Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil)

Markus Bredemeier¹, Roberto Ranza², Adriana M Kakehasi³, Aline Ranzolin⁴, Inês G da Silveira⁵, Ana C M Ribeiro⁶, David C Titton⁷, André L S Hayata⁸, Hellen M S Carvalho⁹, Bárbara S Kahlow¹⁰, Vander Fernandes¹¹, Paulo Louzada Jr¹², Manoel B Bértolo¹³, Ângela L B P Duarte⁴, José C Macieira¹⁴, José R S Miranda¹⁵, Geraldo R C Pinheiro¹⁶, Reginaldo B Teodoro¹⁷, Marcelo M Pinheiro¹⁸, Valéria Valim¹⁹, Ivânio A Pereira²⁰, Maria F L C Sauma²¹, Gláucio R W de Castro²², Laurindo F da Rocha Jr²³, Sâmia A S Studart²⁴, Morgana O Gazzeta²⁵, Leticia G da Silveira²⁶, Cristiano M Lupo²⁷, Ieda M M Laurindo²⁸

Affiliations

¹ M. Bredemeier, MD, PhD, Hospital Nossa Senhora da Conceição, Grupo Hospitalar Conceição, Porto Alegre; markbred@terra.com.br.
² R. Ranza, MD, PhD, Universidade Federal de Uberlândia, Uberlândia.
³ A.M. Kakehasi, MD, PhD, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte.
⁴ A. Ranzolin, MD, PhD, A.L. Duarte, MD, PhD, Universidade Federal de Pernambuco (UFPE), Recife.
⁵ I.G. da Silveira, MD, PhD, Hospital São Lucas, Faculdade de Medicina da PUCRS, Porto Algere.
⁶ A.C. Ribeiro, MD, PhD, Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP), São Paulo.
⁷ D.C. Titton, MD, Universidade Federal do Paraná, Curitiba.
⁸ A.L. Hayata, MD, PhD, Clínica de Reumatologia, Osasco.
⁹ H.M. Carvalho, MD, Hospital de Base do Distrito Federal, Brasília.
¹⁰ B.S. Kahlow, MD, Hospital Universitário Evangélico de Curitiba, Curitiba.
¹¹ V. Fernandes, MD, PhD, Hospital Geral Universitário de Cuiabá, Cuiabá.
¹² P. Louzada Jr., MD, PhD, Faculdade de Medicina USP, Ribeirão Preto.
¹³ M. Bértolo, MD, PhD, Universidade Estadual de Campinas, Campinas.
¹⁴ J.C. Macieira, MD, Universidade Federal de Sergipe, Aracajú.
¹⁵ J.R. Miranda, MD, Artrocenter Clínica Médica de Taubaté, Taubaté.
¹⁶ G.R. Pinheiro, MD, PhD, Universidade Estadual do Rio de Janeiro, Rio de Janeiro.
¹⁷ R.B. Teodoro, MD, Hospital da Universidade Federal do Triângulo Mineiro, Uberaba.
¹⁸ M.M. Pinheiro, MD, PhD, Universidade Federal de São Paulo, São Paulo.
¹⁹ V. Valim, MD, PhD, Universidade Federal do Espírito Santo, Vitória.
²⁰ I.A. Pereira, MD, PhD, Hospital Universitário da Universidade Federal de Santa Catarina, Florianópolis.
²¹ M.F. Sauma, MD, PhD, Universidade Federal do Pará, Belém.
²² G.R. de Castro, MD, Hospital Governador Celso Ramos, Florianópolis.
²³ L.F. da Rocha Jr., MD, PhD, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife.
²⁴ S.A. Studart, MD, Hospital Geral de Fortaleza, Fortaleza.
²⁵ M.O. Gazzeta, MD, Santa Casa de Misericórdia do Rio de Janeiro, Rio de Janeiro.
²⁶ L.G. da Silveira, MS, Universidade Federal do Rio Grande do Sul/Hospital de Clínicas de Porto Alegre, Porto Alegre.
²⁷ C.M. Lupo, MD, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto.
²⁸ I.M. Laurindo, MD, PhD, Faculdade de Medicina da Universidade Nove de Julho, São Paulo, Brazil.

PMID: 33934077
DOI: 10.3899/jrheum.201248

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil)

Markus Bredemeier et al. J Rheumatol. 2021 Oct.

. 2021 Oct;48(10):1519-1527.

doi: 10.3899/jrheum.201248. Epub 2021 May 1.

Authors

Affiliations

¹ M. Bredemeier, MD, PhD, Hospital Nossa Senhora da Conceição, Grupo Hospitalar Conceição, Porto Alegre; markbred@terra.com.br.
² R. Ranza, MD, PhD, Universidade Federal de Uberlândia, Uberlândia.
³ A.M. Kakehasi, MD, PhD, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte.
⁴ A. Ranzolin, MD, PhD, A.L. Duarte, MD, PhD, Universidade Federal de Pernambuco (UFPE), Recife.
⁵ I.G. da Silveira, MD, PhD, Hospital São Lucas, Faculdade de Medicina da PUCRS, Porto Algere.
⁶ A.C. Ribeiro, MD, PhD, Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP), São Paulo.
⁷ D.C. Titton, MD, Universidade Federal do Paraná, Curitiba.
⁸ A.L. Hayata, MD, PhD, Clínica de Reumatologia, Osasco.
⁹ H.M. Carvalho, MD, Hospital de Base do Distrito Federal, Brasília.
¹⁰ B.S. Kahlow, MD, Hospital Universitário Evangélico de Curitiba, Curitiba.
¹¹ V. Fernandes, MD, PhD, Hospital Geral Universitário de Cuiabá, Cuiabá.
¹² P. Louzada Jr., MD, PhD, Faculdade de Medicina USP, Ribeirão Preto.
¹³ M. Bértolo, MD, PhD, Universidade Estadual de Campinas, Campinas.
¹⁴ J.C. Macieira, MD, Universidade Federal de Sergipe, Aracajú.
¹⁵ J.R. Miranda, MD, Artrocenter Clínica Médica de Taubaté, Taubaté.
¹⁶ G.R. Pinheiro, MD, PhD, Universidade Estadual do Rio de Janeiro, Rio de Janeiro.
¹⁷ R.B. Teodoro, MD, Hospital da Universidade Federal do Triângulo Mineiro, Uberaba.
¹⁸ M.M. Pinheiro, MD, PhD, Universidade Federal de São Paulo, São Paulo.
¹⁹ V. Valim, MD, PhD, Universidade Federal do Espírito Santo, Vitória.
²⁰ I.A. Pereira, MD, PhD, Hospital Universitário da Universidade Federal de Santa Catarina, Florianópolis.
²¹ M.F. Sauma, MD, PhD, Universidade Federal do Pará, Belém.
²² G.R. de Castro, MD, Hospital Governador Celso Ramos, Florianópolis.
²³ L.F. da Rocha Jr., MD, PhD, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife.
²⁴ S.A. Studart, MD, Hospital Geral de Fortaleza, Fortaleza.
²⁵ M.O. Gazzeta, MD, Santa Casa de Misericórdia do Rio de Janeiro, Rio de Janeiro.
²⁶ L.G. da Silveira, MS, Universidade Federal do Rio Grande do Sul/Hospital de Clínicas de Porto Alegre, Porto Alegre.
²⁷ C.M. Lupo, MD, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto.
²⁸ I.M. Laurindo, MD, PhD, Faculdade de Medicina da Universidade Nove de Julho, São Paulo, Brazil.

PMID: 33934077
DOI: 10.3899/jrheum.201248

Erratum in

Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil).
Bredemeier M, Ranza R, Kakehasi AM, Ranzolin A, da Silveira IG, Ribeiro ACM, Titton DC, Hayata ALS, Carvalho HMS, Kahlow BS, Fernandes V, Louzada P Jr, Bértolo MB, Duarte ÂLBP, Macieira JC, Miranda JRS, Pinheiro GRC, Teodoro RB, Pinheiro MM, Valim V, Pereira IA, Sauma MFLC, de Castro GRW, da Rocha LF Jr, Studart SAS, Gazzeta MO, da Silveira LG, Lupo CM, Laurindo IMM. Bredemeier M, et al. J Rheumatol. 2022 Jan;49(1):122. doi: 10.3899/jrheum.201248.C1. J Rheumatol. 2022. PMID: 34974425 No abstract available.

Abstract

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.

Keywords: antirheumatic drugs; biologics; drug safety; leflunomide; methotrexate; rheumatoid arthritis.

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Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil)

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Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (BiobadaBrasil)

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