Abstract Introduction Although Rheumatoid Arthritis (RA) extra-articular manifestations (ExtRA) occurrence has been decreasing over time, they are still a major mortality risk factor for patients. Objective To determine the prevalence of ExtRA in a large cohort, and its association with demographic and clinical variables. Method Cross-sectional and observational study, based on a multi-centric database from a prospective cohort, in which 11 public rheumatology centres enrolled RA patients (1987 ARA or 2010 ACR-EULAR). Data collection began in 08-2015, using a single online electronic medical record. Continuous variables were compared using Mann–Whit-ney U-test, and Fisher's exact test or chi-square test, as appropriate, were used for categorical variables. The level of significance was set at 5% (p < 0.05). Results 1115 patients were included: 89% women, age [mean ± SD] 58.2 ± 11.5 years, disease duration 14.5 ± 12.2 years, positive Rheumatoid Factor (RF, n = 1108) in 77%, positive anti-cyclic citrullinated peptide (ACPA, n = 477) in 78%. Regarding ExtRA, 334 occurrences were registered in 261 patients, resulting in an overall prevalence of 23.4% in the cohort. The comparison among ExtRA and Non-ExtRA groups shows significant higher age (p < 0.001), disease duration (p < 0.001), RF high titers (p = 0.018), Clinical Disease Activity index (CDAI) (p < 0.001), Disease Activity Index 28 (DAS 28) (p < 0.001), and Health Assessment Questionnaire (HAQ) (p < 0.001) in ExtRA group. Treatment with Azathioprine (p = 0.002), Etanercept (p = 0.049) Glucocorticoids (GC) (‘p = 0.002), and non-steroidal anti-inflammatory drugs (NSAIDs) (p < 0.001) were more frequent in ExtRA group. Conclusions ExtRA manifestations still show an expressive occurrence that should not be underestimated. Our findings reinforce that long-term seropositive disease, associated with significant disability and persistent inflammatory activity are the key factors related to ExtRA development. (RA extraarticular extra articular (ExtRA time cohort Crosssectional Cross sectional study multicentric multi centric 1 1987 (198 201 ACREULAR. ACREULAR ACR EULAR . ACR-EULAR) 082015, 082015 08 2015, 2015 08-2015 record Mann–Whitney MannWhitney Mann–Whit ney Mann Whit Utest, Utest U U-test Fishers Fisher s chisquare chi square appropriate 5 p 0.05. 005 0.05 0 05 0.05) 111 included 89 women mean SD 582 58 2 58. 115 11. years 145 14 14. 122 12 12. RF, (RF 1108 77 77% anticyclic anti cyclic ACPA, ACPA (ACPA 477 78 78% 33 26 234 23 4 23.4 NonExtRA Non 0.001, 0001 0.001 , 001 0.018, 0018 0.018 018 0.018) CDAI (CDAI DAS HAQ (HAQ group 0.002, 0002 0.002 002 0.002) 0.049 0049 049 GC (GC ‘p nonsteroidal non steroidal antiinflammatory NSAIDs (NSAIDs underestimated longterm long term development 198 (19 20 ACR-EULAR 08201 08-201 Whitney MannWhit 00 0.0 8 110 7 47 3 23. 000 0.00 0.01 01 0.04 004 04 19 (1 0820 08-20 0. ( 082 08-2 08-

Abstract Background Management delays imply worse outcomes in rheumatoid arthritis (RA) and, therefore, should be minimized. We evaluated changes in diagnostic and treatment delays regarding RA in the last decades in Brazil. Methods Adults fulfilling the ACR/EULAR (2010) criteria for RA were assessed. Delays in diagnosis and treatment, and the frequencies of early management initiation within thresholds (windows of opportunity) of 3, 6, and 12 months from symptoms onset were evaluated. The Mann–Kendall trend test, chi-squared tests with Cramer’s V effect sizes and analysis of variance were conducted. Results We included 1116 patients: 89.4% female, 56.8% white, mean (SD) age 57.1 (11.5) years. A downward trend was found in diagnostic (tau = - 0.677, p < 0.001) and treatment (tau = - 0.695, p < 0.001) delays from 1990 to 2015. The frequency of early management increased throughout the period, with ascending effect sizes across the 3-, 6-, and 12-month windows (V = 0.120, 0.200 and 0.261, respectively). Despite all improvements, even in recent years (2011–2015) the diagnostic and treatment delays still remained unacceptably high [median (IQR): 8 (4–12) and 11 (5–17) months, respectively], with only 17.2% of the patients treated within the shortest, 3-month window. Conclusion The delays in diagnosis and treatment of RA decreased during the last decades in Brazil. Improvements (effect sizes) were greater at eliminating extreme delays (≥ 12 months) than in attaining really short management windows (≤ 3 months). Very early treatment was still an unrealistic goal for most patients with RA. (RA therefore minimized Brazil ACREULAR ACR EULAR 2010 (2010 assessed opportunity 6 1 MannKendall Mann Kendall test chisquared chi squared Cramers Cramer s conducted 111 894 89 4 89.4 female 568 56 56.8 white SD (SD 571 57 57. 11.5 115 5 (11.5 tau 0677 0 677 0.677 0.001 0001 001 0695 695 0.695 199 2015 period , 3- 6- 12month month 0120 120 0.120 0200 200 0.20 0261 261 0.261 respectively. respectively . respectively) improvements 2011–2015 20112015 2011 (2011–2015 median IQR (IQR) 4–12 412 (4–12 5–17 517 17 (5–17 respectively, respectively] 172 2 17.2 shortest 3month window ≥ ( ≤ months. 201 (201 89. 56. 11. (11. 067 67 0.67 0.00 000 00 069 69 0.69 19 012 0.12 020 20 0.2 026 26 0.26 2011–201 2011201 (2011–201 (IQR 4–1 41 (4–1 5–1 51 (5–1 17. (20 (11 06 0.6 0.0 01 0.1 02 0. 2011–20 201120 (2011–20 4– (4– 5– (5– (2 (1 2011–2 20112 (2011–2 (4 (5 2011– (2011– (2011

Abstract Background Early rheumatoid arthritis (RA) offers an opportunity for better treatment outcomes. In real-life settings, grasping this opportunity might depend on access to specialized care. We evaluated the effects of early versus late assessment by the rheumatologist on the diagnosis, treatment initiation and long-term outcomes of RA under real-life conditions. Methods Adults meeting the ACR/EULAR (2010) or ARA (1987) criteria for RA were included. Structured interviews were conducted. The specialized assessment was deemed “early” when the rheumatologist was the first or second physician consulted after symptoms onset, and “late” when performed afterwards. Delays in RA diagnosis and treatment were inquired. Disease activity (DAS28-CRP) and physical function (HAQ-DI) were evaluated. Student's t, Mann-Whitney U, chi-squared and correlation tests, and multiple linear regression were performed. For sensitivity analysis, a propensity score-matched subsample of early- vs. late-assessed participants was derived based on logistic regression. The study received ethical approval; all participants signed informed consent. Results We included 1057 participants (89.4% female, 56.5% white); mean (SD) age: 56.9 (11.5) years; disease duration: 173.1 (114.5) months. Median (IQR) delays from symptoms onset to both RA diagnosis and initial treatment coincided: 12 (6–36) months, with no significant delay between diagnosis and treatment. Most participants (64.6%) first sought a general practitioner. Notwithstanding, 80.7% had the diagnosis established only by the rheumatologist. Only a minority (28.7%) attained early RA treatment (≤ 6 months of symptoms). Diagnostic and treatment delays were strongly correlated (rho 0.816; p < 0.001). The chances of missing early treatment more than doubled when the assessment by the rheumatologist was belated (OR 2.77; 95% CI: 1.93, 3.97). After long disease duration, late-assessed participants still presented lower chances of remission/low disease activity (OR 0.74; 95% CI: 0.55, 0.99), while the early-assessed ones showed better DAS28-CRP and HAQ-DI scores (difference in means [95% CI]: −0.25 [−0.46, −0.04] and − 0.196 [−0.306, −0.087] respectively). The results in the propensity-score matched subsample confirmed those observed in the original (whole) sample. Conclusions Early diagnosis and treatment initiation in patients with RA was critically dependent on early access to the rheumatologist; late specialized assessment was associated with worse long-term clinical outcomes. (RA reallife real life settings care longterm term conditions ACREULAR ACR EULAR 2010 (2010 1987 (1987 conducted “early “late afterwards inquired DAS28CRP DASCRP DAS28 CRP DAS (DAS28-CRP HAQDI HAQ DI (HAQ-DI Students Student s t MannWhitney Mann Whitney U chisquared chi squared tests analysis scorematched score vs lateassessed assessed approval consent 105 89.4% 894 89 4 (89.4 female 565 56 5 56.5 white white) SD (SD age 569 9 56. 11.5 115 11 (11.5 years duration 1731 173 1 173. 114.5 1145 114 (114.5 IQR (IQR coincided 6–36 636 36 (6–36 64.6% 646 64 (64.6% practitioner Notwithstanding 807 80 7 80.7 28.7% 287 28 (28.7% ≤ ( symptoms. . symptoms) rho 0.816 0816 0 816 0.001. 0001 0.001 001 0.001) OR 2.77 277 2 77 95 CI 193 93 1.93 3.97. 397 3.97 3 97 3.97) remissionlow remission low 0.74 074 74 055 55 0.55 0.99, 099 0.99 , 99 0.99) earlyassessed difference [95 CI] 025 25 −0.2 −0.46, 046 46 [−0.46 −0.04 004 04 0196 196 0.19 −0.306, 0306 306 [−0.306 −0.087 0087 087 respectively. respectively respectively) propensityscore whole (whole sample 201 (201 198 (198 DAS2 10 89.4 8 (89. 11. (11. 17 114. (114. 6–3 63 (6–3 64.6 (64.6 80. 28.7 (28.7 0.81 081 81 000 0.00 00 2.7 27 19 1.9 39 3.9 0.7 07 05 0.5 09 0.9 [9 02 −0. −0.46 [−0.4 −0.0 019 0.1 −0.306 030 30 [−0.30 −0.08 008 08 20 (20 (19 89. (89 (11 (114 6– (6– 64. (64. 28. (28. 0.8 0.0 2. 1. 3. 0. [ −0 −0.4 [−0. 01 −0.30 03 [−0.3 (2 (1 (8 (6 (64 (28 [−0 −0.3 [−

Abstract Background: Rheumatoid arthritis (RA) is a common autoimmune systemic inflammatory disease. In addition to joint involvement, RA patients frequently have other comorbidities, such as cardiovascular diseases. Drugs used for RA treatment may increase or decrease the risk of a cardiovascular event. This study aims to analyze cardiovascular risk comorbidities in patients with RA and the correlation with the use of anti-rheumatic drugs. Methods: Cross-sectional study conducted based on the real-life rheumatoid arthritis study database - REAL, a prospective observational cohort study. Associations between the use of anti-rheumatic drugs and the presence of comorbidities were represented by their prevalence ratio and evaluated using the Chi-square or Fisher’s Exact tests. Results: We assessed 1116 patients, 89.4% women, mean age of 55.15 years and predominance of seropositive disease. 63.3% had some cardiovascular comorbidity, predominantly hypertension (49.9%). The use of glucocorticoids was observed in 47.4% of patients and there was a significant tendency of lower use of these drugs in the presence of dyslipidemia (PR: 0.790; p = 0.007). We observed that the presence of cardiovascular comorbidities was associated with higher use of bDMARDs (PR:1.147; p = 0.003). Conclusions: The presence of cardiovascular risk comorbidities was confirmed to be higher in RA patients. Different treatment strategies using less glucocorticoids in the presence of dyslipidemia and more common use of bDMARDs in patients with cardiovascular comorbidities suggest that rheumatologists are aware of the potential influence of the DMARDs in the risk of cardiovascular event. Reinforcing these results, we highlight the need for a better baseline assessment to guide the choice of anti-rheumatic drugs in RA patients who have comorbidities.

Abstract Objectives: To compare the efficacy and safety of a new formulation of a fixed dose combination of glucosamine sulfate (GS; 1500 mg) and bovine chondroitin sulfate (CS; 1200 mg) versus the reference product (RP) in patients with knee osteoarthritis (OA). Methods: In this multicenter, randomized, single-blind trial, 627 patients with knee osteoarthritis (OA)—Kellgren-Lawrence grades 2 or 3 and mean score ≥ 40 mm in the WOMAC pain subscale—were randomized to receive GS/ CS or the RP for 24 weeks. The primary efficacy endpoint was the absolute change in WOMAC pain subscale score. The secondary endpoints included the following: WOMAC total and subscale scores, overall assessment of the disease by the patient and the investigator, SF-12 score, OMERACT-OARSI response rate to the treatment, and rescue medication use. Results: Mean reductions of WOMAC pain score were – 35.1 (sd = 23.2) mm in the GS/CS group and – 36.5 (sd = 24.9) mm in the RP group. The difference between the adjusted means of both treatments confirmed the noninferiority of GS/CS versus the RP. Improvement was observed in pain, stiffness, physical function and total WOMAC score, as well as in overall OA assessment by the patient and the investigator for both groups. No improvement was observed in SF-12. The rate of OMERACT-OARSI responders was 89.4% in GS/CS group and 87.9% in the RP group. Headache and changes in glucose tolerance were the most frequent treatment-related adverse events. Conclusions: The new formulation of a fixed-dose combination of glucosamine sulfate and bovine chondroitin sulfate was non-inferior to the RP in symptomatic treatment of knee OA, with a high responder rate and good tolerability profile. Trial registration: ClinicalTrials.gov; Registration number NCT02830919; Date of registration: July 13, 2016; First randomization date: December 05, 2016).

Abstract Background: In Brazil, socioeconomic differences in the incidence of rheumatoid arthritis (RA) have been demonstrated, which are important in the formulation of hypotheses regarding the association between environmental factors, lifestyle and the risk of disease development. This study examines how the socioeconomic condition of the patient with RA in Brazil, assessed according to social class, educational level, employment situation and use of caregivers, affects the times between the beginning of symptoms and diagnosis and the beginning of the use of disease-modifying antirheumatic drugs, as well as the presence of erosive disease and functional status. Methods: This work is part of a multicentric study called REAL - Rheumatoid Arthritis in Real Life in Brazil, which is a prospective observational cohort study. Results: As described in the REAL study, we included a total of 1115 patients. It was noted that patients with an educational classification of up to second grade incomplete presented with erosion percentages above those with a higher grade complete. Patients with caregivers presented a higher percentage of erosion than patients without caregivers. We verified that patients from economic classes above B2 presented fewer occurrences of erosion than those from classes C2, D-E. We also analyzed the average time differences from the beginning of symptoms and diagnosis and the beginning of treatment, according to academic level, erosion and economic classification. Patients with first grade complete showed an HAQ-DI averages higher than those with second grade complete. The patients who had employment showed lower HAQ-DI averages than patients who were not employed. The patients with erosion showed an HAQ-DI value higher than those without erosion. Patients with caregivers showed an HAQ-DI average higher than that of without caregivers. Conclusion: This study showed that the therapeutic window of RA is not being reached, and therefore we should have a policy to expand and ensure access to public health for all patients, especially those with lower levels of education and income. Trial registration: This study was approved by the National Commission of Ethics in Research.

Abstract Background: There are few data on the epidemiology, clinical manifestations and management of RA in Brazil, even with the recognition of the high direct, indirect and societal costs of this disease. Herein, we report the formation of the REAL - Rheumatoid Arthritis in Real Life, the first nationally representative multicenter prospective observational study in Brazil. Methods: The REAL study was designed to include a total of 1300 evaluable patients from 13 tertiary care public health centers specialized in RA management and representative of 5 regions of Brazil. Each center was expected to enroll ~ 100 consecutively seen patients and follow them prospectively in a systematic protocol-driven fashion with scheduled visits at baseline, 6 and 12 months. Core clinical, laboratory and patient-reported outcomes measures were required to be collected at each visit. Results: A total of 1115 patients (89.4% female, mean age of 56.7 years and median disease duration of 12.7 years) were enrolled from 11 participating centers. Almost 80% of patients were of middle-low or low socioeconomic classes. The median educational time was 8 years, with 3.23% being below literacy level. The interval between symptoms and diagnosis varied from 1 to 457 months (median 12 months). Almost half of the patients were on glucocorticoids, 96.5% on DMARDs, with 35.7% on biologics. Median HAQ-DI was 0.875, ranging from 0 to 3. Median DAS28-ESR was 3.5, with 58.7% of patients presenting moderate or high disease activity. Conclusions: The first large cohort of Brazilian patients with RA in a real-life setting shows several striking differences from previously published cohorts from other countries. The long delay for diagnosis and start of DMARDs may partly explain the high frequency of erosive disease. An elevated percentage of patients on moderate or high disease activity was seen, despite of the high frequency of corticosteroid and biologics utilization. Data from this cohort may enable public health managers of developing countries better allocate the limited resources available for the care of RA patients.

OBJETIVOS: Este estudo visou à análise das manifestações da esclerose sistêmica (ES), com ênfase na pesquisa dos autoanticorpos e de suas correlações clínicas, na população de pacientes em acompanhamento no ambulatório de ES do Hospital de Clínicas da Universidade Federal do Paraná. METODOLOGIA: Realizou-se um estudo transversal com 96 pacientes em acompanhamento no ambulatório de ES do hospital, entre setembro de 2007 e setembro de 2009. RESULTADOS: A maioria dos pacientes era do sexo feminino, com idade entre a quarta e quinta décadas e tempo de doença com mediana de 10 anos. A forma cutânea limitada de ES foi a mais prevalente. Na análise dos autoanticorpos, o anticorpo anticentromérico (ACA) associou-se a ES forma limitada, idade mais avançada ao diagnóstico, maior tempo de doença, intervalo maior entre o surgimento do fenômeno de Raynaud (FRy) e o primeiro sintoma não FRy, maior prevalência de hipertensão arterial sistêmica (HAS) e de bloqueios de condução cardíaca. O anticorpo antitopoisomerase-1 (antitopo-1, previamente denominado anti-Scl-70) foi mais comum na forma difusa da ES, na presença de doença ativa e de úlceras digitais. O anticorpo anti-RNA polimerase III (antipol III) correlacionou-se com a forma difusa de ES, presença de doença ativa e sinovite. CONCLUSÕES: Este estudo vem ressaltar e ratificar o papel relevante dos autoanticorpos na avaliação dos pacientes com ES, sendo possível correlacionar o perfil autoimune dessa população com manifestações específicas da doença

OBJECTIVES: To assess the manifestations of systemic sclerosis (SSc), with an emphasis on the analysis of autoantibodies and their clinical correlations, in a population of patients followed up at the SSc Outpatient Clinics of the Hospital de Clínicas of the Universidade Federal do Paraná. METHODOLOGY: Cross-sectional study with 96 patients followed up at the SSc Outpatient Clinics of the hospital between September 2007 and September 2009. RESULTS: Most patients were of the female sex, in their forties or fifties, and the median time of disease was ten years. The limited cutaneous form of SSc was more prevalent. The analysis of the autoantibodies showed the association of anticentromere antibody (ACA) with the following: the limited form of SSc; more advanced age at the time of diagnosis; longer disease time; longer interval between the appearance of the Raynaud's phenomenon (RyP) and the first non-RyP symptom; systemic arterial hypertension (SAH); and cardiac conduction blocks. The antitopoisomerase-1 antibody (ATA-1, previously called anti-Scl-70) was more common in the presence of the diffuse form of SSc, active disease, and digital ulcers. The anti-RNA polymerase III antibody (anti-Pol III) correlated with the diffuse form of SSc, disease activity, and synovitis. CONCLUSIONS: This study emphasizes and confirms the important role of autoantibodies in assessing patients with SSc, allowing the correlation between the autoimmune profile of patients with SSc and specific manifestations of the disease

A esclerose sistêmica (ES) é uma doença inflamatória crônica do tecido conjuntivo, de etiologia desconhecida, caracterizada por fibrose e dano micro vascular dos órgãos afetados. Há várias evidências de que a ativação do sistema imune celular participa de maneira expressiva na sua patogênese. OBJETIVO: Analisar numericamente as subpopulações linfocitárias no sangue periférico de pacientes com ES e sua possível relação com fatores clínicos e laboratoriais. MÉTODOS: Foram analisadas as subpopulações linfocitárias de 42 pacientes com ES e 28 controles normais, através da citometria de fluxo utilizando os antígenos linfocitários: CD2, CD3, CD4, CD8, CD19, CD25, CD45RA, CD56, CD71, HLA-DR , TCRα/β e TCRγ/δ. RESULTADOS: Nos pacientes com ES comparados com o grupo-controle, foram encontrados valores porcentuais normais para os linfócitos T CD2+, CD3+, CD3+CD4+, CD3+CD8+, CD25+, CD4+CD45RA+, CD8+CD45RA+, CD71 + e para a relação CD4+/CD8+. Em contraste, os linfócitos T CD3+TCRγ/δ mostraram-se com porcentuais diminuídos nos pacientes com ES difusa, de longa duração, com envolvimento pulmonar caracterizado por doença pulmonar restritiva, envolvimento muscular e presença de antilcorpo anti-Scl-70. Os pacientes com a forma difusa de ES apresentaram, tanto na fase recente como na tardia, aumento na porcentagem de linfócitos T CD4+ e CD8+ expressando moléculas de ativação HLA-DR. Na fase tardia da doença, não importando a forma clínica, foi encontrado aumento na porcentagem de linfócitos T CD4+CD45RA+. Os pacientes com ES limitada e fase recente mostraram diminuição na porcentagem dos linfócitos B CD19+. Os pacientes com doença difusa e fase tardia apresentaram diminuição na porcentagem dos linfócitos NK CD56+. CONCLUSÕES: Estes resultados sugerem que as alterações dos linfócitos T, B e NK possam estar envolvidas no processo de desencadeamento e/ ou perpetuação da ES, havendo a possibilidade de ter utilidade prognóstica em alguns grupos de pacientes.

Systemic sclerosis (SSc) is a chronic inflammatory connective tissue disease of unknown etioiogy characterized by fibrosis and microvascuiar injury in affected organs. It has become clear that th e activation of celluiar immune system piays a central roie in the pathogenesis of SSc. OBJECTIVE: The purpose oE this study was to anaiyze numerically iymphocytic subpopuiations in the biood of systemic sclerosis patients and their relations with clinicai and iaboratory mani[estations. METHODS: We studied a group of 42 patients with SSc and a group oE 28 matched normai controis by flow cytometry using the following iymphocyte celi-surrace markers: CD2, CD3, CD4, CDS, CD19, CD25, CD45RA, CD56, CD71, HLADR, TCRα/β and TCRγ/δ. RESULTS: SSc patients had similar percentages of CD2+, CD3+, CD3+CD4+, CD3+CDS+, CD25+, CD4+CD45RA+, CDS+CD45RA+, CD71+ cells and CD4+/ CDS+ celi ratio when compared to . normal controis. ln contrast, the percentages of TCRγ/δ cells were significantiy iower in SSc patients with diffuse and iate-stage disease with puimonary and muscle invoivement and the presence of anti-Scl-70 antibodies. Patients with diffuse SSc in early and iate-stage disease had significantly increased percentages of HLA-DR in CD4+ and CDS+ celis; patients with iate-stage disease had increased percentages of CD4+CD45RA+ T celis; patients with iimited and eariy-stage disease had small pereentages of B eelis (CD19+): and patients with diffuse and iate-stage disease had small pereentages of NK eells (CD56 +). CONCLUSIONS: These results suggest that T, B and NK eell alterations may be invoived in the onset of the disease and/ or in the perpetuation of disease, and may eventuaJJy be usefui as a prognostie indieator in seleeted patient subgroups.