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Objective.To evaluate the safety of the methotrexate (MTX)–leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi).Methods.Patients with RA starting a treatment course with a csDMARD (without previous use of bDMARD or JAKi) or their first bDMARD/JAKi were followed up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matching analysis (PSMA) were used for statistical comparisons.Results.In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX + LEF. The overall incidence of SAEs was 5.6 per 100 PY. The hazard of SAEs for MTX + LEF was not higher than for MTX or LEF (adjusted HR [aHR] 1.00, 95% CI 0.76–1.31, P = 0.98). MTX + LEF presented a lower hazard of SAEs (aHR 0.56, 95% CI 0.36–0.88, P = 0.01) and infectious SAEs (aHR 0.48, 95% CI 0.25–0.94, P = 0.03) than bDMARDs/JAKi with MTX or LEF. MTX + LEF presented lower hazard of SAEs than MTX + sulfasalazine (SSZ; aHR 0.33, 95% CI 0.16–0.65, P = 0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis.Conclusion.In our study, MTX + LEF presented a relatively good overall safety profile in comparison to MTX + SSZ and schemes involving advanced therapies in RA.

BACKGROUND The safety profile of biologic drugs might present substantial regional differences. Since 2009, the Brazilian Society of Rheumatology has maintained BIOBADABRASIL (Brazilian Registry for Biologic Drugs), a registry for monitoring of biologic therapies in rheumatic diseases. OBJECTIVES The aim of this study was to verify the incidence rate (IR) of serious infections in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients on biologic drugs. METHODS BIOBADABRASIL prospectively included patients with rheumatic diseases who started the first biologic drug or a synthetic disease-modifying antirheumatic drug as a parallel control group. This study focuses on serious infectious adverse events (SIAEs) in RA and SpA patients on biologic drugs compared with controls, from January 2009 to June 2015. Time of exposure was set from initiation of the drug to the date of last administration or censorship. Serious infectious adverse events IR was calculated per 1000 patient/years with 95% confidence interval (CI). RESULTS A total of 1698 patients (RA, 1121; SpA, 577) were included, 7119 patient/years. Serious infectious adverse events were more common among patients on tumor necrosis factor inhibitors (TNFi's) than controls (adjusted IR ratio, 2.96 [95% CI, 2.01-4.36]; p < 0.001). Subsequent TNFi was associated with a higher SIAEs incidence when compared with first TNFI (adjusted IR ratio, 1.55 [95% CI, 1.15-2.08]; p = 0.004). Serious infectious adverse events were associated with age and corticosteroids intake. Serious infectious adverse events were more frequent in the respiratory tract in all subgroups. CONCLUSIONS In BIOBADABRASIL, biologic drugs, especially the subsequent TNFi, were associated with a higher risk of serious infections compared with synthetic DMARDs. Corticosteroid intake and age represented risk factors for SIAEs. Constant monitoring is required to follow the safety profile of drugs in the clinical setting of rheumatic conditions in Brazil.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Background The combination of methotrexate (MTX) with leflunomide (LEF), despite being effective in the therapy of rheumatoid arthritis (RA)[1], has not been widely accepted[2,3]. In spite of evidence that the MTX-LEF combination is generally safe [1,4,5], the relatively small number of patients and treatment courses have not permitted firm conclusions. Objectives To evaluate the safety of the combination MTX-LEF in Brazilian patients with RA included in BiobadaBrasil. Methods BiobadaBrasil is a multicentric prospective cohort study involving patients with rheumatic diseases who started the first biologic or a synthetic disease modifying anti-rheumatic drug (DMARD)[6]. This analysis includes RA (2010 criteria) patients recruited from Jan 2009 to Aug 2018,followed-up for one or multiple courses of treatment until censoring (latest date, September 03, 2018) or occurrence of the outcome of interest. The primary outcome was the incidence of any serious AE (SAE). Secondary outcomes were infectious, non-mycobacterial pulmonary infectious, hepatic, hematologic and cardiovascular SAE. Multivariate Cox proportional hazards models (with DMARDs included as time-varying covariates) were used to estimate hazard ratios (HR) and 95% confidence intervals (CI); analyses were performed with the Survival package of R. Results Sample: 2055 RA patients, female=85.1%, median disease duration=6.02 yrs; mean (SD) age=50.3 (12.1) yrs; mean (SD) DAS28=5.3 (3.1); seronegative RA=14.1%; median follow-up duration=3.9 yrs. In total, 565 patients received 664 courses of the MTX-LEF combination (median duration, 2.5 years/course; 2209 person-years). The incidence of SAE was 4.75/100 patient-years in the entire sample. There was no significant increase in the risk of any of the outcomes with the use of combined therapy (table 1) comparing with methotrexate (without leflunomide). The use of antimalarials was associated with reduced risk of SAE (adjusted HR=0.62, 95% CI 0.48 to 0.79, P Conclusion BIOBADABRASIL results suggest that the combination of methotrexate and leflunomide is safe in thetreatment of RA. References [1] Ann Intern Med 2002; 137: 726. [2] Ann Rheum Dis 2010; 69: 43. [3] Ann Pharma cother 2004; 38: 1206. [4] J Rheumatol 2013; 40: 228. [5] Rev Bras Reumatol 2011; 51: 141/51:152. Acknowledgement monitor P Cabral Disclosure of Interests Markus Bredemeier: None declared, M Pinheiro Consultant for: Janssen, Pfizer, Speakers bureau: Abbot,Janssen,Novartis, C Macieira: None declared, A Duarte: None declared, B Stadler: None declared, R Ranza: None declared, Ana Medeiros: None declared, V Valim: None declared, M Bertolo: None declared, J Miranda Speakers bureau: Pfizer, C Brenol Speakers bureau: Pfizer, Roche, Janssen, Bristol., G Castro: None declared, V Fernandes Speakers bureau: Janssen, D Titton: None declared, F Sauma: None declared, I Pereira: None declared, R Botelho: None declared, H Carvalho: None declared, A Hayata: None declared, P Louzada: None declared, A Ranzolin: None declared, I Silveira: None declared, S Schowalski: None declared, D Feldman: None declared, I Laurindo Consultant for: Abbvie, UCB, GSK, JANSSEN, LILLY, NOVARTIS, PFIZER, Paid instructor for: Abbvie, JANSSEN, Speakers bureau: Abbvie, UCB, GSK, JANSSEN, LILLY, NOVARTIS, PFIZER, ROCHE, J Provenza: None declared

Most reports on serious infections (SI) in rheumatoid arthritis (RA) patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) are from the USA and Western Europe. Data from other regions are largely missing. We report data from South American countries with different backgrounds and health-care systems but similar registries.We merged 2010-2016 data from two registries, BIOBADABRASIL (Brazil) and BIOBADASAR (Argentina), which share the same protocol, online platform and data monitoring process. Patients with active RA were included when they began the first bDMARD or a conventional synthetic DMARD (csDMARD, control group). The SI incidence rate (IR) per 1000 patient/years and adjusted IR ratio (aIRR) were estimated for bDMARDs and csDMARDs.Data were analysed for 3717 RA patients with an exposure of 13,380 patient/years. The 2591 patients treated with bDMARDs (64% tumour necrosis factor-α inhibitors (TNFi)) had a follow-up of 9300 years, and the 1126 treated with csDMARDs had an exposure of 4081 patient/years. The SI IR was 30.54 (CI 27.18-34.30) for all bDMARDs and 5.15 (CI 3.36-7.89) for csDMARDs. The aIRR between the two groups was 2.03 ([1.05, 3.9] p = 0.034) for the first 6 months of treatment but subsequently increased to 8.26 ([4.32, 15.76] p 0.001). The SI IR for bDMARDs decreased over time in both registries, dropping from 36.59 (28.41-47.12) in 2012 to 7.27 (4.79-11.05) in 2016.While SI remains a major concern in South American patients with RA treated with bDMARDs, a favourable trend toward a reduction was observed in the last years.Key Points• New comprehensive data on biologic drugs safety from international collaboration in South America.• First proposal for national registries data merging in South America.• Serious infections remain a major concern in RA patients treated with biologics.• A significant reduction of serious infections in RA patients exposed to biologics was observed over a 7 years period.

Background:After failure of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) in the therapy of rheumatoid arthritis (RA), treatment may be escalated to biologic (bDMARDs) or JAK inhibitors (JAKi) (1). Analysis of drug survival can provide useful information on the effectiveness of these therapeutic schemes.Objectives:to evaluate the association of the choice of therapeutic agent with the survival of treatment course in RA patients receiving their first bDMARD or JAKi.Methods:BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients starting their first bDMARD/JAKi (2). This analysis includes RA patients recruited from Jan 2009 to Oct 2019, followed-up over the first course of treatment with a bDMARD/JAKi until censoring (latest date, Nov 19, 2019) or occurrence of the outcome of interest. A treatment course is defined as a period during which the medication scheme does not change, except for dose adjustments. The primary outcome was the interruption of treatment course for any reason (except for pregnancy or disease remission); interruption of treatment due to adverse events (AEs) or death and due to inefficacy served as secondary outcomes. Multivariate Cox proportional hazards models were used for analyses.Results:In total, 1177 patients (3800 patient-years [PY]) were enrolled. The overall incidence of treatment interruption was 17.5/100 PY. Adalimumab was the most frequently prescribed agent, followed by infliximab (n= 267). The hazards ratios (HR) of the primary and secondary outcomes are presented in Table 1. Figure 1 compares the survival of treatment curves of different bDMARDs/JAKi.Table 1.Hazard ratios (HR) of interruption of therapy course of each therapeutic agent (the reference category for bDMARDs/ JAKi is infliximab). Results are HR, 95% CIs, and P values*.Agent (number of patients)Interruption for any reason (665 events)Interruption due to adverse events or death (196 events)Interruption due to inefficacy (319 events)Adalimumab (354)0.83 (0.68 to 1.01), P= 0.0620.68 (0.48 to 0.96), P=0.0291.08 (0.80 to 1.44), P=0.621Etanercept (257)0.81 (0.66 to 1.01), P=0.0630.56 (0.37 to 0.83), P=0.0040.93 (0.68 to 1.29), P=0.674Certolizumab (80)0.74 (0.47 to 1.16), P=0.1850.33 (0.13 to 0.86), P=0.0241.32 (0.74 to 2.35), P=0.350Golimumab (53)0.86 (0.53 to 1.38), P=0.5300.46 (0.18 to 1.19), P=0.1111.07 (0.53 to 2.15), P=0.849JAKi (tofacitinib) (59)0.54 (0.30 to 0.99), P=0.0470.19 (0.04 to 0.82), P=0.0260.89 (0.41 to 1.96), P=0.779Rituximab (48)0.87 (0.55 to 1.37), P=0.5400.48 (0.20 to 1.18), P=0.1090.58 (0.26 to 1.34), P=0.205Abatacept (30)0.52 (0.25 to 1.07), P=0.0770.46 (0.14 to 1.56), P=0.2150.46 (0.14 to 1.52), P=0.203Tocilizumab (29)0.29 (0.14 to 0.63), P=0.0020.40 (0.12 to 1.30), P=0.1260.28 (0.09 to 0.90), P=0.033Methotrexate (792)0.95 (0.79 to 1.14), P=0.5610.86 (0.62 to 1.19), P=0.3620.98 (0.75 to 1.28), P=0.860Leflunomide (497)1.17 (0.99 to 1.39), P=0.0611.44 (1.06 to 1.96), P=0.0201.02 (0.80 to 1.30), P=0.856Sulfasalazine (48)1.18 (0.80 to 1.75), P=0.4011.94 (1.07 to 3.54), P=0.0300.85 (0.45 to 1.59), P=0.605Antimalarials (230)0.80 (0.65 to 0.98), P=0.0270.67 (0.45 to 0.99), P=0.0430.67 (0.50 to 0.92), P=0.011* All tests adjusted for other variables presented in the table and for age, baseline DAS28, disease duration, gender, smoking, seropositivity (RF/anti-CCP), previous malignancy, diabetes, hypertension, hypercholesterolemia, renal failure, ischemic cardiomyopathy, COPD, heart failure, use of corticosteroids, starting year, hypercholesterolemia, osteoporosis, hepatitis B and C.Conclusion:In our study, infliximab was related to an overall higher hazard of treatment course interruption than tolicizumab and tofacitinib, and higher hazard of interruption due to AEs than most other anti-TNF agents and tofacitinib. Maintaining antimalarials in patients receiving advanced therapies for RA may reduce interruption of treatment due to inefficacy and AEs.Disclosure of Interests:None declared

Objectives To assess the incidence of tuberculosis and to screen for latent tuberculosis infection among Brazilians with rheumatoid arthritis using biologics in clinical practice. Patients and methods This cohort study used data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil), from 01/2009 to 05/2013, encompassing 1552 treatments, including 415 with only synthetic disease-modifying anti-rheumatic drugs, 942 synthetic DMARDs combined with anti-tumor necrosis factor (etanercept, infliximab, adalimumab) and 195 synthetic DMARDs combined with other biologics (abatacept, rituximab and tocilizumab). The occurrence of tuberculosis and the drug exposure time were assessed, and screening for tuberculosis was performed. Statistical analysis: Unpaired t-test and Fisher's two-tailed test; p < 0.05. Results The exposure times were 981 patient-years in the controls, 1744 patient-years in the anti-TNF group (adalimumab = 676, infliximab = 547 and etanercept = 521 patient-years) and 336 patient-years in the other biologics group. The incidence rates of tuberculosis were 1.01/1000 patient-years in the controls and 2.87 patient-years among anti-TNF users (adalimumab = 4.43/1000 patient-years; etanercept = 1.92/1000 patient-years and infliximab = 1.82/1000 patient-years). No cases of tuberculosis occurred in the other biologics group. The mean drug exposure time until the occurrence of tuberculosis was 27(11) months for the anti-TNF group. Conclusions The incidence of tuberculosis was higher among users of synthetic DMARDs and anti-TNF than among users of synthetic DMARDs and synthetic DMARDs and non-anti-TNF biologics and also occurred later, suggesting infection during treatment and no screening failure. Resumo Objetivos Avaliar incidência de tuberculose e triagem para tuberculose latente em brasileiros com artrite reumatoide em uso de agentes biológicos na prática clinica. Pacientes e métodos Estudo de coorte com dados do Registro Brasileiro de Monitoração de Terapias Biológicas (BiobadaBrasil), de 01/2009 a 05/2013, abrangeu 1.552 tratamentos, 415 somente com drogas modificadoras do curso da doença (MMCDs) sintéticas, 942 MMCDs sintéticas em associação com anti-TNF (etanercepte, infliximabe, adalimumabe) e 195 MMCDs sintéticas em associação com outros biológicos (abatacepte, rituximabe e tocilizumabe). Avaliaram-se ocorrência de tuberculose, tempo de exposição às drogas e triagem para TB. Análise estatística: teste t não pareado e teste de Fisher bicaudal; p < 0,05. Resultados O tempo de exposição dos controles foi de 981 pacientes-ano, do grupo de anti-TNF foi de 1.744 pacientes-ano (adalimumabe = 676, infliximabe = 547 e etanercepte = 521 pacientes-ano) e o de outros biológicos de 336 pacientes-ano. A incidência de TB foi de 1,01/1.000 pacientes-ano nos controles e de 2,87 pacientes-ano nos usuários de anti-TNF (adalimumabe = 4,43/1.000 pacientes-ano; etanercepte = 1,92/1.000 pacientes-ano e infliximabe = 1,82/1.000 pacientes-ano). Não houve casos de tuberculose no grupo de outros biológicos. O tempo médio de exposição até a ocorrência de tuberculose foi de 27(11) meses para o grupo anti-TNF. Conclusões A incidência de tuberculose foi maior nos usuários de MMCDs sintéticas e anti-TNF do que nos usuários de MMCDs sintéticas e de MMCDs sintéticas e biológicos não anti-TNF, e também mais tardia, sugerindo infecção durante o tratamento, e não falha na triagem.