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

Markus Bredemeier; Roberto Ranza; Adriana M Kakehasi; Aline Ranzolin; Inês G da Silveira; Ana C M Ribeiro; David C Titton; André L S Hayata; Hellen M S Carvalho; Bárbara S Kahlow; Vander Fernandes; Paulo Louzada Jr; Manoel B Bértolo; Ângela L B P Duarte; José C Macieira; José R S Miranda; Geraldo R C Pinheiro; Reginaldo B Teodoro; Marcelo M Pinheiro; Valéria Valim; Ivânio A Pereira; Maria F L C Sauma; Gláucio R W de Castro; Laurindo F da Rocha Jr; Sâmia A S Studart; Morgana O Gazzeta; Leticia G da Silveira; Cristiano M Lupo; Ieda M M Laurindo

doi:10.3899/jrheum.201248

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

J Rheumatol. 2021 Oct;48(10):1519-1527. doi: 10.3899/jrheum.201248. Epub 2021 May 1.

Authors

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; [email protected].
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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid* / drug therapy
Cohort Studies
Drug Therapy, Combination
Humans
Isoxazoles / therapeutic use
Leflunomide / therapeutic use
Methotrexate* / adverse effects
Registries

Substances

Isoxazoles
Leflunomide
Methotrexate