Real-world safety data of first-line drugs for rheumatoid arthritis: insights from the Portuguese Reuma.pt database

Authors

Joana Ramos Rodrigues; Luís Silva Pires; Luís Inês; Manuel Morgado; Maria Pontes Ferreira; Anita Cunha; Susana Almeida; Mariana Emília Santos; Ana Catarina Moniz; Daniel Melim; Miguel Bernardes; Carlos Marques Gomes; Mariana Diz Lopes; Daniel Carvalho; Joaquim Polido Pereira; João Aguiar; Inês Sopa; Cátia Duarte; Filipa Canhão André; Sara Alves Costa; Cláudia Miguel; Ana Rita Vieira; Leonor Reynolds; Marina Oliveira; Filipe Pinheiro; Catarina Abreu; Susana Matias; Ana Catarina Duarte; Ana Teodósio Chícharo; Vítor Silvestre Teixeira; Pedro Miguel Teixeira; Rita Fonseca; Maria Helena Lourenço; Catarina Rua; Catarina Silva; Margarida Oliveira; Ana Águeda; Marília Rodrigues; Helena Assunção; Patrícia Nero; Maura Couto; Helena Santos; Duarte Augusto; Maria Francisca Magalhães; João Dias; Teresa Melo; Carla Campinho Ferreia; Paulo Pereira; João Lagoas Gomes; Ana Raposo; Ana Valido; Filipa Farinha; José António Pereira Silva; António Vilar; José Tavares-Costa; Jorge Garcia; Filipe Araújo; Graça Sequeira; Ana Cordeiro; Ana Filipa Mourao;

Keywords

Adverse Drug Reaction Reporting Systems;Rheumatoid arthritis ;Antirheumatic Agents;Methotrexate;Treatment Outcome;

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Objectives: To assess adverse events (AE) associated with first-line therapies for rheumatoid arthritis (RA) in a real-world setting. Material and Methods: Retrospective multicenter cohort study of patients fulfilling classification criteria for RA and followed up in 66 rheumatology centers from the Rheumatic Diseases Portuguese Registry (Reuma.pt). All AE reports associated with first-line disease-modifying antirheumatic drugs (DMARDs) up to November 2024 were included. Demographic and clinical data were analyzed, and AE characteristics were investigated. Categorical and continuous variables were compared using chi-square tests and Mann–Whitney U tests, respectively. Statistical significance was defined as p < .05. Results: Among 1 880 AE entries, 377 (20.1%) were attributed to first-line DMARDs, most commonly methotrexate (62.9%) although no information on drug dosage was available. The median age at AE occurrence was 58.6 years (IQR: 19.32), and 82% were female. A causality assessment was available in 317 reports, with 40.3% deemed “probable,” 28.1% “possible,” and 10.6% “definitive.” Severe AE were reported in 13.2% of cases, with pulmonary involvement being the most common (20.8%).Overall, 46.7% of patients discontinued treatment for any reason. Male sex was significantly associated with severe AE (OR = 2.31; 95% CI: 1.17–4.55; p = .014), and older patients were more likely to experience severe AE (median age 65.7 vs. 57.9 years; p < .001). The most affected body organ systems were gastrointestinal (9.3%), skin (8.2%), and hematological (8.2%). The median time to AE onset from treatment initiation was 1.27 years (IQR: 2.63), and from disease onset was 8.56 years (IQR: 11.76). Conclusions: AE related to first-line RA therapies can lead to significant clinical consequences, including treatment discontinuation. Male sex and advanced age were associated with increased AE severity. The most affected systems appear consistent with known drug safety profiles, particularly that of methotrexate; however, the absence of information regarding drug dosage precludes more detailed conclusions. These findings emphasize the need for individualized monitoring strategies and improved pharmacovigilance to optimize long-term treatment safety and adherence in RA management.

Joana Ramos Rodrigues
Unidade Local de Saúde da Cova da Beira

Luís Silva Pires
Center for Research in Neuropsychology and Cognitive-Behavioral Intervention (CINEICC), Faculty of Psychology and Educational Sciences, University of Coimbra, Portugal

Luís Inês
Rheumatology Department, Unidade Local de Saúde de Coimbra, Coimbra, Portugal

Manuel Morgado
Pharmaceutical Services, Unidade Local de Saúde da Cova da Beira, Alameda Pêro da Covilhã, Portugal

Maria Pontes Ferreira
Rheumatology Department, Unidade Local do Alto Minho, Ponte de Lima, Portugal

Anita Cunha
Rheumatology Department, Unidade Local do Alto Minho, Ponte de Lima, Portugal

Susana Almeida
Unidade Local de Saúde do Alto Minho (ULSAM)

Mariana Emília Santos
Rheumatology Department, Centro Hospitalar Lisboa Ocidental – EPE, Hospital de Egas Moniz, Lisboa, Portugal

Ana Catarina Moniz
Unidade Local de Saúde de Lisboa Ocidental

Daniel Melim
Centro Hospitalar do Funchal, SESARAM E.P.E

Miguel Bernardes
Rheumatology Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal

Carlos Marques Gomes
Centro Hospitalar Universitário de São João, Porto, Portugal

Mariana Diz Lopes
Centro Hospitalar Universitário de São João, Porto, Portugal

Daniel Carvalho
Unidade Local de Saúde Santa Maria, Centro Académico de Medicina de Lisboa, Lisboa, Portugal

Joaquim Polido Pereira
Unidade Local de Saúde de Santa Maria, Centro Académico de Medicina de Lisboa, Lisboa, Portugal

João Aguiar
Rheumatology Department, Local Health Unit of Santa Maria, Lisbon Academic Medical Centre

Inês Sopa
Rheumatology Department, Local Health Unit of Santa Maria, Lisbon Academic Medical Centre

Cátia Duarte
Centro Hospitalar e Universitário de Coimbra

Filipa Canhão André
Unidade Local de Saúde de Coimbra

Sara Alves Costa
Unidade Local de Saúde de Coimbra

Cláudia Miguel
Portuguese Institute of Rheumatology, Lisbon, Portugal

Ana Rita Vieira
Instituto Português de Reumatologia

Leonor Reynolds
Instituto Português de Reumatologia

Marina Oliveira
Rheumatology Department, Hospital do Divino Espírito Santo de Ponta Delgada, Açores, Portugal

Filipe Pinheiro
Rheumatology Department, Hospital do Divino Espírito Santo de Ponta Delgada, Açores, Portugal

Catarina Abreu
Hospital Garcia de Orta, Unidade Local de Saúde Almada-Seixal

Susana Matias
Hospital Garcia de Orta, Unidade Local de Saúde Almada-Seixal

Ana Catarina Duarte
Hospital Garcia de Orta

Ana Teodósio Chícharo
Unidade Local de Saúde de Santa Maria

Vítor Silvestre Teixeira
Unidade Local de Saúde do Algarve

Pedro Miguel Teixeira
Rheumatology Department, ULS Região de Aveiro, Aveiro, Portugal

Rita Fonseca
Unidade Local de Saúde Entre Douro e Vouga

Maria Helena Lourenço
Rheumatology, Hospital de Egas Moniz, Lisbon, Portugal

Catarina Rua
ULS Gaia e Espinho

Catarina Silva
Unidade Local de Saúde Gaia e Espinho

Margarida Oliveira
Unidade Local de Saúde da Cova da Beira

Ana Águeda
Unidade Local de Saúde da Cova da Beira

Marília Rodrigues
Unidade Local de Saúde da Região de Leiria, Leiria, Portugal

Helena Assunção
Rheumatology Department, ULS of Trás-os-Montes and Alto Douro, Vila Real

Patrícia Nero
Hospital CUF Descobertas

Maura Couto
Rheumatology Unit, Viseu Dão-Lafões Local Health Unit (ULS), Portugal

Helena Santos
Instituto Português de Reumatologia

Duarte Augusto
Unidade Local de Saúde da Guarda

Maria Francisca Magalhães
Rheumatology Department of Unidade Local de Saúde da Guarda, Portugal

João Dias
Unidade Local de Saúde Médio Tejo

Teresa Melo
Rheumatology Unit, Unidade Local de Saúde S. José, Lisbon, Portugal

Carla Campinho Ferreia
Hospital de Braga

Paulo Pereira
Hospital de Braga

João Lagoas Gomes
Rheumatology Unit, Tâmega e Sousa Local Health Unit (ULS), Portugal

Ana Raposo
Rheumatology Unit, Tâmega e Sousa Local Health Unit (ULS), Portugal

Ana Valido
Unidade Local de Saúde do Litoral Alentejano

Filipa Farinha
Serviço de Reumatologia, Unidade Local de Saúde da Lezíria, E.P.E., Hospital Distrital de Santarém, Santarém, Portugal

José António Pereira Silva
Centro Hospitalar e Universitário de Coimbra

António Vilar
HeyDoc Clinic Avenida de Roma, Lisbon, Portugal

José Tavares-Costa
Rheumatology Department, Unidade Local do Alto Minho, Ponte de Lima, Portugal

Jorge Garcia
Rheumatology Department, Santa Casa da Misericórdia de Montemor-o-Velho, Montemor-o-Velho, Portugal

Filipe Araújo
Rheumatology Department, Orthopedic Hospital of Sant’Ana, Santa Casa da Misericórdia de Lisboa, Parede, Portugal

Graça Sequeira
Rheumatology Department, Hospital de Loulé, Loulé, Portugal

Ana Cordeiro
Hospital Garcia de Orta

Ana Filipa Mourao
Unidade Local de Saúde de Lisboa Ocidental

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