Morales Torres, Jorge Luis Alberto MD; Vidal Neira, Luis Fernando MD; Messina, Osvaldo Daniel MD; Lems, Willem MD; Zerbini, Cristiano Author Information

Summary Fracture probabilities derived from the original FRAX model for Brazil were compared to those from an updated model based on more recent regional estimates of the incidence of hip fracture. Fracture probabilities were consistently lower in the updated FRAX model. Despite large differences between models, differences in the rank order of fracture probabilities were minimal. Objective Recent epidemiological data indicate that the risk of hip fracture in Brazil is lower than that used to create the original FRAX model. This paper describes the epidemiology of hip fracture in Brazil and the synthesis of an updated FRAX model with the aim of comparing this new model with the original model. Methods Hip fracture rates from three cities in three regions were combined, weighted by the population of each region. For other major fractures, incidence rates for Brazil were estimated using Swedish ratios for hip to other major osteoporotic fracture (humerus, forearm or clinical vertebral fractures). Mortality estimates were taken from the UN. Results Compared to the original FRAX model, the updated model gave lower 10-year fracture probabilities in men and women at all ages. Notwithstanding, there was a very close correlation in fracture probabilities between the original and updated models ( r > 0.99) so that the revisions had little impact on the rank order of risk. Conclusion The disparities between the original and updated FRAX models indicate the importance of updating country-specific FRAX models with the advent of significant changes in fracture epidemiology.

Normal bone remodeling depends of a balance between bone forming cells, osteoblasts and bone resorbing cells, the osteoclasts. In chronic arthritides and some inflammatory and autoimmune diseases such as rheumatoid arthritis, there is a great constellation of cytokines produced by pannus that impair bone formation and stimulate bone resorption by inducing osteoclast differentiation and inhibiting osteoblast maturation. Patients with chronic inflammation have multiple causes that lead to low bone mineral density, osteoporosis and a high risk of fracture including circulating cytokines, impaired mobility, chronic administration of glucocorticoids, low vitamin D levels and post-menopausal status in women, among others. Biologic agents and other therapeutic measures to reach prompt remission might ameliorate these deleterious effects. In many cases, bone acting agents need to be added to conventional treatment to reduce the risk of fractures and to preserve articular integrity and independency for daily living activities. A limited number of studies related to fractures in chronic arthritides were published, and future investigation is needed to determine the risk of fractures and the protective effects of different treatments to reduce this risk.

Background Upadacitinib (UPA) is an oral JAK inhibitor that has demonstrated safety and efficacy in patients (pts) with moderate-to-severe active RA in the phase 3 SELECT clinical program.[1–6] Objectives To describe the long-term integrated safety profile of UPA relative to active comparators in pts with RA from the SELECT clinical program through the cutoff date of 15 August 2022. Methods Pooled safety data were analyzed from 6 randomized controlled trials evaluating UPA in RA.[1–6] Treatment-emergent adverse events (TEAEs) and AEs of special interest were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15, 6 trials), MTX (1 trial), and adalimumab (ADA) 40 mg every other week (EOW; 1 trial). TEAEs were defined as AEs with an onset after the first dose and ≤ 30 days (UPA and MTX) or ≤ 70 days (ADA) after the last dose of study drug and reported as exposure-adjusted event rates (EAERs) per 100 patient-years (PY; E/100 PY). The standardized mortality ratio (SMR) was estimated for the general population using World Health Organization country-age-gender specific mortality rates through 2016. Results 3209 pts received ≥ 1 dose of UPA15 with 10 782.7 PY of exposure. EAERs of AEs, serious AEs (SAEs), and AEs leading to discontinuation on UPA15 were comparable to MTX and ADA (Table 1). COVID-19 pneumonia was the most common SAE with UPA15 (0.7 E/100 PY). Rates of serious infections were similar between UPA15 and ADA but higher compared with MTX (Figure 1). Herpes zoster (HZ) rates were higher with UPA15 vs MTX and ADA. Most HZ cases with UPA15 were non-serious (95%) and affected a single dermatome (75%) or unilateral multiple dermatomes (16%); 8% of cases were reported as disseminated and none involved the central nervous system. Creatine phosphokinase elevations were transient and more common with UPA15 than MTX or ADA. Anemia and neutropenia rates were similar between UPA15 and ADA. Most hepatic disorders were mild or moderate transaminase elevations. Treatment discontinuation due to these lab events was rare (≤ 0.1 E/100 PY). Similar rates of adjudicated MACE, adjudicated VTE, and malignancy (excluding non-melanoma skin cancer [NMSC]) were observed across treatment groups. The rate of NMSC was numerically higher with UPA15 vs ADA; no cases occurred with MTX. SMR analysis indicated that the mortality rate among pts with RA treated with UPA15 was not higher than what would be expected among the general population (SMR [95% CI]: 0.67 [0.52, 0.86] including COVID-19 deaths; 0.41 [0.29, 0.56] excluding COVID-19 deaths). Conclusion The integrated safety profile of UPA in pts with RA remained consistent with previous findings,[7] with no new safety risks identified up to 6.5 years of exposure. Similar rates of AEs of special interest were observed for UPA15 and ADA, except for higher rates of HZ, CPK elevations, and NMSC with UPA. References [1]Burmester GR, et al. Lancet. 2018;391:2503–12.[2]Smolen JS, et al. Lancet. 2019;393:2303–11.[3]Fleischmann R, et al. Arthritis Rheumatol. 2019;71:1788–1800.[4]Genovese MC, et al. Lancet. 2018;391:2513–24.[5]van Vollenhoven R, et al. Arthritis Rheumatol. 2020;72:1607–20.[6]Rubbert-Roth A, et al. N Engl J Med. 2020;383:1511–21.[7]Cohen SB, et al. Ann Rheum Dis 2020;79:319–20. Acknowledgements AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie. Disclosure of Interests Stanley B. Cohen Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Gilead, Pfizer, Roche, and Sandoz, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Gilead, Pfizer, Roche, and Sandoz, Ronald van Vollenhoven Speakers bureau: AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Jeffrey Curtis Consultant of: AbbVie, Amgen, BMS, CorEvitas, Eli Lilly, Janssen, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, BMS, CorEvitas, Eli Lilly, Janssen, Pfizer, Sanofi, and UCB, Leonard Calabrese Speakers bureau: AbbVie, BMS, Crescendo, Genentech, Gilead, GSK, Horizon, Janssen, Novartis, and Sanofi, Consultant of: AbbVie, BMS, Crescendo, Genentech, Gilead, GSK, Horizon, Janssen, Novartis, and Sanofi, Cristiano Zerbini Speakers bureau: Amgen, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, Consultant of: Amgen, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, Grant/research support from: Amgen, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, Yoshiya Tanaka Speakers bureau: AbbVie, Amgen, Asahi-Kasei, Astellas, AstraZeneca, Boehringer-Ingelheim, BMS, Chugai, Corrona, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Kowa, Mitsubishi-Tanabe, Takeda, YL Biologics, and Takeda, Consultant of: AbbVie, Amgen, Asahi-Kasei, Astellas, AstraZeneca, Boehringer-Ingelheim, BMS, Chugai, Corrona, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Kowa, Mitsubishi-Tanabe, Takeda, YL Biologics, and Takeda, Grant/research support from: AbbVie, Amgen, Asahi-Kasei, Astellas, AstraZeneca, Boehringer-Ingelheim, BMS, Chugai, Corrona, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Kowa, Mitsubishi-Tanabe, Takeda, YL Biologics, and Takeda, Louis Bessette Speakers bureau: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Organon, TEVA, and UCB, Consultant of: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Organon, TEVA, and UCB, Grant/research support from: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Organon, TEVA, and UCB, Christophe Richez Speakers bureau: Amgen, AstraZeneca, Biogen, BMS, Eli Lilly, Galapagos, GSK, Hospira, Mylan, Novartis, Pfizer, Roche, and Sandoz, Consultant of: Amgen, AstraZeneca, Biogen, BMS, Eli Lilly, Galapagos, GSK, Hospira, Mylan, Novartis, Pfizer, Roche, and Sandoz, sander strengholt Shareholder of: AbbVie, Employee of: AbbVie, Derek Coombs Shareholder of: AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Andrew Gara Shareholder of: AbbVie, Employee of: AbbVie, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Amgen, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Pfizer, Roche, and UCB.Table 1Treatment-emergent Adverse Events in Patients Treated with UPA, ADA, and MTXUPA 15 mg QDADA 40 mg EOWMTXn (number of subjects)3209579314ExposureTotal PY10 782.71573.2865.1Mean (SD), years3.4 (1.9)2.7 (2.3)2.8 (2.0)Median (range), years4.0 (0.0, 6.6)2.2 (0.0, 6.6)2.6 (0.0, 5.4)E/100 PY (95% CI)Any AE206.1(203.4, 208.8)195.5(188.6, 202.5)203.2(193.8, 212.9)Any SAE12.8(12.2, 13.5)13.5(11.7, 15.4)9.0(7.1, 11.3)Any AE leading to study drug discontinuation4.8(4.4, 5.2)5.5(4.4, 6.8)5.5(4.1, 7.4)Any COVID-19-related AE4.6(4.2, 5.0)4.7(3.7, 5.9)2.4(1.5, 3.7)Deathsa0.8(0.7, 1.0)1.0(0.5, 1.6)0.9(0.4, 1.8)ADA, adalimumab; E/100 PY, exposure-adjusted event rates per 100 patient-years; QD, once daily; SAE, serious AE; UPA, upadacitinib.aIncludes treatment-emergent, non-treatment-emergent, and COVID-related deaths.

L’upadacitinib (UPA) est un inhibiteur de JAK administré par voie orale, dont la tolérance et l’efficacité ont été démontrées chez des patients ayant eu Polyarthrite Rhumatoide (PR) active, modérée à sévère, lors du programme clinique de phase III SELECT. Décrire le profil de tolérance intégré à long terme de l’UPA par rapport à des comparateurs actifs chez des patients atteints de PRdu programme clinique SELECT, jusqu’à la date du Cutoff du 15 août 2022. Les données de tolérance poolées de 6 essais cliniques randomisés contrôlés, évaluant l’UPA dans la PR, ont été analysées [1], [2], [3], [4], [5], [6]. Les événements indésirables apparus au cours du traitement (EIAT) et les EI d’intérêt particulier ont été résumés pour les groupes suivants : données poolées pour l’UPA 15 mg une fois par jour (1×/j ; UPA15, 6 essais), MTX (1 essai) et adalimumab (ADA) 40 mg toutes les deux semaines (/2 sem ; 1 essai). Les EIAT étaient définis comme des EI survenant après l’administration de la première dose et ≤ 30 jours (UPA et MTX) ou ≤ 70 jours (ADA) après celle de la dernière dose de médicament à l’étude, et rapportés sous forme de taux d’événements ajusté en fonction de l’exposition (TEAE) pour 100 patients-années (PA ; E/100 PA). L’indice standardisé de mortalité (SMR : Standardized Mortality Ratio) a été estimé pour la population générale à l’aide des taux de mortalité spécifique (pays-âge-sexe) jusqu’en 2016 publiés par l’Organisation Mondiale de la Santé. 3209 patients ont reçu ≥ 1 dose d’UPA15 avec 10 782 7 PA d’exposition. Les TEAE des EI, EI graves (EIG) et EI ayant entraîné l’arrêt du traitement avec UPA15 ont été comparables à ceux observés pour le MTX et l’ADA. La pneumonie à COVID-19 était l’EIG le plus fréquent sous UPA15(0,7 E/100 PA). Le taux d’infection grave était similaire entre UPA15 et ADA, mais plus élevé que celui observé sous MTX. Le taux de zona était plus élevé sous UPA15 versus MTX et ADA. La plupart des cas de zona signalés sous UPA15 étaient non graves (95 %) et limités à un seul dermatome (75 %) ou à l’atteinte unilatérale de plusieurs dermatomes (16 %) ; 8 % des cas étaient disséminés, sans atteinte du système nerveux central. Les élévations de la créatine kinase étaient transitoires et plus fréquentes sous UPA15 que sous MTX ou ADA. Les taux d’anémie et de neutropénie étaient similaires entre UPA15 et ADA. La grande majorité des troubles hépatiques étaient des élévations légères ou modérées des transaminases. Le traitement a rarement été interrompu en raison de ces événements biologiques (≤ 0,1 E/100 PA). Des taux similaires de MACE confirmés par le comité d’adjudication, VTE confirmées par le comité d’adjudication et tumeurs malignes (hors cancer cutané non mélanome [CCNM]) ont été observés entre les groupes de traitement. Le taux de CCNM était numériquement plus élevé sous UPA15 versus ADA ; aucun cas n’a été signalé avec le MTX. L’analyse SMR a montré que le taux de mortalité parmi les patients ayant une PR traités par UPA15 n’était pas plus élevé que celui attendu dans la population générale (ISM [IC à 95 %] : 0,67 [0,52,0,86] en incluant les décès dus à la COVID-19 ; 0,41 [0,29,0,56] hors décès dus à la COVID-19). Le profil des données poolées de tolérance d’upadacitinb chez les patients atteints de PR concordait avec celui déjà décrit [7], sans observation de nouveaux signaux de sécurité après une durée d’exposition pouvant aller jusqu’à 6,5 ans. Des taux similaires d’EI d’intérêt particulier ont été observés sous UPA 15 et ADA, à l’exception de taux plus élevés de zona, élévation de la CPK et de CCNM avec l’UPA.

Guidelines and recommendations developed and endorsed by the International Osteoporosis Foundation (IOF) are intended to provide guidance for particular pattern of practice for physicians who usually prescribe glucocorticoid (GC) therapy, and not to dictate the care of a particular patient. Adherence to the recommendations within this guideline is voluntary and the ultimate determination regarding their application should be made by the physician in light of each patient's circumstances. Guidelines and recommendations are intended to promote a desirable outcome but cannot guarantee any specific outcome. This guideline and its recommendations are not intended to dictate payment, reimbursement or insurance decisions. Guidelines and recommendations are subjected to periodic revisions as a consequence of the evolution of medicine, technology and clinical practice. A panel of Latin American (LATAM) experts specialized in osteoporosis with recognized clinical experience in managing patients with glucocorticoid-induced osteoporosis (GIO) met to produce evidence-based LATAM recommendations for the diagnosis and management of GIO. These guidelines are particularly intended to general practitioners and primary care physicians who prescribe GC treatments in LATAM to guide their daily clinical practice in terms of evaluation, prevention and treatment of GIO. These recommendations were based on systematic literature review using MEDLINE, EMBASE, SCOPUS and COCHRANE Library database during the period from 2012 to 2021. Randomized clinical trials (RCT), systematic reviews of RCT, controlled observational studies, guidelines and consensus were considered. Based on the review and expert opinion the panel members voted recommendations during two successive rounds of voting by panel members. Agreements for each statement were considered if a concordance of at least 70% was achieved following Delphi methodology. Grading of recommendations was made according to the Oxford Centre for the Evidence-based Medicine (EBM) criteria. Among five GIO guidelines and consensus initially identified, two of them (American College of Rheumatology 2017 and the Brazilian Guidelines 2021) were selected for comparison considering the latter as the most current guides in the LATAM region. Based on this methodology fifty statements were issued. All of them but four (1.20, 1.21, 1.23 and 4.2) attained agreement.

Several drugs are available for the treatment of osteoporosis in postmenopausal women. Over the last decades, most patients requiring pharmacological intervention were offered antiresorptive drugs as first-line therapy, while anabolic agents were considered a last resource for those with therapeutic failure. However, recent randomized trials in patients with severe osteoporosis have shown that anabolic agents reduce fractures to a greater extent than antiresorptive medications. Additionally, evidence indicates that increases in bone mineral density (BMD) are maximized when patients are treated with anabolic agents first, followed by antiresorptive therapy. This evidence is key, considering that greater increases in BMD during osteoporosis treatment are associated with a more pronounced reduction in fracture risk. Thus, international guidelines have recently proposed an individualized approach to osteoporosis treatment based on fracture risk stratification, in which the stratification risk has been refined to include a category of patients at very high risk of fracture who should be managed with anabolic agents as first-line therapy. In this document, the Brazilian Society of Endocrinology and Metabolism and the Brazilian Association of Bone Assessment and Metabolism propose the definition of very high risk of osteoporotic fracture in postmenopausal women, for whom anabolic agents should be considered as first-line therapy. This document also reviews the factors associated with increased fracture risk, trials comparing anabolic versus antiresorptive agents, efficacy of anabolic agents in patients who are treatment naïve versus those previously treated with antiresorptive agents, and safety of anabolic agents.

What is this summary about? This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in September 2021. The part of the study described in the article began in July 2020 and is ongoing. This means that the final results may be different from the results included in this summary. What happened in this study? The participants in this study received 2 injections of either the BNT162b2 vaccine or a placebo, 21 days apart. The placebo looked like the BNT162b2 vaccine but had no active vaccine in it. None of the trial participants or study teams knew who received vaccine or placebo. What were the results? Most of the reactions to the injections were mild or moderate and lasted for a short period of time. The most common reactions were pain at the injection site, extreme tiredness (fatigue), and headache. These reactions usually happened in the first 7 days after receiving a vaccine dose. A small number of participants had severe reactions to the vaccine. Compared to participants who received the placebo, participants who received the BNT162b2 vaccine were much less likely to become ill if they were infected with the virus that causes COVID-19. The vaccine also had very good efficacy at preventing severe COVID-19. Participants in South Africa who received the BNT162b2 vaccine were less likely to become ill after infection with the beta variant of the virus compared to participants who received the placebo. The beta variant was very common in South Africa when the study was taking place. Clinical Trial Registration: NCT04368728 ( ClinicalTrials.gov )

Hip fracture incidence rates in three representative geographic areas in Brazil over a period of 2 years (2010–2012) were assessed for the first time. Estimated incidence rates varied regionally, and markedly differed from those previously reported. Thus, national guidelines as well as FRAX Brazil should be revised in light of this new data. To determine the annual incidence of hip fractures in individuals aged 50 years and over, living in 3 cities located in different regions of the country. To investigate the age, gender, and regional differences in fracture rates. Based on the obtained data, to estimate the national incidence of hip fractures resulting from osteoporosis, in order to improve prevention strategies. Retrospective, observational study including all patients aged ≥ 50 years admitted in hospitals because of a hip fracture in three cities (Belem, Joinville, and Vitoria) from representative geographic areas in Brazil from 2010 to 2012. Data were obtained from medical records in those cities. We analyzed incidence rates (crude and age- and gender-standardized rates) for hip fractures. There were 1025 (310 in men and 715 in women) hip fractures in the over 50-year-old merged population from the three cities. The crude incidence rate for hip fracture was 103.3/100,000 (95% confidence interval [CI = 97.0; 109.7), in men 77.4/100,000 (95% CI = 68.8; 86.0), and in women 125.2/100,000 (95% CI = 116.0; 134.4). Incidence standardized for age and gender was 105.9 cases per 100,000 persons per year (95% CI = 99.4; 112.4); 78.5 cases per 100,000 (95% CI = 69.8; 87.3) in men and 130.6 cases 100,000 in women (95% CI = 121.0, 140.2) per year. Belem, located in the equatorial region (latitude 1° 27′ S), had significantly lower crude and age-adjusted incidence than Joinville (latitude 26° 18′ S) and Vitoria (latitude 20° 19′ S), which were no different from each other. The incidence of fractures increased exponentially with age, and women had about twice the risk of fractures than men. Hip fracture mainly affects elderly women and presents great variability in incidence between the different regions in Brazil. The incidence of hip fractures in Brazil differed markedly from that reported previously, so that national guidelines and the FRAX model for Brazil should be revised.

Abstract Background This ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination. Methods Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination. Results Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9–89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2–93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels. Conclusions Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.

BACKGROUND & nbsp;Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older.& nbsp;METHODS & nbsp;In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-mu g doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose.& nbsp;RESULTS & nbsp;A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3).& nbsp;CONCLUSIONS & nbsp;A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months.

INTRODUCTION:To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX).METHODS:This was a 52-week, randomized, double-blind, placebo controlled, phase III study in patients with RA who had an inadequate response to MTX. Patients (n = 290) receiving stable background MTX were randomly assigned (1:1) to receive placebo or baricitinib 4 mg once daily with a primary endpoint at week 12. PROs assessed included Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity, patient's assessment of pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), European Quality of Life-5 Dimensions-5 Level index scores and visual analogue scale, and measures collected in electronic patient daily diaries: duration of morning joint stiffness, Worst Tiredness, and Worst Joint Pain. Treatment comparisons were made with logistic regression and analysis of covariance models for categorical and continuous variables, respectively.RESULTS:Statistically significant (p ⩽ 0.05) improvements in all PROs were observed in the baricitinib 4 mg group compared to placebo as early as week 1 to week 4; and were sustained to week 24. These improvements were maintained until week 52 for the baricitinib group. A significantly larger proportion of patients met or exceeded the minimum clinically important difference for HAQ-DI (⩾0.22) and FACIT-F (3.56) profiles in the baricitinib group.CONCLUSION:Baricitinib provided significant improvements in PROs compared to placebo to 52 weeks of treatment in patients with RA who had an inadequate response to MTX.Clinicaltrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT02265705; NCT02265705; RA-BALANCE. Registered 13 October 2014.

Background: The safety and efficacy of the oral Janus kinase inhibitor upadacitinib (UPA) has been evaluated across a spectrum of patients with rheumatoid arthritis (RA) in the phase 3 SELECT clinical program. 1–6 Objectives: To describe the long-term integrated safety profile of UPA relative to active comparators (cutoff date: June 30, 2020) in patients with RA treated in the SELECT clinical program. Methods: This analysis included updated data from 6 randomized controlled UPA RA trials. 1–6 Treatment-emergent adverse events (TEAEs; onset after first dose and ≤30 days after last dose of study drug or ≤70 days for adalimumab [ADA]) including AEs of special interest were summarized as follows: pooled UPA 15 mg once daily (QD; UPA15, 6 trials); pooled UPA 30 mg QD (UPA30, 4 trials); methotrexate (MTX, 1 trial), and ADA (1 trial). TEAEs were reported as exposure-adjusted adverse event rates (EAERs; events/100 patient-years [E/100 PY]), which included both incident and recurrent events. Results: 4413 patients (UPA15, n=3209; UPA30, n=1204) received ≥1 dose of UPA, providing 10,115.4 PY of exposure. EAERs for AEs, serious AEs (SAEs), and AEs leading to discontinuation were similar for UPA15, MTX, and ADA; rates for UPA30 were numerically higher than UPA15 (Table 1). The most common AEs were upper respiratory tract infection, nasopharyngitis, and urinary tract infection for both UPA doses, and for UPA30 only, increased creatine phosphokinase (CPK). Pneumonia was the most common SAE for both UPA15 and UPA30. Serious infection rates were similar for UPA15, MTX, and ADA but higher for UPA30 (Figure 1). Rates of herpes zoster (HZ) were higher for both UPA groups (dose-dependent) vs MTX and ADA. Most HZ cases with UPA were non-serious (94%) and involved a single dermatome (74%). CPK elevations, which were mostly asymptomatic, were more common for both UPA groups (dose-dependent) vs MTX and ADA. EAERs of adjudicated gastrointestinal perforations were <0.1 and 0.2 E/100 PY for UPA15 and UPA30, respectively. Rates of non-melanoma skin cancer (due in part to more recurrent events with UPA30), anemia, and neutropenia were higher with UPA30 vs other treatment groups. Events of anemia and neutropenia were generally mild/moderate and treatment discontinuation due to these events was uncommon (<0.4%). Rates of other AEs of special interest, including major adverse cardiovascular and venous thromboembolic events, were broadly similar across treatment groups. The rate of deaths in UPA-treated patients with RA was not higher than expected for the general population (standardized mortality ratio [95% confidence interval (CI)]: UPA15, 0.43 [0.29, 0.63]; UPA30, 0.68 [0.40, 1.08]). Table 1. TEAEs in patients treated with UPA, MTX, and ADA UPA 15 mg QD UPA 30 mg QD ADA 40 mg EOW MTX n 3209 1204 579 314 Exposure Total, PY 7023.8 3091.6 1051.8 637.4 Mean (SD), weeks 114 (64) 134 (66) 95 (70) 106 (67) Median (range), weeks 136 (0, 232) 160 (0, 231) 118 (2, 231) 144 (1, 221) E/100 PY (95% CI ) Any AE 230.7 (227.2, 234.3) 283.6 (277.7, 289.6) 216.6 (207.8, 225.7) 227.8 (216.2, 239.8) Any SAE 13.0 (12.2, 13.9) 18.8 (17.3, 20.4) 13.3 (11.2, 15.7) 10.4 (8.0, 13.2) Any AE leading to discontinuation of study drug 5.6 (5.0, 6.1) 8.5 (7.5, 9.6) 6.8 (5.3, 8.5) 6.3 (4.5, 8.5) Deaths a 0.4 (0.3, 0.6) 0.6 (0.3, 0.9) 0.9 (0.4, 1.6) 0.5 (0.1, 1.4) a Both treatment and non-treatment-emergent deaths EOW, every other week Conclusion: The updated safety profile of UPA with up to 4.5 years of exposure in patients with RA was comparable to previous analyses, 7 with no new safety signals reported. With the exception of HZ and elevated CPK, the safety profile of UPA15, the approved dose for RA, was similar to that observed for ADA. References: [1]Burmester GR, et al. Lancet 2018;391:2503–12; [2]Smolen JS, et al. Lancet 2019;393:2303–11; [3]Fleischmann R, et al. Arthritis Rheumatol 2019;71:1788–800; [4]Genovese MC, et al. Lancet 2018;391:2513–24; [5]van Vollenhoven R, et al. Arthritis Rheumatol 2020;72:1607–20; [6]Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21; [7]Cohen SB, et al. Ann Rheum Dis 2020;79(Suppl 1):319–20. Acknowledgements: AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Hilary Wong, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests: Stanley B. Cohen Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Gilead, Pfizer, Roche, and Sandoz, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Gilead, Pfizer, Roche, and Sandoz, Ronald van Vollenhoven Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, Medac, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Arthrogen, Bristol-Myers Squibb, Eli Lilly, GSK, Pfizer, and UCB, Jeffrey R. Curtis Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo, Janssen, Pfizer, Sanofi/Regeneron, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo, Janssen, Pfizer, Sanofi/Regeneron, and UCB, Leonard Calabrese Speakers bureau: AbbVie, Crescendo, Genentech, Horizon, Janssen, Novartis, and Sanofi, Consultant of: AbbVie, Bristol-Myers Squibb, Crescendo, Genentech, Gilead, GSK, Horizon, Janssen, Novartis, and Sanofi, Cristiano Zerbini Speakers bureau: MSD, Pfizer, and Sanofi, Consultant of: MSD, Pfizer, and Sanofi, Grant/research support from: Amgen, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, and Servier, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Sanofi, and YL Biologics, Grant/research support from: Asahi Kasei, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Takeda, and UCB, Louis Bessette Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Christophe Richez Speakers bureau: AbbVie, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, GSK, MSD, and Pfizer, Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, GSK, MSD, and Pfizer, Ivan Lagunes-Galindo Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jianzhong Liu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB

The Brazilian guidelines for prevention and treatment of glucocorticoid-induced osteoporosis were updated and important topics were included such as assessment of risk fracture using FRAX Brazil, use of denosumab, and also recommendations for the use of glucocorticoid pulse therapy and inhaled glucocortiocoid. INTRODUCTION:Glucocorticoids (GCs) are used in almost all medical specialties and the incidences of vertebral/nonvertebral fractures range from 30 to 50% in individuals treated with GCs for over 3 months. Thus, osteoporosis and frailty fractures should be prevented and treated in patients initiating treatment or already being treated with GCs. The Committee for Osteoporosis and Bone Metabolic Disorders of the Brazilian Society of Rheumatology (BSR) established in 2012 the Brazilian Guidelines for glucocorticoid-induced osteoporosis (GIO). Herein, we provide a comprehensive update of the original guidelines based on improved available scientific evidence and/or expert experience. METHODS:From March to June 2020, the Osteoporosis Committee of the BRS had meetings to update the questions presented in the first consensus (2012). Thus, twenty-six questions considered essential for the preparation of the recommendations were selected. A systematic literature review based on real-life scenarios was undertaken to answer the proposed questions. The MEDLINE, EMBASE, and SCOPUS databases were searched using specific search keywords. RESULTS:Based on the review and expert opinion, the recommendations were updated for each of the 26 questions. We included 48 new bibliographic references that became available after the date of the publication of the first version of the consensus. CONCLUSION:We updated the Brazilian guidelines for the prevention/treatment of GIO. New topics were added in this update, such as the assessment of risk fracture using FRAX Brazil, the use of denosumab, and approaches for the treatment of children and adolescents. Furthermore, we included recommendations for the use of inhaled GCs and GC pulse therapy in clinical settings.

BACKGROUND:BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS:In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-μg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS:BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS:Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).

ABSTRACTBackgroundBNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. BNT162b2 is highly efficacious against COVID-19 and is currently authorized for emergency use or conditional approval worldwide. At the time of authorization, data beyond 2 months post-vaccination were unavailable.MethodsIn an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study, 44,165 ≥16-year-old participants and 2,264 12-15-year-old participants were randomized to receive 2 doses, 21 days apart, of 30 µg BNT162b2 or placebo. Study endpoints reported here are vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data, both up to 6 months post-vaccination.ResultsBNT162b2 continued to be safe and well tolerated. Few participants had adverse events leading to study withdrawal. VE against COVID-19 was 91% (95% CI 89.0-93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection. VE of 86%-100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% (95% CI 80.3−99.9). In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed.ConclusionWith up to 6 months of follow-up and despite a gradually declining trend in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19. (ClinicalTrials.govnumber,NCT04368728)

The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; ) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for >= 12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. (c) 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).