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Original Article
Available online 3 June 2026

Protective effect of methotrexate against severe forms of COVID-19 in rheumatoid arthritis: A retrospective cohort study

Efecto protector de metotrexato frente a formas graves de COVID-19 en artritis reumatoide: estudio de cohortes retrospectivo
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Freddy Liñán-Poncea,
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droctavio77@gmail.com

Corresponding author.
, Juan Leiva-Goicocheaa, Fernando Gross-Melob
a Médico Reumatólogo. Departamento de Medicina, Hospital Víctor Lazarte Echegaray, Trujillo, Peru
b Médico Internista, Departamento de Medicina, Hospital Víctor Lazarte Echegaray, Trujillo, Peru
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Abstract
Introduction

The COVID-19 pandemic posed a unique challenge for patients with rheumatoid arthritis (RA) receiving immunomodulatory therapy. Methotrexate (MTX), a first-line agent for RA, has pleiotropic effects that may modulate both viral replication and the inflammatory response. This study aimed to determine whether MTX use is associated with a lower incidence of severe or critical COVID-19.

Materials and methods

A retrospective cohort study was conducted among patients with a confirmed diagnosis of RA and a documented episode of COVID-19 between 2020 and 2023 at Hospital Víctor Lazarte Echegaray (Trujillo, Peru). Patients with additional autoimmune diseases, neoplasia, pregnancy, significant organ damage, or use of biologic therapy were excluded. Two groups were compared: 207 patients treated with MTX and 155 treated with other conventional disease-modifying antirheumatic drugs (DMARDs). Primary outcomes were severe/critical COVID-19 and 28-day mortality; secondary outcomes included oxygen supplementation, ICU admission, mechanical ventilation, and length of hospitalization.

Results

MTX use was associated with a lower frequency of severe/critical COVID-19 (10.6% vs. 22.6%; RR 0.47; 95% CI 0.29–0.77; p = 0.003) and reduced 28-day mortality (1.4% vs. 5.2%; RR 0.27; 95% CI 0.07–0.98; p = 0.041). MTX-treated patients required less supplemental oxygen (16.9% vs. 35.5%; p = 0.001), fewer ICU admissions (4.8% vs. 12.9%) and mechanical ventilation (1.9% vs. 5.8%), and had a shorter median hospital stay (7 vs. 9 days; p = 0.002).

Conclusions

Methotrexate use was associated with reduced disease severity, mortality, and hospitalization duration in RA patients with COVID-19. These findings support a potential protective effect of MTX and highlight the need for multicenter prospective studies to confirm its clinical benefit.

Keywords:
Rheumatoid arthritis
Methotrexate
Disease-modifying antirheumatic drug
Pharmacological treatment of COVID-19
Resumen
Introducción

La pandemia por COVID-19 ha supuesto un reto especial para los pacientes con artritis reumatoide (AR) en tratamiento inmunomodulador. El metotrexato (MTX), fármaco de primera línea en AR, posee efectos pleiotrópicos que podrían modular la replicación viral y la respuesta inflamatoria. El objetivo fue determinar si el uso de MTX se asocia con menor incidencia de COVID-19 grave o crítica.

Material y métodos

Se realizó un estudio de cohorte retrospectivo en pacientes con diagnóstico confirmado de AR y episodio de COVID-19 atendidos entre 2020 y 2023 en el Hospital Víctor Lazarte Echegaray. Se excluyeron casos con enfermedades autoinmunes adicionales, neoplasia, embarazo, daño orgánico severo o uso de biológicos. Se compararon 207 pacientes en tratamiento con MTX frente a 155 con otros fármacos antirreumáticos modificadores de enfermedad (FARME). Los desenlaces principales fueron COVID-19 grave/crítico, mortalidad a 28 días, necesidad de oxígeno, ingreso a UCI, ventilación mecánica y duración de hospitalización.

Resultados

El uso de MTX se asoció a menor frecuencia de COVID-19 grave/crítico (10,6 % vs. 22,6 %; RR 0,47; IC 95 % 0,29–0,77; p = 0,003) y menor mortalidad (1,4 % vs. 5,2 %; RR 0,27; IC 95 % 0,07–0,98; p = 0,041). Asimismo, se redujo la necesidad de oxígeno suplementario (16,9 % vs. 35,5 %; p = 0,001), ingreso a UCI (4,8 % vs. 12,9 %) y ventilación mecánica (1,9% vs. 5,8%), además de una menor mediana de hospitalización (7 vs. 9 días; p = 0,002).

Conclusiones

El tratamiento con metotrexato se asocia a menor gravedad, mortalidad y duración de hospitalización en pacientes con AR y COVID-19. Estos hallazgos apoyan su potencial efecto protector y justifican estudios prospectivos multicéntricos que confirmen su beneficio clínico.

Palabras clave:
Artritis reumatoide
Metotrexato
Fármaco antirreumático modificador de enfermedad
Tratamiento farmacológico de COVID-19

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