Molecular mechanisms and risk factors in rheumatoid arthritis: a comprehensive review

Rheumatoid arthritis is a chronic systemic inflammatory disease that predominantly affects synovial joints, resulting in progressive joint damage, disability, and systemic effects. There are still unanswered questions regarding the origin and pathophysiological complexities of the disease despite advances in treatment. A systematic review of the complex molecular pathways involved in RA pathophysiology is presented. Among the molecular processes involved in RA pathophysiology are oxidative stress, activation of fibroblast-like synoviocytes, aberrant innate and adaptive immunity, and dysregulated cytokine signalling. Important inflammatory signalling pathways related to the inflammation and destruction of joints including NF-κB, JAK/STAT, and RANK will be detailed. We will discuss the molecular components of the disease and the genetic and epigenetic predispositions such as HLA-DRB1 alleles, non-HLA loci, and regulation of miRNA and DNA methylation. We will highlight environmental and lifestyle related risk factors including smoking, infections, gut dysbiosis, and hormones contributing to disease manifestation and maintenance. We will describe the autoantibodies, rheumatoid factor and anti-citrullinated protein antibodies, as diagnostic and prognostic RA biomarkers. This review will summarize studies from in vivo animal models and translational studies to illustrate contemporary treatment strategies and drug development based on lessons from molecular knowledge of RA studies. Furthermore, progressive paradigms such as personalized medicine and multi-omics methodologies are discussed as potential future strategies to advance prediction, monitoring, and management of RA. This review seeks to provide an updated, broader view of the molecular biology and risk factors for RA, ultimately supporting better clinical outcomes and precision therapy.