimally modeling and analyzing these sparse and discrete sequencing data is still very challenging due to variable read depth, missing data patterns, long-range correlations, data errors, and confounding from cell type mixtures. We propose a regression-based hierarchical model that allows covariate effects to vary smoothly along genomic positions and we have built a specialized EM algorithm, which explicitly allows for experimental errors and cell type mixtures, to make inference about smooth covariate effects in the model. Simulations show that the proposed method provides accurate estimates of covariate effects and captures the major underlying methylation patterns with excellent power. We also apply our method to analyze data from rheumatoid arthritis patients and controls. The method has been implemented in R package SOMNiBUS.

Health-related quality of life in systemic sclerosis before and after autologous haematopoietic stem cell transplant-a systematic review.

OBJECTIVES: In severe rapidly progressive SSc, autologous haematopoietic stem cell transplantation (AHSCT) allows significant improvements in overall and event-free survival. We undertook this study to identify, appraise and synthesize the evidence on health-related quality of life (HRQoL) before and after AHSCT for SSc. METHODS: We performed a systematic review of the literature, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, in PubMed and ScienceDirect from database inception to 1 February 2019. All articles with original HRQoL data were selected. RESULTS: The search identified 1080 articles, of which 8 were selected: 3 unblinded randomized controlled trials [American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST), Autologous Stem Cell Transplantation International Scleroderma, Scleroderma: Cyclophosphamide or Transplantation), 3 uncontrolled phase I or II trials and 2 cohort studies. HRQoL data from 289 SSc patients treated with AHSCT and 125 treated with intravenous CYC as a comparator with median 1.25-4.5 years follow-up were included. HRQoL was evaluated with the HAQ Disability Index (HAQ-DI; 275 patients), the 36-item Short Form Health Survey (SF-36; 249 patients) and the European Quality of Life 5-Dimensions questionnaire (EQ-5D; 138 patients). The quality of the studies was moderate to low. AHSCT was associated with significant improvement in the HAQ-DI (P = 0.02-<0.001), SF-36 Physical Component Summary score (P = 0.02-<0.0001) and EQ-5D index-based utility score (P < 0.001). The SF-36 Mental Component Summary score improved in the ASSIST (n = 19) and one small retrospective cohort (n = 30 patients, P = 0.005) but did not improve significantly in 2 randomized controlled trials (n = 200 patients, P = 0.1-0.91). CONCLUSION: AHSCT in severe SSc patients is associated with significant and durable improvement in physical HRQoL.

Mitochondrial Oxidative Stress Reduces the Immunopotency of Mesenchymal Stromal Cells in Adults With Coronary Artery Disease.

RATIONALE: Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive. OBJECTIVE: The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis. METHODS AND RESULTS: Adipose tissue-derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4+T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular (P=0.006) and mitochondrial (P=0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P<0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P=0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P=0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N-acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity (P=0.03). CONCLUSIONS: An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency.

Long-term exposure to a mixture of industrial SO2, NO2, and PM2.5 and anti-citrullinated protein antibody positivity.

BACKGROUND: Studies of associations between industrial air emissions and rheumatic diseases, or diseases-related serological biomarkers, are few. Moreover, previous evaluations typically studied individual (not mixed) emissions. We investigated associations between individual and combined exposures to industrial sulfur dioxide (SO2), nitrogen dioxide (NO2), and fine particles matter (PM2.5) on anti-citrullinated protein antibodies (ACPA), a characteristic biomarker for rheumatoid arthritis (RA). METHODS: Serum ACPA was determined for 7600 randomly selected CARTaGENE general population subjects in Quebec, Canada. Industrial SO2, NO2, and PM2.5 concentrations, estimated by the California Puff (CALPUFF) atmospheric dispersion model, were assigned based on residential postal codes at the time of sera collection. Single-exposure logistic regressions were performed for ACPA positivity defined by 20 U/ml, 40 U/ml, and 60 U/ml thresholds, adjusting for age, sex, French Canadian origin, smoking, and family income. Associations between regional overall PM2.5 exposure and ACPA positivity were also investigated. The associations between the combined three industrial exposures and the ACPA positivity were assessed by weighted quantile sum (WQS) regressions. RESULTS: Significant associations between individual industrial exposures and ACPA positivity defined by the 20 U/ml threshold were seen with single-exposure logistic regression models, for industrial emissions of PM2.5 (odds ratio, OR = 1.19, 95% confidence intervals, CI: 1.04-1.36) and SO2 (OR = 1.03, 95% CI: 1.00-1.06), without clear associations for NO2 (OR = 1.01, 95% CI: 0.86-1.17). Similar findings were seen for the 40 U/ml threshold, although at 60 U/ml, the results were very imprecise. The WQS model demonstrated a positive relationship between combined industrial exposures and ACPA positivity (OR = 1.36, 95% CI: 1.10-1.69 at 20 U/ml) and suggested that industrial PM2.5 may have a closer association with ACPA positivity than the other exposures. Again, similar findings were seen with the 40 U/ml threshold, though 60 U/ml results were imprecise. No clear association between ACPA and regional overall PM2.5 exposure was seen. CONCLUSIONS: We noted positive associations between ACPA and industrial emissions of PM2.5 and SO2. Industrial PM2.5 exposure may play a particularly important role in this regard.

Cellular senescence is associated with reorganization of the microtubule cytoskeleton.

Senescent cells undergo structural and functional changes that affect essentially every aspect of cell physiology. To date, the impact of senescence on the cytoskeleton is poorly understood. This study evaluated the cytoskeleton in two independent cellular models of kidney epithelium senescence. Our work identified multiple senescence-related alterations that impact microtubules and filamentous actin during interphase. Both filamentous systems reorganized profoundly when cells became senescent. As such, microtubule stability increased during senescence, making these filaments more resistant to disassembly in the cold or by nocodazole. Microtubule stabilization was accompanied by enhanced α-tubulin acetylation on lysine 40 and the depletion of HDAC6, the major deacetylase for α-tubulin lysine 40. Rho-associated kinase Rock1 is an upstream regulator that modulates key properties of the cytoplasmic cytoskeleton. Our research shows that Rock1 concentrations were reduced significantly in senescent cells, and we revealed a mechanistic link between microtubule stabilization and Rock1 depletion. Thus, Rock1 overexpression partially restored the cold sensitivity of microtubules in cells undergoing senescence. Additional components relevant to microtubules were affected by senescence. Specifically, we uncovered the senescence-related loss of the microtubule nucleating protein γ-tubulin and aberrant formation of γ-tubulin foci. Concomitant with the alterations of microtubule and actin filaments, senescent cells displayed functional changes. In particular, cell migration was impaired significantly in senescent cells. Taken together, our study identified new senescence-associated deficiencies of the microtubule and actin cytoskeleton, provided insights into the underlying molecular mechanisms and demonstrated functional consequences that are important to the physiology and function of renal epithelial cells.

Methotrexate exposure and risk of strongyloidiasis.

OBJECTIVE: Rheumatologic disease patients receiving immunomodulating drugs such as methotrexate (MTX) have increased infection rates. Strongyloides, a global endemic intestinal parasite, can cause significant or fatal disease in immunocompromised patients. The risk of serious Strongyloides infection with MTX dosed for rheumatologic disease is unknown. METHODS: We performed a systematic literature review searching EMBASE, Medline and Web of Science databases. All studies reporting humans exposed to MTX and tested for Strongyloides were reviewed. Exclusion criteria were bone marrow transplantation, intrathecal route and MTX exposure completed >1 year prior to clinically apparent Strongyloides disease. RESULTS: After excluding duplicates, 294 articles were reviewed. Of these, 29 cases were described in 27 papers. Twenty cases (69%) had an underlying rheumatologic or dermatologic disease, the rest had a haematologic disease. Hyperinfection or dissemination was found in 59% of cases (52% low-dose MTX; 75% high-dose MTX). Death occurred in 34% of cases (19% low-dose MTX; 75% high-dose MTX, P < 0.01). All eight patients on high-dose MTX received other immunosuppressants. Corticosteroids were taken in 18/21 patients on low-dose MTX. One of the three patients on MTX monotherapy had hyperinfection syndrome. None had disseminated Strongyloides. CONCLUSIONS: Serious Strongyloides infection can occur with low-dose MTX particularly when given with other immunosuppression. Global travel and greater awareness of rheumatologic conditions in low- to middle-income countries will increase the exposure of individuals prescribed MTX (with or without corticosteroids) to Strongyloides. Strongyloides screening and treatment should be considered for individuals receiving low-dose MTX therapy, particularly if combined with additional immunosuppression.

OBJECTIF: Les patients atteints de maladies rhumatologiques recevant des médicaments immunomodulateurs tels que le méthotrexate (MTX) présentent des taux d'infection plus élevés. Strongyloides, un parasite intestinal endémique mondial, peut causer une maladie grave ou fatale chez les patients immunodéprimés. Le risque d'infection sévère à Strongyloides sous administration de MTX pour le traitement de la maladie rhumatologique est inconnu. MÉTHODES: Nous avons effectué une revue systématique de la littérature en recherchant les bases de données EMBASE, Medline et Web of Science. Toutes les études rapportant sur des humains exposés au MTX et testés pour Strongyloides ont été passées en revue. Les critères d'exclusion étaient la greffe de moelle osseuse, la voie intrathécale et l'exposition au MTX complétée plus d'un an avant l'apparition de la maladie à Strongyloides cliniquement apparente. RÉSULTATS: Après exclusion des doublons, 294 articles ont été analysés. Parmi ceux-ci, 29 cas ont été décrits dans 27 articles. Vingt cas (69%) avaient une maladie rhumatologique ou dermatologique sous-jacente, les autres avaient une maladie hématologique. Une hyperinfection ou dissémination a été constatée dans 59% des cas (52% sous MTX à faible dose; 75% sous MTX à forte dose). La mort est survenue dans 34% des cas (19% des cas sous MTX à faible dose; 75% des cas sous MTX à forte dose, p <0,01). Tous les huit patients ayant reçu une dose élevée de MTX avaient reçu d'autres immunosuppresseurs. Des corticostéroïdes ont été administrés à 18 patients sur 21 sous MTX à faible dose. Un des trois patients sous MTX en monothérapie avait un syndrome d'hyperinfection. Aucun n'avait une infection disséminée à Strongyloides. CONCLUSIONS: Une infection sévère à Strongyloides peut survenir avec le MTX à faible dose, en particulier lorsqu'administré avec une autre immunosuppression. Les voyages à travers le monde et une plus grande sensibilisation aux conditions rhumatologiques dans les pays à revenu faible et intermédiaire augmenteront l'exposition à Strongyloides chez les individus chez qui le MTX (avec ou sans corticostéroïdes) est prescrit. Le dépistage et le traitement de Strongyloides devraient être envisagés chez les personnes recevant un traitement au MTX à faible dose, en particulier lorsqu'associé à une immunosuppression supplémentaire.

Dissecting the molecular mechanisms that impair stress granule formation in aging cells.

Aging affects numerous aspects of cell biology, but the senescence-associated changes in the stress response are only beginning to emerge. To obtain mechanistic insights into these events, we examined the formation of canonical and non-canonical stress granules (SGs) in the cytoplasm. SG generation is a key event after exposure to physiological or environmental stressors. It requires the SG-nucleating proteins G3BP1 and TIA-1/TIAR and stress-related signaling events. To analyze SG formation, we used two independent models of somatic cell aging. In both model systems, cellular senescence impaired the assembly of two SG classes: (i) it compromised the formation of canonical SGs, and (ii) skewed the production of non-canonical SGs. We dissected the mechanisms underlying these senescence-dependent changes in granule biogenesis and identified several specific targets that were modulated by aging. Thus, we demonstrate a depletion of G3BP1 and TIA-1/TIAR in senescent cells and show that the loss of G3BP1 contributed to impaired SG formation. We further reveal that aging reduced Sp1 levels; this transcription factor regulated G3BP1 and TIA-1/TIAR abundance. The assembly of canonical SGs relies on the phosphorylation of translation initiation factor eIF2α. We show that senescence can cause eIF2α hyperphosphorylation. CReP is a subunit of protein phosphatase 1 and critical to reverse the stress-dependent phosphorylation of eIF2α. We demonstrate that the loss of CReP correlated with the aging-related hyperphosphorylation of eIF2α. Together, we have identified significant changes in the stress response of aging cells and provide mechanistic insights. Based on our work, we propose that the decline in SG formation can provide a new biomarker to evaluate cellular aging.

funtooNorm: an R package for normalization of DNA methylation data when there are multiple cell or tissue types.

MOTIVATION: DNA methylation patterns are well known to vary substantially across cell types or tissues. Hence, existing normalization methods may not be optimal if they do not take this into account. We therefore present a new R package for normalization of data from the Illumina Infinium Human Methylation450 BeadChip (Illumina 450 K) built on the concepts in the recently published funNorm method, and introducing cell-type or tissue-type flexibility. RESULTS: funtooNorm is relevant for data sets containing samples from two or more cell or tissue types. A visual display of cross-validated errors informs the choice of the optimal number of components in the normalization. Benefits of cell (tissue)-specific normalization are demonstrated in three data sets. Improvement can be substantial; it is strikingly better on chromosome X, where methylation patterns have unique inter-tissue variability. AVAILABILITY AND IMPLEMENTATION: An R package is available at https://github.com/GreenwoodLab/funtooNorm, and has been submitted to Bioconductor at http://bioconductor.org.

Industrial air emissions, and proximity to major industrial emitters, are associated with anti-citrullinated protein antibodies.

OBJECTIVE: To determine the association of anti-citrullinated antibodies (ACPA) with the ambient air pollutants fine particulate matter (PM2.5) and sulfur dioxide (SO2). METHODS: The CARTaGENE first-wave cohort includes 20,000 general population subjects from Quebec (Canada). On a sample of unselected 1586 subjects, we determined serum, ACPA and performed multivariable logistic regression, for the outcome of positive ACPA, assessing for independent effects of our air pollution variables, adjusting for age, sex, smoking, and French Canadian origin. Two models assessed distance to main industrial emitters of PM2.5, and of SO2, and two models assessed tons of SO2 and of PM2.5 annual emissions. We also assessed associations with PM2.5 regional ambient concentrations estimated with satellite imagery. RESULTS: Adjusted analyses suggested a positive association between annual industrial PM2.5 and SO2 emissions and the presence of ACPA antibodies (OR: 1.02, 95%CI 1.00-1.04 per 10t of PM2.5 and 100t of SO2). The data were also consistent with a negative association between the presence of ACPA, and distance to a major industrial emitter of both PM2.5 and SO2. We found no association with PM2.5 estimates of ambient levels. CONCLUSIONS: These analyses suggest that exposure to industrial emissions of air pollutants is related to ACPA positivity.

Cytokine priming enhances the antifibrotic effects of human adipose derived mesenchymal stromal cells conditioned medium.

BACKGROUND: Fibrosis is a pathological scarring process characterized by persistent myofibroblast activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC. As a result, we lack evidence on the effect of cytokine priming on MSC's antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming. METHODS: We compared the antifibrotic effects of resting versus interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) primed MSC-CM in four in vitro assays: prevention of fibroblast activation, myofibroblasts deactivation, ECM degradation and fibrosis resolution in lung explant cultures. Furthermore, we performed transcriptomic analysis of myofibroblasts treated or not with resting or primed MSC-CM and proteomic characterization of resting and primed MSC-CM. RESULTS: We isolated MSC from adipose tissue of 8 donors, generated MSC-CM and tested each MSC-CM independently. We report that MSC-CM treatment prevented TGF-ß induced fibroblast activation to a similar extent as nintedanib but, in contrast to nintedanib, MSC-CM reduced fibrogenic myofibroblasts (i.e. transcriptomic upregulation of apoptosis, senescence, and inflammatory pathways). These effects were larger when primed rather than resting MSC-CM were used. Priming increased the ability of MSC-CM to remodel the ECM, reducing its content of collagen I and fibronectin, and reduced the fibrotic load in TGF-ß treated lung explant cultures. Priming increased the following antifibrotic proteins in MSC-CM: DKK1, MMP-1, MMP-3, follistatin and cathepsin S. Inhibition of DKK1 reduced the antifibrotic effects of MSC-CM. CONCLUSIONS: In vitro, MSC-CM promote fibrosis resolution, an effect enhanced following MSC cytokine priming. Specifically, MSC-CM reduces fibrogenic myofibroblasts through apoptosis, senescence, and by enhancing ECM degradation. Future studies will establish the in vivo relevance of MSC priming to fibrosis resolution.

Methotrexate and Tumor Necrosis Factor Inhibitors Independently Decrease Neutralizing Antibodies after SARS-CoV-2 Vaccination: Updated Results from the SUCCEED Study.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied the effects of methotrexate and tumor necrosis factor inhibitor (TNFi) on neutralization responses after COVID-19 vaccination in immune-mediated inflammatory disease (IMID). Methods: Prospective data and sera of adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and systemic lupus (SLE) were collected at six academic centers in Alberta, Manitoba, Ontario, and Quebec between 2022 and 2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between five laboratories, and each lab's results were analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for the effects of methotrexate and TNFi were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID-19 vaccinations (number/type), and infections in the 6 months prior to sampling. The adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for the ancestral strains and the Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) were RA, and the remainder were PsA, SpA, and SLE. The mean age was 57 (62.2% female). For both the individual labs and the meta-analyses, the adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval (CI) 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

Duration of Postvaccination Neutralizing Antibodies to SARS-CoV-2 and Medication Effects: Results from the Safety and Immunogenicity of COVID-19 Vaccination in Systemic Immune-Mediated Inflammatory Diseases Cohort Study.

OBJECTIVE: In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications. METHODS: Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5. RESULTS: Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses. CONCLUSION: Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.

How Safe Are COVID-19 Vaccines in Individuals with Immune-Mediated Inflammatory Diseases? The SUCCEED Study.

We were tasked by Canada's COVID-19 Immunity Task Force to describe severe adverse events (SAEs) associated with emergency department (ED) visits and/or hospitalizations in individuals with immune-mediated inflammatory diseases (IMIDs). At eight Canadian centres, data were collected from adults with rheumatoid arthritis (RA), axial spondyloarthritis (AxS), systemic lupus (SLE), psoriatic arthritis (PsA), and inflammatory bowel disease (IBD). We administered questionnaires, analyzing SAEs experienced within 31 days following SARS-CoV-2 vaccination. About two-thirds (63%) of 1556 participants were female; the mean age was 52.5 years. The BNT162b2 (Pfizer) vaccine was the most common, with mRNA-1273 (Moderna) being second. A total of 49% of participants had IBD, 27.4% had RA, 14.3% had PsA, 5.3% had SpA, and 4% had SLE. Twelve (0.77% of 1556 participants) SAEs leading to an ED visit or hospitalization were self-reported, occurring in 11 participants. SAEs included six (0.39% of 1556 participants) ED visits (including one due to Bell's Palsy 31 days after first vaccination) and six (0.39% of 1556 participants) hospitalizations (including one due to Guillain-Barré syndrome 15 days after the first vaccination). Two SAEs included pericarditis, one involved SLE (considered a serious disease flare), and one involved RA. Thus, in the 31 days after SARS-CoV-2 vaccination in our IMID sample, very few serious adverse events occurred. As SARS-CoV2 continues to be a common cause of death, our findings may help optimize vaccination acceptance.

Autoimmune sensorineural hearing loss: the otology-rheumatology interface.

Autoimmune sensorineural hearing loss (SNHL) is a rare clinical entity characterized by a progressive fluctuating bilateral asymmetric SNHL that develops over several weeks to months. Vestibular symptoms, tinnitus and aural fullness are present in up to 50% of patients. Due to the lack of specific diagnostic tests, both clinical suspicion and responsiveness to corticosteroids are the pillars for the diagnosis of autoimmune SNHL. The evaluation of patients in whom this condition is suspected should include a detailed history and physical examination, an audiogram, an MRI and a limited laboratory workup to exclude secondary causes of hearing loss. The low frequency of this condition, the heterogeneity in the designs of the available studies and the absence of randomized trials comparing treatment responses and assessing long-term outcomes are some of the factors accounting for the limited evidence to guide the clinician in the approach to the diagnosis and treatment of autoimmune SNHL.

Assessing process of care in rheumatoid arthritis at McGill University hospitals.

OBJECTIVE: In rheumatoid arthritis (RA), quality indicators (QIs) are tools used to measure process of care. This study aimed to assess performance of selected QIs from the 2004 Arthritis Foundation's QI Set at 2 major sites of a university network of teaching hospitals. METHODS: The charts and electronic hospital records of 76 RA patients were audited to determine adherence to QIs. Logistic multivariate regression analyses were performed to investigate potential determinants of nonadherence and propose measures to facilitate better QI compliance, as a potential strategy towards RA care improvement. RESULTS: We identified consistent observance of QIs mandating prescription of disease-modifying antirheumatic drug therapy for all patients, drug adjustment with disease activity, prednisone tapering, and bisphosphonate therapy if indicated for patients on glucocorticoids. However, there was either lack of documentation or true inconsistent adherence to QIs dealing with radiograph performance, functional capacity assessment, and screening for hepatitis and tuberculosis before commencement of methotrexate and biologic agents, respectively. For the specific QIs analyzed, we did not find any definite independent associations with the studied variables. CONCLUSIONS: Our findings indicate that while there is frequent evidence for adherence to certain RA quality care standards at our centers, there is less compliance to others. Strategies to optimize the performance or documentation of those found most lacking, namely, functional capacity and screening for specific drug contraindications, could improve patient care. Radiographic disease monitoring, while lacking, may represent a move toward other more sensitive methods of RA progression detection, such as joint ultrasound. The inclusion of patient- and physician-derived information could help elucidate the reasons underlying nonadherence.