Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation that leads to pain, stiffness, and progressive joint damage [1,2]. Methotrexate (MTX) is the cornerstone of RA treatment because of its immunosuppressive and anti-inflammatory properties [3]. However, there is substantial inter-individual variability in the response to MTX, with some patients experiencing significant clinical benefits, whereas others exhibit limited or no response [4,5]. Additionally, MTX can cause adverse effects including hepatotoxicity and myelosuppression, further highlighting the need for personalized treatment strategies [6].

Genetic factors have been proposed as potential contributors to the variable response to and toxicity of MTX in patients with RA. Identifying genetic markers that can predict individual responses to and toxicity from MTX will ultimately facilitate personalized treatment strategies for patients with RA. The 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) plays a crucial role in the de novo purine synthesis pathway, and variations in this gene have been associated with altered enzymatic activity and impaired MTX metabolism [7]. The ATIC 347 C/G (rs2372536) polymorphism, which results in a threonine-to-serine substitution at position 116 of the gene [8], has emerged as a promising candidate for influencing MTX treatment outcomes.

Several studies have investigated the association of the ATIC 347 C/G polymorphism with MTX response and toxicity in patients with RA [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. However, individual studies have reported conflicting findings, necessitating a comprehensive meta-analysis to provide a more robust and reliable assessment of this relationship. Meta-analysis enables the pooling of data from multiple studies, thereby increasing the sample size and statistical power to detect associations that may not be apparent in smaller individual studies [22], [23], [24].

By systematically reviewing the available literature and quantitatively summarizing the findings, we aimed to provide a comprehensive and updated overview of the existing information [24,25]. By elucidating the role of this genetic variant, we hope to contribute to current understanding of individual variability in MTX treatment outcomes and support the development of tailored therapeutic approaches for patients with RA. The objective of this meta-analysis is to evaluate the association between ATIC 347 C/G polymorphism, responsiveness to MTX, and toxicity in patients with RA.