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Objective: As part of the first phase of the OARSI Early-stage Symptomatic Knee Osteoarthritis (EsSKOA) initiative, we explored the first symptoms and experiences recalled by individuals with knee osteoarthritis (OA)., Design: This qualitative study, informed by qualitative description, was a secondary analysis of focus groups (n ​= ​17 groups) and one-on-one interviews (n ​= ​3) conducted in 91 individuals living with knee OA as part of an international study to better understand the OA pain experience. In each focus group or interview, participants were asked to describe their first symptoms of knee OA. We inductively coded these transcripts and conducted thematic analysis., Results: Mean age of participants was 70 years (range 47-92) and 68 ​% were female. We developed four overarching themes: Insidious and Episodic Onset , Diverse Early Symptoms, Must be Something Else , and Adjustments . Participants described the gradual and intermittent way in which symptoms of knee OA developed over many years; many could not identify a specific starting point. Participants described diverse initial knee symptoms, including activity-exacerbated joint pain, stiffness and crepitus. Most participants dismissed early symptoms or rationalized their presence, employing various strategies to enable continued participation in recreational and daily activities. Few sought medical attention until physical functioning was demonstrably impacted., Conclusions: The earliest symptoms of knee OA are frequently insidious in onset, episodic and present long before individuals present to health professionals. These results highlight challenges to identifying people with knee OA early and support the development of specific classification criteria for EsSKOA to capture individuals at an early stage., Competing Interests: LKK reports support from Canadian Institutes of Health Research Doctoral Award, and grant funding from Physician Services Incorporated (PSI) Resident Grant; JWL reports a Pfizer research grant completed in 2021, unrelated to this work; QW reports support from Osteoarthritis and Cartilage as an Associate Editor for statistics; AT reports support from Osteoarthritis and Cartilage as an Associate Editor for statistics, IKH reports consulting fees from AbbVie, GSK and Grünenthal, and leadership role as the OARSI Board of Directors Secretary; CTA reports grant funding and consulting/honoraria from AbbVie, Novartis, Pfizer, and Servier; LSL reports consulting/honoraria from Arthro Therapeutics AB, Sweden, and participation on a DSMB board for AstraZeneca; ME reports grant funding from Swedish Research Council, ERC, ALF, Kock Foundations, Gustav V 80 ​Year ​B-day foundation, NORDFORSK, FOREUM, Foundation for support to people with movement disability in Skåne, Österlund Foundation, SUS donations, consulting from Cellcolabs AB, and leadership role as the OARSI President-elect; JR reports a leadership role on the OARSI Ethics & Governance Committee, Nominating Committee; and TN reports grant funding and consulting/honoraria from Pfizer/Lilly, Regeneron and Novartis. All other authors report no competing interests., (© 2023 The Author(s).)

Competing Interests: JWL reports research grant from Pfizer, unrelated to this work, completed in 2021. SES reports research support from AstraZeneca, unrelated to this work.

Background: Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally., Methods: In this observational study, we derived individual-level data on adults (aged 18-99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death., Findings: 14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 μg/m 3 [95% CI 1·01-1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10-1·30]; p<0·0001), and population mobility (1·03 per 1% increase in number of visits to grocery and pharmacy stores [1·02-1·05]; p<0·0001 and 1·02 per 1% increase in number of visits to workplaces [1·00-1·03]; p=0·032) were independently associated with higher odds of mortality. Number of hospital beds (0·94 per 1-unit increase per 1000 people [0·88-1·00]; p=0·046), human development index (0·65 per 0·1-unit increase [0·44-0·96]; p=0·032), government response stringency (0·83 per 10-unit increase in containment index [0·74-0·93]; p=0·0018), as well as follow-up time (0·78 per month [0·69-0·88]; p<0·0001) were independently associated with lower odds of mortality. These factors sufficiently explained country-level variations in death attributable to COVID-19 (intraclass correlation coefficient 1·2% [0·1-9·5]; p=0·14)., Interpretation: Our findings highlight the importance of environmental and societal factors as potential explanations of the observed regional disparities in COVID-19 outcomes among people with rheumatic disease and lay foundation for a new research agenda to address these disparities., Funding: American College of Rheumatology and European Alliance of Associations for Rheumatology., Competing Interests: MID reports research support from Pfizer for unrelated work. AS reports grants from a consortium of 13 companies (AbbVie, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Lilly, Mylan, Hexal, Merck, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB) supporting the German RABBIT register, and personal fees from lectures for AbbVie, Merck, Roche, Bristol Myers Squibb, and Pfizer, outside of the submitted work. EFM reports that the Portuguese League Against Rheumatic Diseases received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal SA, Merck, Celgene, Medac, Pharmakern, the Global Alliance for Patient Access; grants and non-financial support from Pfizer; and non-financial support from Grünenthal GmbH, outside of the submitted work. KLH reports receiving speaker fees from Abbvie and grant income from Bristol Myers Squibb, UCB, and Pfizer, unrelated to this work. KLH is also supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre. LG reports research grants from Amgen, Galapagos, Janssen, Lilly, Pfizer, Sandoz, and Sanofi; and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Biogen, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB, all unrelated to this work. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, SA Pharma, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi, Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal GmbH, and UCB Pharma. JAS has performed consultancy for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, and Optum, unrelated to this work. LW has received consulting or speaking fees from Aurinia Pharma, outside of the submitted work. MFU-G reports grant or research support from Jannsen and Pfizer, unrelated to this work. The Swedish Rheumatology Quality Register, with LL as register holder, has agreements with Abbvie, Amgen, Eli Lilly, Gilead, Novartis, Pfizer, Sanofi, Sobi, and UCB for register data analyses, unrelated to this work. CR has received consulting or speaker fees from Abbvie, Amgen, AstraZeneca, BMS, Biogen, Eli Lilly, Glenmark, GlaxoSmithKline, Merck, Mylan, and Pfizer; and grants from Biogen, Lilly, and Nordic Pharma, all unrelated to this work. MJS has received speaker fees from Abbvie, AstraZeneca, Novartis, and Pfizer. AR has received speaker fees from Janssen, Pfizer, and Novartis. GP-E reports reports personal consulting fees, speaking fees, or both from Pfizer, GlaxoSmithKline, Janssen, Sandoz, and Sanofi, outside of the submitted work. PCR reports personal consulting fees, speaking fees, or both from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and travel assistance from Roche. PMM has received consulting fees, speaker fees, or both from Abbvie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, and UCB, unrelated to this work. PMM is supported by the NIHR University College London Hospitals Biomedical Research Centre. ES is a Board Member of the Canadian Arthritis Patient Alliance, a patient-run, volunteer-based organisation whose activities are largely supported by independent grants from pharmaceutical companies. JWL has received research funding from Pfizer, outside of the submitted work. JSH is supported by grants from the Rheumatology Research Foundation and has salary support from the Childhood Arthritis and Rheumatology Research Alliance. JSH has performed consulting for Novartis, Sobi, and Biogen, unrelated to this work. PS reports honorarium for doing social media for American College of Rheumatology journals. RG reports personal fees, speaking fees, or both from Abbvie, Janssen, Novartis, Pfizer, and Cornerstones; and travel assistance from Pfizer. SB reports non-branded consulting fees for AbbVie, Horizon, and Novartis; and is employed by Pfizer. ZSW reports grant support from Bristol Myers Squibb and Principia–Sanofi; and performed consultancy for Viela Bio and MedPace, outside of the submitted work. ZSW's work is supported by grants from the National Institutes of Health. JY has performed consulting for Eli Lilly, Pfizer, Aurinia, and AstraZeneca, outside of the submitted work. All other authors declare no competing interests., (Published by Elsevier Ltd.)

Background: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica., Methods: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease., Findings: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes., Interpretation: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases., Funding: American College of Rheumatology and the European Alliance of Associations for Rheumatology., Competing Interests: SES reports funding from a Vasculitis Clinical Research Consortium (VCRC)–Vasculitis Foundation Fellowship (the VCRC is part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Science [NCATS], and is funded by a collaboration between NCATS and the National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS; U54 AR057319]). RC reports speaker's fees from Janssen, Roche, Sanofi, and Abbvie outside the submitted work. CH received funding under a sponsored research agreement from Vifor Pharmaceuticals, outside the submitted work. SLM has received consulting fees from AbbVie; consulting fees from AstraZeneca; other from Roche-Chugai; consulting fees from Sanofi; and non-financial support from Roche, all outside the submitted work; and is a patron of the patient charity PMRGCAuk. PM is a Medical Research Council-GlaxoSmithKline (MRC-GSK) EMINENT clinical training fellow, who has received project funding from this organisation, outside the submitted work; has received funding from the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (UCLH BRC); reports grants from MRC-GSK; reports personal fees from Swedish Orphan Biovitrum and Lilly; and reports consultancy fees from Abbvie and Pfizer, all outside the submitted work. LN reports being a trustee of the charity PMR-GRA Scotland. JSA reports grants from the National Institute of Health (NIH) and NIAMS, the Rheumatology Research Foundation, the Brigham Research Institute, the R Bruce and Joan M Mickey Research Scholar Fund, and Amgen; grants and personal fees from Bristol-Myers Squibb; and personal fees from Gilead, Inova, Janssen, Optum, and Pfizer, all outside the submitted work. AD-G is supported by the US Centers for Disease Control and Prevention, the Rheumatology Research Foundation Scientist Development Award, the Robert D and Patricia E Kern Center for the Science of Health Care Delivery, and the Women's Health Career Enhancement Award outside the submitted work. KLH reports receiving speaker's fees from Abbvie; grant income from Bristol-Myers Squibb, UCB Pharma, and Pfizer, all outside the submitted work; and is supported by the NIHR Manchester Biomedical Research Centre outside the submitted work. RG reports non-financial support from Pfizer Australia and Janssen Australia; and personal fees from Pfizer Australia, Cornerstones, Janssen New Zealand, and Novartis, all outside the submitted work. UM-L is supported by grants from the German Ministry of Research and Education and the German Research Foundation outside the submitted work. MAG reports funding from the NIH and the NIAMS. PCR reports personal fees from Abbvie and Gilead; grants and personal fees from Janssen, Novartis, UCB Pharma, and Pfizer; non-financial support from Bristol-Myers Squibb and Pfizer; and personal fees from Lilly and Roche, all outside the submitted work. JY reports no competing interests related to this work; is supported by grants from NIH (K24 AR074534 and P30 AR070155); and reports consulting fees from Eli Lilly, Pfizer, Aurinia, and AstraZeneca, all outside the submitted work. PMM has received consulting or speaker's fees from Abbvie, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB Pharma, all outside the submitted work (all <$10 000); and is supported by the NIHR UCLH BRC outside the submitted work. ES is a board member of the Canadian Arthritis Patient Alliance, which is a patient-run, volunteer-based organisation, whose activities are largely supported by independent grants from pharmaceutical companies. JWL reports grants from Pfizer, outside the submitted work. JSH reports no competing interests related to this work; is supported by grants from the Rheumatology Research Foundation; receives salary support from the Childhood Arthritis and Rheumatology Research Alliance; and reports consulting fees for Novartis, Swedish Orphan Biovitrum, and Biogen, all outside the submitted work (<$10 000). PS reports no competing interests related to this work, but reports receiving honorarium for editing social media for the American College of Rheumatology journals (<$10 000). SBh reports receiving non-branded consulting fees from AbbVie, Amgen, Horizon, Novartis, and Pfizer (<$10 000 from each)outside the submitted work. ZSW reports receiving grant support from Bristol-Myers Squibb and Principia-Sanofi; has consulted for Viela Bio and MedPace; and is supported by grants from the National Institutes of Health, all outside the submitted work. AS reports personal fees for lectures from AbbVie, Celltrion, Lilly, Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, and Pfizer outside the submitted work. EFM has received grants from Abbvie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal SA, Merck Sharp & Dohme, Medac, and A Menarini Portugal-Farmacêutica SA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, all outside the submitted work. LG reports research grants from Amgen, Galapagos, Janssen, Lilly, Pfizer, Sandoz, and Sanofi; consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Biogen, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB Pharma, all outside the submitted work. LC declares no competing interests related to this study, but her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España SA, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal, and UCB Pharma. NJP reports grants from NIH during the conduct of the study. MU-G reports grants from Pfizer and Janssen, outside the submitted work. SBa reports grants and personal fees from Alexion Pharma, outside the submitted work. RV reports grants from Novartis, Pfizer, and Bristol-Myers Squibb, outside the submitted work. All other authors declare no competing interests., (© 2021 Elsevier Ltd. All rights reserved.)

Background: Anti-nerve growth factor (NGF) has shown promise for osteoarthritis (OA) pain efficacy, but an unanticipated joint safety signal occurred in trials. To what extent this was related to OA natural history, or was a consequence of anti-NGF agents is unclear. Of the adverse joint safety events identified, osteonecrosis has specific diagnostic codes available in the medical record to enable assessment of its frequency in the general community. We therefore investigated the rates of knee osteonecrosis in three real-world cohorts using two data sources to place these trial data in context., Methods: We used data from UK-based IQVIA Medical Research Data (IMRD) of adults diagnosed with incident knee OA between 2000-2018 to examine the incidence of knee osteonecrosis using different definitions. Additionally, we evaluated the incidence of knee osteonecrosis in the year prior to knee replacement in IMRD and among US Medicare beneficiaries who received a knee replacement in 2011-2014., Results: In IMRD, among 122,343 subjects with incident knee OA (mean age 68 years, 58% female), incidence estimates for knee osteonecrosis were 0.006-0.10%, with incidence rates of 0.01-0.17 per 1000 person-years. Among the 81,807 who had a knee replacement, the incidence of knee osteonecrosis in the year prior to knee replacement was 0.004-0.06%. In Medicare, among 316,593 with knee replacement (mean age 74, 68% female), the incidence of knee osteonecrosis was 0.24-0.7%., Conclusion: Knee osteonecrosis is rare among people with knee OA, including in the year prior to knee replacement. These data provide context for interpreting osteonecrosis events in NGF trials., Competing Interests: Competing interest statement Jean Liew received a research grant from Pfizer for unrelated studies. Seoyoung Kim received research grants to the Brigham and Women’s Hospital from Pfizer, AbbVie, Roche and Bristol-Myers Squibb for unrelated studies. Christine Peloquin has no disclosures David Felson has no disclosures Yinzhu Jin has no disclosures. Joyce Lii has no disclosures. Tuhina Neogi: consultant – Pfizer/Lilly, Regeneron, Novartis, EMD Merck-Serono, Flexion