Rheumatoid arthritis in Latin America: pharmacotherapy and clinical challenges.

INTRODUCTION: Rheumatoid arthritis (RA) poses significant healthcare challenges in Latin America (LA) due to its high prevalence and unique healthcare dynamics. Despite global advancements, LA faces specific hurdles in effectively managing RA. AREAS COVERED: This review examines RA epidemiology, treatment strategies, and clinical challenges in LA. RA prevalence varies, with higher rates among indigenous populations. While conventional disease-modifying antirheumatic drugs (csDMARDs) are recommended as first-line therapy, access remains inconsistent. Biologics and targeted synthetic DMARDs are available, but biosimilars have limited accessibility, with drug prices varying significantly. Key barriers include supply interruptions, diagnosis delays, and high non-adherence rates driven by socioeconomic factors. A severe shortage of rheumatologists, particularly in rural areas, affects patient care. Cardiovascular events, comorbidities, and endemic infections further complicate RA management. EXPERT OPINION: Although RA care in LA has improved through better use of csDMARDs and advanced treatments, major challenges persist, such as a shortage of specialists, limited medical education, and fragmented healthcare systems. Expanding training programs, enhancing telemedicine, and ensuring drug supply continuity are essential. Strengthening clinical research, improving access to affordable treatments, and developing comprehensive, region-specific strategies are crucial to closing the gap between LA and more developed regions in RA care..

Socioeconomic factors and COVID-19 mortality in immune-mediated rheumatic diseases patients: regional analysis from Argentina, Mexico and Brazil.

BACKGROUND: SARS-CoV-2 infection has become a major international issue, not only from a medical point of view, but also social, economic and political. Most of the available information comes from the United States, Europe, and China, where the population and the socioeconomic status are very different from Latin American countries. This study evaluates the effect of regional socioeconomic characteristics on mortality due SARS-CoV-2 infection in patients with immune-mediated rheumatic diseases (IMRD) from Argentina, Mexico and Brazil. METHODS: Data from three national registries, SAR-COVID (Argentina), CMR-COVID (Mexico) and ReumaCoV-Brasil (Brazil), were combined. Adult IMRD patients with SARS-CoV-2 infection were recruited. National data for each province/state, including population density, number of physicians per inhabitant, income, unemployment, GINI index, Municipal Human Development Index (MHDI), stringency index, vaccination rate and most frequent viral strains per period were assessed as risk factors for mortality due to COVID-19. RESULTS: A total of 4744 patients were included, 2534 (53.4%) from SAR-COVID, 1166 (24.6%) from CMRCOVID and 1044 (22.0%) from ReumaCoV-Brasil. Mortality due to COVID-19 was 5.4%. In the multivariable analysis, higher number of physicians per 1000 inhabitants and being infected during the vaccination period of each country were associated with lower mortality. After adjustment for socioeconomic factors, there was no association with country of residence and mortality. CONCLUSION: These findings corroborate the complex interplay between socioeconomic factors, rheumatic disease activity, and regional disparities as determinants of death due to COVID-19 in Argentina, Brazil and Mexico. Thus, this research provides valuable insights for guiding public health policies and clinical practice in the ongoing fight against the COVID-19 pandemic.

Predictors of Hospitalization in Breakthrough COVID-19 among Fully Vaccinated Individuals with Immune-Mediated Rheumatic Diseases: Data from SAFER-Study.

Breakthrough COVID-19 (occurring in fully vaccinated people) has been described. Data on its characteristics among immune-mediated rheumatic disease (IMRD) patients are scarce. This study describes breakthrough COVID-19 occurring in IMRD patients participating in the SAFER-study, a Brazilian multicentric cohort evaluating the safety, effectiveness, and immunogenicity of SARS-CoV-2 vaccines in patients with autoimmune diseases. A descriptive analysis of the population and a binary logistic regression model were performed to evaluate the predictors of COVID-19-related hospitalization. A p-value < 0.05 was significant. The included 160 patients were predominantly females (83.1%), with a mean (SD) age of 40.23 (13.19) years. The patients received two (19%), three (70%), or four (11%) vaccine doses. The initial two-dose series was mainly with ChAdOx1 (Oxford/AstraZeneca) (58%) or BBIBP-CorV (Sinopharm-Beijing) (34%). The first booster (n = 150) was with BNT162b2 (BioNtech/Fosun Pharma/Pfizer) (63%) or ChAdOx1 (29%). The second booster (n = 112) was with BNT162b2 (40%) or ChAdOx1 (26%). The COVID-19 hospitalization rate was 17.5%. IMRD moderate/high activity (OR: 5.84; CI: 1.9-18.5; p = 0.002) and treatment with corticosteroids (OR: 2.94; CI: 1.02-8.49; p = 0.0043) were associated with higher odds of hospitalization, while increasing the number of vaccine doses was protective (OR: 0.37; CI: 0.15-0.9; p = 0.032). These findings, along with previous reassuring results about the safety of the COVID-19 vaccines, argue in favor of booster vaccination in IMRD patients.

Challenges in implementing treat-to-target in rheumatoid arthritis: a perspective from Brazilian rheumatologists.

BACKGROUND: Patient management in rheumatoid arthritis (RA) has evolved to a "treat-to-target" (T2T) approach, which entails intensive treatment and regular follow-up with the goal of achieving low levels of disease activity or clinical remission. Even though a T2T approach is endorsed by professional organizations and yields superior outcomes, its implementation remains incomplete. EVEREST (EleVatE care in RhEumatoid arthritiS with Treat-to-target) is a quality-improvement initiative designed to improve the widespread implementation of a personalized T2T strategy and enable patients with RA to reach their full potential for remission. We describe the Brazilian results from the Global T2T Survey, first part of the EVEREST program. METHODS: Between June and September 2022, we conducted an online survey targeting rheumatologists in Brazil. Our objective was to evaluate the barriers and knowledge gaps hindering the effective implementation of T2T strategies. To achieve this, we employed a set of multiple-choice questions specifically crafted to elicit responses categorized in a structured order. RESULTS: 166 rheumatologists participated in the survey, 51% of them with more than 21 years of experience in rheumatology. Regarding the perceived challenges in the management of RA in clinical practice, the highest percentage of agreement/strong agreement among the participants was related to the contradictory results of disease activity measures (60%). In terms of the main barriers to assess the disease activity in clinical practice, the lack of adherence to treatment and contradictory assessments between patient-reported outcomes and composite measures were indicated by 75% and 59% of the participants, respectively, as a moderate/serious barrier. The most frequently knowledge and skill gaps related to the management of RA pointed out by the participants were on the difficulty to assess patients' health literacy (54% stated to have no more than intermediate knowledge on standardized methods to assess it and 43% no more than intermediate skills on determining the level of health literacy of the patients). In general, the use of tools to support the management of RA patients in clinical practice was indicated to be unusual by the participants. Self-reflection questionnaires, patient education materials and treatment consideration checklists were pointed out as the least frequently used tools (85%, 64% and 62% of the participants stated to use them never, rarely, or only sometimes, respectively). CONCLUSIONS: Our findings indicate a greater need for design, selection, and uptake of practical strategies to further improve communication between healthcare providers and patients with RA, as well as for promoting well-informed, collaborative decision-making in their care.

Muscle fibre morphometric analysis (MusMA) correlates with muscle function and cardiovascular risk prognosis.

Morphometry of striated muscle fibres is critical for monitoring muscle health and function. Here, we evaluated functional parameters of skeletal and cardiac striated muscle in two experimental models using the Morphometric Analysis of Muscle Fibre tool (MusMA). The collagen-induced arthritis model was used to evaluate the function of skeletal striated muscle and the non-alcoholic fatty liver disease model was used for cardiac striated muscle analysis. After euthanasia, we used haeamatoxylin and eosin stained sections of skeletal and cardiac muscle to perform muscle fibre segmentation and morphometric analysis. Morphometric analysis classified muscle fibres into six subpopulations: normal, regular hypertrophic, irregular hypertrophic, irregular, irregular atrophic and regular atrophic. The percentage of atrophic fibres was associated with lower walking speed (p = 0.009) and lower body weight (p = 0.026), respectively. Fibres categorized as normal were associated with maximum grip strength (p < 0.001) and higher march speed (p < 0.001). In the evaluation of cardiac striated muscle fibres, the percentage of normal cardiomyocytes negatively correlated with cardiovascular risk markers such as the presence of abdominal adipose tissue (p = .003), miR-33a expression (p = .001) and the expression of miR-126 (p = .042) Furthermore, the percentage of atrophic cardiomyocytes correlated significantly with the Castelli risk index II (p = .014). MusMA is a simple and objective tool that allows the screening of striated muscle fibre morphometry, which can complement the diagnosis of muscle diseases while providing functional and prognostic information in basic and clinical research.

Comparative study of two laboratory techniques for the detection of HLA-B27 in patients with axial spondyloarthritis: a cross-sectional analysis.

BACKGROUND: The diagnostic and prognostic relevance of Human Leukocyte Antigen B-27 (HLA-B27) in Axial Spondyloarthritis (AxSpA) is undeniable, with 70% of Ankylosing Spondylitis (AS) patients carrying the B27 gene, contrasted with a mere 4.35% in the general population. Flow cytometry (FC) and Polymerase Chain Reaction (PCR) have emerged as the predominant techniques for routine HLA-B27 typing. While various studies have compared these methods, none have catered to the unique characteristics of the Brazilian demographic. Therefore, this research aims to compare FC and PCR in a Brazilian cohort diagnosed with AxSpA. METHODS: An analytical cross-sectional study was undertaken involving 62 AxSpA outpatients from a Brazilian University Hospital. Both FC and PCR-SSP assays were utilized to ascertain HLA-B27 typing. The outcomes (either confirming or refuting the allele's presence) underwent rigorous scrutiny. Agreement between the methodologies was assessed using the kappa statistic. A p-value of < 0.05 was deemed statistically significant. RESULTS: Of the participants, 90.3% (n = 56) were HLA-B27 positive according to FC, while 79% (n = 49) were identified as positive using the PCR method. FC exhibited a sensitivity rate of 98% paired with a specificity of 38.5%. The Positive Predictive Value for FC stood at 85.7%, and the Negative Predictive Value was 83.5%. Consequently, the overall accuracy of the FC method was gauged at 85.5%. A kappa coefficient of κ = 0.454 was derived. CONCLUSIONS: FC demonstrated noteworthy sensitivity and satisfactory accuracy in HLA-B27 detection, albeit with a reduced specificity when contrasted with PCR-SSP. Nevertheless, given its cost-effectiveness and streamlined operation relative to PCR, FC remains a pragmatic option for preliminary screening in clinical practice, especially in low-income regions. To optimize resource allocation, we advocate for a refined algorithm that initiates by assessing the relevance of HLA-B27 typing based on Choosing Wisely recommendations. It then leans on FC, and, if results are negative yet clinical suspicion persists, advances to PCR. This approach aims to balance diagnostic accuracy and financial prudence, particularly in regions contending with escalating medical costs.

Development of a novel clinimetric tool: PAtient Reported Disease Activity Index in Rheumatoid Arthritis (PARDAI-RA) by PANLAR, for the assessment of patients living with rheumatoid arthritis.

BACKGROUND: Clinical experience has shown that a single measure is not sufficient to assess disease activity in rheumatoid arthritis (RA). Various clinimetric tools are necessary to address the many clinical situations that can arise. METHODS: In order to develop a comprehensive measurement tool, the Pan American League of Associations for Rheumatology searched for the most frequent measures of disease activity applied in RA by means of a semi-systematic review of the available literature. RESULTS: We found that the most frequently reported measures of disease activity were the 28-joint Disease Activity Score, C-reactive protein, and the erythrocyte sedimentation rate, followed by patient-reported measures of pain and stiffness and many other composite indices and patient-reported outcome measures. The most frequent physician-reported sign of disease was the swollen joint count, and the most frequently self-reported feature was the increase in disease activity or flares. CONCLUSION: In this article, we present a new clinimetric tool developed based on expert consensus and on data retrieved from our search. Disease activity can be better assessed by combining various data sources, such as clinical, laboratory, and self-reported outcomes. These variables were included in our novel clinimetric tool. Key Points • The goal of treatment of RA is to achieve the best possible control of inflammation, or even remission; therefore, disease management should include systematic and regular evaluation of inflammation and health status. • Clinimetric tools evaluate a series of variables (e.g., symptoms, functional capacity, disease severity, quality of life, disease progression) and can reveal substantial prognostic and therapeutic differences between patients. • Our clinimetric tool, which is based on a combination of data (e.g., clinical variables, laboratory results, PROMs), can play a relevant role in patient assessment and care.

Factors Associated With Mortality in Patients With Immune-Mediated Rheumatic Diseases and COVID-19 From Latin America: Data From Argentina, Mexico, and Brazil.

OBJECTIVE: To describe characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) from Argentina, Mexico and Brazil, and to assess factors associated with mortality in this population. METHODS: Data from 3 national registries, SAR-COVID (Argentina), CMR-COVID (Mexico), and ReumaCoV-Brasil (Brazil), were combined. Adult patients with IMIDs and SARS-CoV-2 infection were recruited. Sociodemographic data, comorbidities, IMID clinical characteristics and treatment, and SARS-CoV-2 infection presentation and outcomes were recorded. RESULTS: A total of 4827 individuals were included: 2542 (52.7%) from SAR-COVID, 1167 (24.2%) from CMR-COVID, and 1118 (23.1%) from ReumaCoV-Brasil. Overall, 82.1% were female with a mean age of 49.7 (SD, 14.3) years; 22.7% of the patients were hospitalized, and 5.3% died because of COVID-19 (coronavirus disease 2019). Argentina and Brazil had both 4% of mortality and Mexico 9.4%. In the multivariable analysis, older age (≥60 years; odds ratio [OR], 7.4; 95% confidence interval [CI], 4.6-12.4), male sex (OR, 1.5; 95% CI, 1.1-2.1), living in Mexico (OR, 3.0; 95% CI, 2.0-4.4), comorbidity count (1 comorbidity: OR, 1.5; 95% CI, 1.0-2.1), diagnosis of connective tissue disease or vasculitis (OR, 1.8; 95% CI, 1.3-2.4), and other diseases (OR, 2.6; 95% CI, 1.6-4.1) compared with inflammatory joint disease, high disease activity (OR, 4.2; 95% CI, 2.5-7.0), and treatment with glucocorticoids (OR, 1.9; 95% CI, 1.4-2.5) or rituximab (OR, 4.2; 95% CI, 2.7-6.6) were associated with mortality. CONCLUSIONS: Mortality in patients with IMIDs was particularly high in Mexicans. Ethnic, environmental, societal factors, and different COVID-19 mitigation measures adopted have probably influenced these results.

CCR5 promoter region polymorphisms in systemic lupus erythematosus.

This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected  = .012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected  = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.

The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

The II Brazilian Guidelines for the pharmacological treatment of patients hospitalized with COVID-19 Joint Guidelines of the Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia and Sociedade Brasileira de Reumatologia.

OBJECTIVE: To update the recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. METHODS: Experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. RESULTS: Twenty-one recommendations were generated, including strong recommendations for the use of corticosteroids in patients using supplemental oxygen and conditional recommendations for the use of tocilizumab and baricitinib for patients on supplemental oxygen or on noninvasive ventilation and anticoagulants to prevent thromboembolism. Due to suspension of use authorization, it was not possible to make recommendations regarding the use of casirivimab + imdevimab. Strong recommendations against the use of azithromycin in patients without suspected bacterial infection, hydroxychloroquine, convalescent plasma, colchicine, and lopinavir + ritonavir and conditional recommendations against the use of ivermectin and remdesivir were made. CONCLUSION: New recommendations for the treatment of hospitalized patients with COVID-19 were generated, such as those for tocilizumab and baricitinib. Corticosteroids and prophylaxis for thromboembolism are still recommended, the latter with conditional recommendation. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and to promote resource economy.

Funcionality assessed by the core set of the international classification of functionality and health for rheumatoid arthritis: A cohort study.

OBJECTIVE: The aim of this study was to evaluate the function of a cohort of patients with rheumatoid arthritis (RA) from the core set of the International Classification of Functioning and Health (ICF) for RA over 12 months. METHODS: We used prospective longitudinal data to conduct a cohort study among a well-characterized group of RA patients. Ninety RA patients aged between 40 and 70 years were included in the study. Patients were evaluated at baseline and after 12 months. Age, disease duration, current smoking, erosions, disease activity, functional test, disability and physical activity were evaluated. Then, the ICF core set classification for RA was applied. RESULTS: 81 patients completed the assessments, the majority of patients were female (88.9%) and the mean age was 56.5 ± 7.3 years. At baseline, the median disease activity was 3.0. There was a statistically significant (p < 0.02) improvement in "Exercise tolerance functions" over 12 months and also a statistically significant (p < 0.001) decrease in "Muscle strength functions" over 12 months. The activity and participation domain showed a weak correlation with the clinical data of the DAS28-PCR (p<0.02). CONCLUSION: We conclude that relevant aspects of the ICF Core Set for RA were able to adequately express the physical and functional factors of the RA cohort. This tool provides a common language for the interdisciplinary team, which can enhance the use of timely interventions to prevent physical disability in clinical practice.

The II Brazilian Guidelines for the pharmacological treatment of patients hospitalized with COVID-19 Joint Guidelines of the Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia and Sociedade Brasileira de Reumatologia / II Diretrizes Brasileiras para o tratamento farmacológico de pacientes hospitalizados com COVID-19 Diretriz conjunta da Associação Brasileira de Medicina de Emergência, Associação de Medicina Intensiva Brasileira, Associação Médica Brasileira, Sociedade Brasileira de Angiologia e Cirurgia Vascular, Sociedade Brasileira de Infectologia, Sociedade Brasileira de Pneumologia e Tisiologia e Sociedade Brasileira de Reumatologia

ABSTRACT Objective: To update the recommendations to support decisions regarding the pharmacological treatment of patients hospitalized with COVID-19 in Brazil. Methods: Experts, including representatives of the Ministry of Health and methodologists, created this guideline. The method used for the rapid development of guidelines was based on the adoption and/or adaptation of existing international guidelines (GRADE ADOLOPMENT) and supported by the e-COVID-19 RecMap platform. The quality of the evidence and the preparation of the recommendations followed the GRADE method. Results: Twenty-one recommendations were generated, including strong recommendations for the use of corticosteroids in patients using supplemental oxygen and conditional recommendations for the use of tocilizumab and baricitinib for patients on supplemental oxygen or on noninvasive ventilation and anticoagulants to prevent thromboembolism. Due to suspension of use authorization, it was not possible to make recommendations regarding the use of casirivimab + imdevimab. Strong recommendations against the use of azithromycin in patients without suspected bacterial infection, hydroxychloroquine, convalescent plasma, colchicine, and lopinavir + ritonavir and conditional recommendations against the use of ivermectin and remdesivir were made. Conclusion: New recommendations for the treatment of hospitalized patients with COVID-19 were generated, such as those for tocilizumab and baricitinib. Corticosteroids and prophylaxis for thromboembolism are still recommended, the latter with conditional recommendation. Several drugs were considered ineffective and should not be used to provide the best treatment according to the principles of evidence-based medicine and to promote resource economy.

RESUMO Objetivo: Atualizar as recomendações para embasar as decisões para o tratamento farmacológico de pacientes hospitalizados com COVID-19 no Brasil. Métodos: A elaboração desta diretriz foi feita por especialistas, incluindo representantes do Ministério da Saúde e metodologistas. O método utilizado para o desenvolvimento rápido de diretrizes baseou-se na adoção e/ou adaptação de diretrizes internacionais existentes (GRADE ADOLOPMENT) e contou com o apoio da plataforma e-COVID-19 RecMap. A qualidade das evidências e a elaboração das recomendações seguiram o método GRADE. Resultados: Chegaram-se a 21 recomendações, incluindo recomendações fortes quanto ao uso de corticosteroides em pacientes em uso de oxigênio suplementar e recomendações condicionais para o uso de tocilizumabe e baricitinibe, em pacientes com oxigênio suplementar ou ventilação não invasiva, e de anticoagulantes, para prevenção de tromboembolismo. Devido à suspensão da autorização de uso, não foi possível fazer recomendações para o tratamento com casirivimabe + imdevimabe. Foram feitas recomendações fortes contra o uso de azitromicina em pacientes sem suspeita de infecção bacteriana, hidroxicloroquina, plasma convalescente, colchicina e lopinavir + ritonavir, além de recomendações condicionais contra o uso de ivermectina e rendesivir. Conclusão: Foram criadas novas recomendações para o tratamento de pacientes hospitalizados com COVID-19, como as recomendações de tocilizumabe e baricitinibe. Ainda são recomendados corticosteroides e profilaxia contra tromboembolismo, esta em caráter condicional. Vários medicamentos foram considerados ineficazes e não devem ser usados, no intuito de proporcionar o melhor tratamento segundo os princípios da medicina baseada em evidências e promover a economia de recursos.

Compared efficacy of rituximab, abatacept, and tocilizumab in patients with rheumatoid arthritis refractory to methotrexate or TNF inhibitors agents: a systematic review and network meta-analysis.

BACKGROUND: Our aim was to compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with rheumatoid arthritis (RA) refractory to treatments with MTX or TNFi agents. METHODS: We searched 6 databases until January 2023 for phase 2-4 RCTs evaluating patients with RA refractory to MTX or TNFi therapy treated with rituximab, abatacept, and tocilizumab (intervention arm) compared to controls. Study data were independently assessed by two investigators. The primary outcome was considered as achieving ACR70 response. RESULTS: The meta-analysis included 19 RCTs, with 7,835 patients and a mean study duration of 1.2 years. Hazard ratios for achieving an ACR70 response at six months were not different among the bDMARDs, however, we found high heterogeneity. Three factors showing a critical imbalance among the bDMARD classes were identified: baseline HAQ score, study duration, and frequency of TNFi treatment in control arm. Multivariate meta-regression adjusted to these three factors were conducted for the relative risk (RR) for ACR70. Thus, heterogeneity was attenuated (I2 = 24%) and the explanatory power of the model increased (R2 = 85%). In this model, rituximab did not modify the chance of achieving an ACR70 response compared to abatacept (RR = 1.773, 95%CI 0.113-10.21, p = 0.765). In contrast, abatacept was associated with RR = 2.217 (95%CI 1.554-3.161, p < 0.001) for ACR70 compared to tocilizumab. CONCLUSION: We found high heterogeneity among studies comparing rituximab, abatacept, and tocilizumab. On multivariate metaregressions, if the conditions of the RCTs were similar, we estimate that abatacept could increase the chance of reaching an ACR70 response by 2.2-fold compared to tocilizumab.

Urinary metabolomic biomarker candidates for skeletal muscle wasting in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints, leading to chronic synovial inflammation and local tissue destruction. Extra-articular manifestations may also occur, such as changes in body composition. Skeletal muscle wasting is often observed in patients with RA, but methods for assessing loss of muscle mass are expensive and not widely available. Metabolomic analysis has shown great potential for identifying changes in the metabolite profile of patients with autoimmune diseases. In this setting, urine metabolomic profiling in patients with RA may be a useful tool to identify skeletal muscle wasting. METHODS: Patients aged 40-70 years with RA have been recruited according to the 2010 ACR/EULAR classification criteria. Further, the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) determined the disease activity. The muscle mass was measured by Dual X-ray absorptiometry (DXA) to generate the appendicular lean mass index (ALMI) by summing the lean mass measurements for both arms and legs and dividing them by height squared (kg/height2 ). Finally, urine metabolomic analysis by 1 H nuclear magnetic resonance (1 H-NMR) spectroscopy was performed and the metabolomics data set analysed using the BAYESIL and MetaboAnalyst software packages. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were applied to the 1 H-NMR data, followed by Spearman's correlation analysis. The combined receiver operating characteristic curve (ROC) was calculated, as well as the logistic regression analyses to establish a diagnostic model. The significance level at P < 0.05 was set for all analyses. RESULTS: The total set of subjects investigated included 90 patients with RA. Most patients were women (86.7%), with a mean age of 56.5 ± 7.3 years old and a median DAS28-CRP of 3.0 (IQR 1.0-3.0). Fifteen metabolites were identified in the urine samples with high variable importance in projection (VIP scores) by MetaboAnalyst. Of these, dimethylglycine (r = 0.205; P = 0.053), oxoisovalerate (r = -0.203; P = 0.055), and isobutyric acid (r = -0.249; P = 0.018) were significantly correlated with ALMI. Based on the low muscle mass (ALMI ≤6.0 kg/m2 for women and ≤8.1 kg/m2 for men) a diagnostic model have been established with dimethylglycine (area under the curve [AUC] = 0.65), oxoisovalerate (AUC = 0.49), and isobutyric acid (AUC = 0.83) with significant sensitivity and specificity. CONCLUSIONS: Isobutyric acid, oxoisovalerate, and dimethylglycine from urine samples were associated with low skeletal muscle mass in patients with RA. These findings suggest that this group of metabolites may be further tested as biomarkers for identification of skeletal muscle wasting.

The role of proteasome in muscle wasting of experimental arthritis.

BACKGROUND: Rheumatoid arthritis is an autoimmune inflammatory disease that often leads patients to muscle impairment and physical disability. This study aimed to evaluate changes in the activity of proteasome system in skeletal muscles of mice with collagen-induced arthritis (CIA) and treated with etanercept or methotrexate. METHODS: Male DBA1/J mice were divided into four groups (n = 8 each): CIA-Vehicle (treated with saline), CIA-ETN (treated with etanercept, 5.5 mg/kg), CIA-MTX (treated with methotrexate, 35 mg/kg) and CO (healthy control group). Mice were treated two times a week for 6 weeks. Clinical score and hind paw edema were measured. Muscles were weighted after euthanasia and used to quantify proteasome activity, gene (MuRF-1, PMSα4, PSMß5, PMSß6, PSMß7, PSMß8, PSMß9, and PSMß10), and protein (PSMß1, PSMß5, PSMß1i, PSMß5i) expression of proteasome subunits. RESULTS: Both treatments slowed disease development, but only CIA-ETN maintained muscle weight compared to CIA-MTX and CIA-Vehicle groups. Etanercept treatment showed caspase-like activity of 26S proteasome similar to CO group, while CIA-Vehicle and CIA-MTX had higher activity compared to CO group (p: 0.0057). MuRF-1 mRNA expression was decreased after etanercept administration compared to CIA-Vehicle and CO groups (p: 0.002, p: 0.007, respectively). PSMß8 and PSMß9 mRNA levels were increased in CIA-Vehicle and CIA-MTX compared to CO group, while CIA-ETN presented no difference from CO. PMSß6 mRNA expression was higher in CIA-Vehicle and CIA-MTX groups than in CO group. Protein levels of the PSMß5 subunit were increased in CO group compared to CIA-Vehicle; after both etanercept and methotrexate treatments, PSMß5 expression was higher than in CIA-Vehicle group and did not differ from CO group expression (p: 0.0025, p: 0.001, respectively). The inflammation-induced subunit ß1 (LMP2) was enhanced after methotrexate treatment compared to CO group (p: 0.043). CONCLUSIONS: The results of CIA-Vehicle show that arthritis increases muscle proteasome activation by enhanced caspase-like activity of 26S proteasome and increased PSMß8 and PSMß9 mRNA levels. Etanercept treatment was able to maintain the muscle weight and to modulate proteasome so that its activity and gene expression were compared to CO after TNF inhibition. The protein expression of inflammation-induced proteasome subunit was increased in muscle of CIA-MTX group but not following etanercept treatment. Thus, anti-TNF treatment may be an interesting approach to attenuate the arthritis-related muscle wasting.

Brazilian society of rheumatology methodological guide for the development of evidence-based clinical guidelines in rheumatology.

Clinical practice guidelines (CPG) are developed to align standards of health care around the world, aiming to reduce the incidence of misconducts and enabling more effective use of health resources. Considering the complexity, cost, and time involved in formulating CPG, strategies should be used to facilitate and guide authors through each step of this process. The main objective of this document is to present a methodological guide prepared by the Epidemiology Committee of the Brazilian Society of Rheumatology for the elaboration of CPG in rheumatology. Through an extensive review of the literature, this study compiles the main practical recommendations regarding the following steps of CPG drafting: distribution of working groups, development of the research question, search, identification and selection of relevant studies, evidence synthesis and quality assessment of the body of evidence, the Delphi methodology for consensus achievement, presentation and dissemination of the recommendations, CPG quality assessment and updating. This methodological guide serves as an important tool for rheumatologists to develop reliable and high-quality CPG, standardizing clinical practices worldwide.

Systemic lupus erythematosus: a systematic review with meta-analysis on muscle strength, muscle mass, and physical function.

To perform a systematic review with meta-analysis to verify muscle strength, muscle mass, and physical function of patients with systemic lupus erythematosus (SLE) and compare then with healthy individuals and patients with rheumatoid arthritis (RA). A systematic review with meta-analysis of observational studies published in English up to 2022 was performed using MEDLINE (via PubMed) and other relevant sources. Search strategies were based on pre-defined keywords and medical subject headings. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Mean difference (MD) or standardized mean difference (SMD) and 95% confidence intervals (CI) were combined using a random-effects model. Sensitivity analyses were performed when necessary. The significance level was set at p < 0.05. The systematic review included 19 studies and the meta-analysis included 11 studies. SLE patients appear to have less muscle strength assessed by handgrip than healthy controls (SLE = 21.74 kg; healthy controls = 29.34 kg; p < 0.05). SLE patients seem to have greater strength than patients with RA, but this difference was not statistically significant (RA = 17.24 kg; p = 0.210). However, in the sensitivity analysis, SLE group without deforming arthropathy showed higher muscle strength than the RA (p = 0.0001). SLE patients with deforming arthropathy have lower muscle strength compared to SLE patients without deforming arthropathy (p < 0.01). Muscle mass was similar in SLE patients compared to the RA group and healthy controls (p > 0.05). However, RA patients have a higher BMI than the two groups (p < 0.05). Patients with SLE have regular physical function. Muscle strength is affected in SLE patients. SLE patients with deforming arthropathy have less muscle strength than patients without deforming arthropathies.

Morphofunctional analysis of fibroblast-like synoviocytes in human rheumatoid arthritis and mouse collagen-induced arthritis.

BACKGROUND: Fibroblast-like synoviocytes (FLS) play a prominent role in rheumatoid synovitis and degradation of the extracellular matrix through the production of inflammatory cytokines and metalloproteinases (MMPs). Since animal models are frequently used for elucidating the disease mechanism and therapeutic development, it is relevant to study the ultrastructural characteristics and functional responses in human and mouse FLS. The objective of the study was to analyze ultrastructural characteristics, Interleukin-6 (IL-6) and Metalloproteinase-3 (MMP-3) production and the activation of intracellular pathways in Fibroblast like synoviocytes (FLS) cultures obtained from patients with rheumatoid arthritis (RA) and from mice with collagen-induced arthritis (CIA). METHODS: FLSs were obtained from RA patients (RA-FLSs) (n = 8) and mice with CIA (CIA-FLSs) (n = 4). Morphology was assessed by transmission and scanning electron microscopy. IL-6 and MMP-3 production was measured by ELISA, and activation of intracellular signaling pathways (NF-κB and MAPK: p-ERK1/2, p-P38 and p-JNK) was measured by Western blotting in cultures of RA-FLSs and CIA-FLSs stimulated with tumor necrosis factor-alpha (TNF-α) and IL-1ß. RESULTS: RA-FLS and CIA-FLS cultures exhibited rich cytoplasm, rough endoplasmic reticula and prominent and well-developed Golgi complexes. Transmission electron microscopy demonstrated the presence of lamellar bodies, which are cytoplasmic structures related to surfactant production, in FLSs from both sources. Increased levels of pinocytosis and numbers of pinocytotic vesicles were observed in RA-FLSs (p < 0.05). Basal production of MMP-3 and IL-6 was present in RA-FLSs and CIA-FLSs. Regarding the production of MMP-3 and IL-6 and the activation of signaling pathways, the present study demonstrated a lower response to IL-1ß by CIA-FLSs than by RA-FLSs. CONCLUSION: This study provides a comprehensive understanding of the biology of RA-FLS and CIA-FLS. The differences and similarities in ultrastructural morphology and important inflammatory cytokines shown, contribute to future in vitro studies using RA-FLS and CIA-FLS, in addition, they indicate that the adoption of CIA-FLS for studies should take careful and be well designed, since they do not completely resemble human diseases.