Pathogenic, glycolytic PD-1+ B cells accumulate in the hypoxic RA joint

While autoantibodies are used in the diagnosis of rheumatoid arthritis (RA), the function of B cells in the inflamed joint remains elusive. Extensive flow cytometric characterization and SPICE algorithm analyses of single-cell synovial tissue from patients with RA revealed the accumulation of switched and double-negative memory programmed death-1 receptor–expressing (PD-1–expressing) B cells at the site of inflammation. Accumulation of memory B cells was mediated by CXCR3, evident by the observed increase in CXCR3-expressing synovial B cells compared with the periphery, differential regulation by key synovial cytokines, and restricted B cell invasion demonstrated in response to CXCR3 blockade. Notably, under 3% O2 hypoxic conditions that mimic the joint microenvironment, RA B cells maintained marked expression of MMP-9, TNF, and IL-6, with PD-1+ B cells demonstrating higher expression of CXCR3, CD80, CD86, IL-1β, and GM-CSF than their PD-1– counterparts. Finally, following functional analysis and flow cell sorting of RA PD-1+ versus PD-1– B cells, we demonstrate, using RNA-Seq and emerging fluorescence lifetime imaging microscopy of cellular NAD, a significant shift in metabolism of RA PD-1+ B cells toward glycolysis, associated with an increased transcriptional signature of key cytokines and chemokines that are strongly implicated in RA pathogenesis. Our data support the targeting of pathogenic PD-1+ B cells in RA as a focused, novel therapeutic option

Predictors of hospitalization in patients with rheumatic disease and COVID-19 in Ireland: data from the COVID-19 global rheumatology alliance registry

Objectives Given the limited data regarding the risk of hospitalization in patients with rheumatic disease and coronavirus disease 2019 (COVID-19) in Ireland, we used the COVID-19 Global Rheumatology Alliance (GRA) registry data to study outcomes and their predictors. The primary objective was to explore potential predictors of hospitalization. Methods We examined data on patients and their disease-related characteristics entered in the COVID-19 GRA provider registry from Ireland (from 24 March 2020 to 31 August 2020). Multivariable logistic regression was used to assess the association of demographic and clinical characteristics with hospitalization. Results Of 105 patients, 47 (45.6%) were hospitalized and 10 (9.5%) died. Multivariable logistic regression analysis showed that age [odds ratio (OR) = 1.06, 95% CI 1.01, 1.10], number of co-morbidities (OR = 1.93, 95% CI 1.11, 3.35) and glucocorticoid use (OR = 15.01, 95% CI 1.77, 127.16) were significantly associated with hospitalization. A diagnosis of inflammatory arthritis was associated with lower odds of hospitalization (OR = 0.09, 95% CI 0.02, 0.32). Conclusion Increasing age, co-morbidity burden and glucocorticoid use were associated with hospitalization, whereas a diagnosis of inflammatory arthritis was associated with lower odds of hospitalization

Outcomes of COVID-19 in people with rheumatic and musculoskeletal disease in Ireland over the first 2 years of the pandemic

Background: Poor COVID-19 outcomes occur with higher frequency in people with rheumatic and musculoskeletal diseases (RMD). Better understanding of the factors involved is crucial to informing patients and clinicians regarding risk mitigation. Aim: To describe COVID-19 outcomes for people with RMD in Ireland over the first 2 years of the pandemic. Methods: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 31st March 2022 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated. Results: Of 237 cases included, 59.9% were female, 95 (41.3%) were hospitalised, and 22 (9.3%) died. Hospitalisation was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular and pulmonary disease, and cancer. Hospitalisation was less frequent in people with inflammatory arthritis and conventional synthetic or biologic disease-modifying antirheumatic drug use. Hospitalisation had a U-shaped relationship with disease activity, being more common in both high disease activity and remission. Mortality was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular disease, pulmonary disease, and obesity. Inflammatory arthritis was less frequent in those who died. Conclusion: Hospitalisation or death were more frequently experienced by RMD patients with increasing age, certain comorbidities including potentially modifiable ones, and certain medications and diagnoses amongst other factors. These are important 'indicators' that can help risk-stratify and inform the management of RMD patients.</p

Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 global rheumatology alliance registry

Objectives: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland.Methods: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 9th July 2021 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalisation and mortality over time were investigated using logistic regression with the time period as a categorical variable.Results: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities, and specific comorbidities of cancer, cardiovascular, and pulmonary disease were more common in those hospitalised. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalised. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalisation or mortality did not change over time.Conclusion: No temporal trend was observed in either COVID-19 related hospitalisation or mortality outcomes for people with rheumatic disease in Ireland.</div

Proceedings of the American College of Rheumatology/Association of Physicians of Great Britain and Ireland Connective Tissue Disease-Associated Interstitial Lung Disease Summit: A Multidisciplinary Approach to Address Challenges and Opportunities

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147838/1/art40769.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147838/2/art40769_am.pd

Lack of effect of acute oral ingestion of vitamin C on oxidative stress, arterial stiffness or blood pressure in healthy subjects

10.1080/10715760802087431Free Radical Research425514-52

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

Background: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT). Methods: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. Findings: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273. The results were similar between those aged 30–69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. Interpretation: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. Funding: UK Vaccine Taskforce and National Institute for Health Research