TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity

Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C+ monocytes from old (18–22 mo) mice and CD14+CD16+ intermediate/inflammatory monocytes from older adults also contributed to this “age-associated inflammation” as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C+ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C+ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C+ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity

Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases : Results from the COVID-19 Global Rheumatology Alliance Vaccine Survey

Funding Information: Competing interests SES has received funding from the Vasculitis Foundation and the Vasculitis Clinical Research Consortium unrelated to this work. JL has received research grant funding from Pfizer unrelated to this work. ES is a Board Member of the Canadian Arthritis Patient Alliance, a patient run, volunteer-based organisation whose activities are primarily supported by independent grants from pharmaceutical companies. MP was supported by a Rheumatology Research Foundation Scientist Development grant. DA-R is a Scientific Advisor for GlaxoSmithKilne unrelated to this work. FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica and 4P Pharma outside of the submitted work. No funding relevant to this manuscript. RC: speakers bureau for Janssen, Roche, Sanofi, AbbVie. KD reports no COI-unpaid volunteer president of the Autoinflammatory Alliance. Any grants or funding from pharma is received by the non-profit organisation only. CLH received funding under a sponsored research agreement unrelated to the data in the paper from Vifor Pharmaceuticals. LeK has received a research grant from Lilly unrelated to this work. AHJK participated in consulting, advisory board or speaker's bureau for Alexion Pharmaceuticals, Aurinia Pharmaceuticals, Annexon Biosciences, Exagen Diagnostics and GlaxoSmithKilne and received funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. JSingh has received consultant fees from Crealta/ Horizon, Medisys, Fidia, PK Med, Two Labs, Adept Field Solutions, Clinical Care Options, Clearview Healthcare Partners, Putnam Associates, Focus Forward, Navigant Consulting, Spherix, MedIQ, Jupiter Life Science, UBM, Trio Health, Medscape, WebMD and Practice Point Communications; and the National Institutes of Health and the American College of Rheumatology. JSingh owns stock options in TPT Global Tech, Vaxart Pharmaceuticals and Charlotte’s Web Holdings. JSingh previously owned stock options in Amarin, Viking and Moderna Pharmaceuticals. JSingh is on the speaker’s bureau of Simply Speaking. JSingh is a member of the executive of Outcomes Measures in Rheumatology (OMERACT), an organisation that develops outcome measures in rheumatology and receives arms-length funding from eight companies. JSingh serves on the FDA Arthritis Advisory Committee. JSingh is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. JSingh is the editor and the Director of the University of Alabama at Birmingham (UAB) Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. NSingh is supported by funding from the Rheumatology Research Foundation Investigator Award and the American Heart Association. MFU-G has received research support from Pfizer and Janssen, unrelated to this work. SB reports personal fees from Novartis, AbbVie, Pfizer and Horizon Pharma, outside the submitted work. RG reports personal fees from AbbVie New Zealand, Cornerstones, Janssen New Zealand and personal fees and non-financial support Pfizer New Zealand (all <US$10 000) outside the submitted work. PMM reports personal fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and UCB, grants and personal fees from Orphazyme, outside the submitted work. PCR reports personal fees from AbbVie, Gilead, Lilly and Roche, grants and personal fees from Novartis, UCB Pharma, Janssen and Pfizer and non-financial support from BMS, outside the submitted work. PS reports honoraria from Social media editor for @ACR_Journals, outside the submitted work. ZSW reports grants from NIH, BMS and Principia/ Sanofi and personal fees from Viela Bio and MedPace, outside the submitted work. JY reports personal fees from Pfizer and Eli Lilly, and grants and personal fees from AstraZeneca, outside the submitted work. MJL reports grants from American College of Rheumatology, during the conduct of the study and consulting fees from AbbVie, Amgen, Actelion, Boehringer Ingelheim, BMS, Celgene, Gilead, J&J, Mallinckrodt, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi and UCB, outside the submitted work. LGR was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS; ZIAES101074) of the National Institutes of Health. JH reports grants from Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Rheumatology Research Alliance, and personal fees from Novartis, Pfizer and Biogen, outside the submitted work. JSimard received research grant funding from the National Institutes of Health unrelated to this work (NIAMS: R01 AR077103 and NIAID R01 AI154533). JSparks has performed consultancy for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Optum and Pfizer unrelated to this work. Funding Information: Funding This study was supported by the European Alliance of Associations for Rheumatology and American College of Rheumatology Research and Education Foundation. Dr. Lisa Rider's involvement was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Background. We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion. Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.publishersversionPeer reviewe

Prolonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey

OBJECTIVE: We investigated prolonged COVID-19 symptom duration, defined as lasting 28 days or longer, among people with systemic autoimmune rheumatic diseases (SARDs). METHODS: We analysed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (2 April 2021-15 October 2021) to identify people with SARDs reporting test-confirmed COVID-19. Participants reported COVID-19 severity and symptom duration, sociodemographics and clinical characteristics. We reported the proportion experiencing prolonged symptom duration and investigated associations with baseline characteristics using logistic regression. RESULTS: We identified 441 respondents with SARDs and COVID-19 (mean age 48.2 years, 83.7% female, 39.5% rheumatoid arthritis). The median COVID-19 symptom duration was 15 days (IQR 7, 25). Overall, 107 (24.2%) respondents had prolonged symptom duration (≥28 days); 42/429 (9.8%) reported symptoms lasting ≥90 days. Factors associated with higher odds of prolonged symptom duration included: hospitalisation for COVID-19 vs not hospitalised and mild acute symptoms (age-adjusted OR (aOR) 6.49, 95% CI 3.03 to 14.1), comorbidity count (aOR 1.11 per comorbidity, 95% CI 1.02 to 1.21) and osteoarthritis (aOR 2.11, 95% CI 1.01 to 4.27). COVID-19 onset in 2021 vs June 2020 or earlier was associated with lower odds of prolonged symptom duration (aOR 0.42, 95% CI 0.21 to 0.81). CONCLUSION: Most people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about 1 in 4 experienced COVID-19 symptom duration 28 days or longer; 1 in 10 experienced symptoms 90 days or longer. Future studies are needed to investigate the possible relationships between immunomodulating medications, SARD type/flare, vaccine doses and novel viral variants with prolonged COVID-19 symptoms and other postacute sequelae of COVID-19 among people with SARDs

results from the COVID-19 Global Rheumatology Alliance Vaccine Survey

Funding Information: MP, KK, and ES contributed equally and are co-first authors. JHS, JASp, and JFS contributed equally and are co-senior authors. The authors thank Berk Degirmenci, Christele Feliix, Shangyi Jin, Candace A Palmerlee, Andrea Peirce, Lisa G Rider, Esra Sari, Robert Tseng, and Leslie Wang for their invaluable contributions to the GRA Vax Survey. MP, KK, ES, SES, and JWL contributed to data collection, data quality control, and data analysis and interpretation. AAA, DA-R, SA, RPB, FB, IB, YPEC, RC, AD-G, ED, KLD, TAG, CLH, RH, BFH, EH, LK, AK, AHJK, DFLL, CL, EFM, BM, SM, MN, ADS, JASi, NS, MFU-G, JW, KJY, and EAZ-T, critically revised the manuscript and provided intellectual content. TTM, CH, MJL, ML, GF, and LT contributed to planning and data collection, reviewed the manuscript, and provided important intellectual content. SB, WC, RG, PMM, PCR, PS, ZSW, and JY contributed to the acquisition, analysis, and interpretation of the data. JASp, JFS, and JSH directed the work, designed the data collection methods, and contributed to the analysis and interpretation of the data. MP, KK, ES, SES, JWL, SB, WC, RG, PMM, PCR, PS, ZSW, JY, JASp, JFS, and JSH drafted and revised the manuscript critically for important intellectual content and gave final approval of the version to be published. SES, JWL, KK, JFS, and JASp had full access to the data and verify the credibility of the underlying data. All authors have read, revised, and approved this manuscript and take final responsibility for the decision to submit for publication. MP reports clinical trials participation with AbbVie and grants from Rheumatology Research Foundation, outside the submitted work. ES is a board member of the Canadian Arthritis Patient Alliance, a patient run, volunteer-based organisation whose activities are primarily supported by independent grants from pharmaceutical companies. JWL has received research grant funding from Pfizer unrelated to this work. SES reports research funding related to clinical trials from AstraZeneca (MANDARA), outside of the submitted work and is supported by the Vasculitis Clinical Research Consortium and Vasculitis Foundation outside of the submitted work. DA-R is a scientific advisor for GlaxoSmithKilne unrelated to this work. RC reports speaker fees from Janssen, Roche, Sanofi, and AbbVie, outside of the submitted work. AD-G reports grants from the Center for Disease Control and Prevention, Rheumatology Research Foundation, and Mayo Clinic, outside the submitted work. KLD is an unpaid volunteer president of the Autoinflammatory Alliance and reports grants from Novartis, Sobi, National Institutes of Health (NIH), and Horizon Bio, all received by the non-profit organisation outside of the submitted work. CLH received funding under a sponsored research agreement unrelated to the data in the paper from Vifor Pharmaceuticals. RH reports grants from AbbVie, Amgen, Boehringer Ingleheim, Johnson and Johnson, Lilly, Novartis, Pfizer, and Union Chimique Belge, all paid to Spondylitis Association of America, consultant fees from GlaxoSmithKline and Novartis, outside the submitted work. RH also owns stocks (<20 shares and representing <4% of personal investments) in AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Eli Lilly, Merck, Novartis, Pfizer, Teva, and Union Chimique Belge. AHJK reports personal fees from Exagen Diagnostics, Alexion Pharmaceuticals, and Aurinia Pharmaceuticals, grants from National Institutes of Health, Rheumatology Research Foundation, and Helmsley Charitable Trust, grants and personal fees from GlaxoSmithKline, outside the submitted work. EFM reports personal fees from Boehringer Ingelheim, and that Liga Portuguesa Contra as Doenças Reumaticas has received grants from AbbVie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal, Merck Sharp & Dohme, Medac and from A Menarini Portugal–Farmacêutica; grants and non-financial support from Pfizer and Grünenthal, outside the submitted work. JASi has received consultant fees from Crealta/Horizon, Medisys, Fidia, PK Med, Two labs, Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, MedIQ, Jupiter Life Science, United BioMed, Trio Health, Medscape, WebMD, and Practice Point communications; and the National Institutes of Health, and the American College of Rheumatology. JASi owns stock options in TPT Global Tech, Vaxart pharmaceuticals, and Charlotte's Web Holdings and previously owned stock options in Amarin, Viking and Moderna pharmaceuticals. JASi is on the speaker's bureau of Simply Speaking and is a member of the executive of Outcomes Measures in Rheumatology, an organisation that develops outcome measures in rheumatology and receives funding from eight companies . JASi also serves on the FDA Arthritis Advisory Committee and is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. JASi is also the editor and the Director of the University of Alabama at Birmingham Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. MFU-G has received research support from Pfizer and Janssen, unrelated to this work. SB reports non-branded consulting fees from Novartis, AbbVie, Pfizer, and Horizon Pharma, outside the submitted work, and is a Pfizer employee as of September, 2021. RG reports personal fees from AbbVie New Zealand, Cornerstones, Janssen New Zealand, and Novartis, and personal fees and non-financial support Pfizer Australia (all <AU$10,000) outside the submitted work. PMM reports personal fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and Union Chimique Belge; and grants and personal fees from Orphazyme, outside the submitted work. PCR reports personal fees from AbbVie, Gilead, Lilly, and Roche; grants and personal fees from Novartis, Union Chimique Belge, Janssen, and Pfizer; and non-financial support from Bristol Myers Squibb, outside the submitted work. PS reports honoraria from bring the social media editor for the American College of Rheumatology journals, outside the submitted work. ZSW reports grants from NIH, Bristol Myers Squibb, and Principia/Sanofi; and personal fees from Viela Bio and MedPace, outside the submitted work. JY reports personal fees from Pfizer and Eli Lilly, and grants and personal fees from AstraZeneca, outside the submitted work. CH reports personal fees from AstraZeneca and Aurinia Pharmaceuticals, outside the submitted work. MJL reports grants from American College of Rheumatology, during the conduct of the study and consulting fees from AbbVie, Amgen, Actelion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead, Johnson and Johnson, Mallinckrodt, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi, and Union Chimique Belge, outside the submitted work. JSH reports grants from Childhood Arthritis and Rheumatology Research Alliance and Rheumatology Research Alliance, and personal fees from Novartis, Pfizer, and Biogen, outside the submitted work. JASp reports grants from National Institute of Arthritis and Musculoskeletal and Skin Diseases, Rheumatology Research Foundation, and R Bruce and Joan M Mickey Research Scholar Fund; and consulting fees for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Optum, and Pfizer, unrelated to this work. JFS received research grant funding from the National Institutes of Health unrelated to this work (NIAMS R01 AR077103, and NIAID R01 AI154533). All other authors report no competing interests. This study was funded by the American College of Rheumatology (ACR). The ACR was not involved in any aspect of study design, collection, analysis, or interpretation of data, writing of the report, or the decision to submit the paper for publication. The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the ACR, the European Alliance of Associations for Rheumatology, the UK National Health Service, the National Institute for Health Research, or the UK Department of Health, or any other organisation. Researchers interested in performing additional analyses from survey data are invited to submit proposals through the COVID-19 Global Rheumatology Alliance at rheumcovid.org . For approved projects, we will provide summary tables and data analyses as requested. We do not currently have institutional review board approval to make the raw data available to other researchers.publishersversionpublishe

Sedentary Time and Screen-Based Sedentary Behaviors of Children With a Chronic Disease

The objectives of this study were to (i) assess sedentary time and prevalence of screen-based sedentary behaviors of children with a chronic disease and (ii) compare sedentary time and prevalence of screen-based sedentary behaviors to age- and sex-matched healthy controls. Sixty-five children (aged 6-18 years) with a chronic disease participated: survivors of a brain tumor, hemophilia, type 1 diabetes mellitus, juvenile idiopathic arthritis, cystic fibrosis, and Crohn's disease. Twenty-nine of these participants were compared with age- and sex-matched healthy controls. Sedentary time was measured objectively by an ActiGraph GT1M or GT3x accelerometer worn for 7 consecutive days and defined as less than 100 counts per min. A questionnaire was used to assess screen-based sedentary behaviors. Children with a chronic disease engaged in an average of 10.2 +/- 1.4 hr of sedentary time per day, which comprised 76.5 +/- 7.1% of average daily monitoring time. There were no differences between children with a chronic disease and controls in sedentary time (adjusted for wear time, p = .06) or in the prevalence of TV watching, and computer or video game usage for varying durations (p = .78, p = .39 and, p = .32 respectively). Children with a chronic disease, though relatively healthy, accumulate high levels of sedentary time, similar to those of their healthy peer

Immunomodulatory drugs have divergent effects on humoral and cellular immune responses to SARS-CoV-2 vaccination in people living with rheumatoid arthritis

Abstract Understanding the efficacy of SARS-CoV-2 vaccination in people on immunosuppressive drugs, including those with rheumatoid arthritis (RA), is critical for their protection. Vaccine induced protection requires antibodies, CD4+ T cells, and CD8+ T cells, but it is unclear if these are equally affected by immunomodulatory drugs. Here, we determined how humoral and cellular SARS-CoV-2 vaccination responses differed between people with RA and controls, and which drug classes impacted these responses. Blood was collected from participants with RA on immunomodulatory drugs and controls after their second, third, and fourth SARS-CoV-2 vaccinations. Receptor binding domain (RBD)-specific antibodies were quantified by ELISA. Spike-specific memory T cells were quantitated using flow cytometry. Linear mixed models assessed the impact of age, sex, and immunomodulatory drug classes on SARS-CoV-2 vaccination responses. Compared to non-RA controls (n = 35), participants with RA on immunomodulatory drugs (n = 62) had lower anti-RBD IgG and spike-specific CD4+ T cell levels, but no deficits in spike-specific CD8+ T cells, following SARS-CoV-2 vaccination. Use of costimulation inhibitors was associated with lower humoral responses. JAK inhibitors were associated with fewer spike-specific CD4+ T cells. Participants with RA on immunomodulatory drugs mounted weaker responses to SARS-CoV-2 vaccination, with different drug classes impacting the cellular and humoral compartments