Rheumatoid arthritis (RA) is a systematic autoimmune disorder characterized by a persistent joint inflammation. A subset of HLA-DRB1 alleles known as shared epitope (SE) are the strongest genetic risk factors to develop anti-citrullinated protein antibody positive (ACPA-positive) RA. A strong enrichment of interactions exists between ACPA-positive RA-associated genetic variants and HLA-DRB1 SE alleles in disease development. Pathway analysis was performed to investigate how the interactions between risk variants (SNPs) with HLA-DRB1 from a previous study related to ACPA-positive RA. Gene-gene interactions analysis was performed between non-HLA risk variants and HLA-DRB1 SE alleles in SRQ biobank (SRQb) case-control cohort. We also evaluated whether the reported gene-gene interactions from a previous study relate to methotrexate (MTX) response for RA patients, at three and six months of follow-up in EIRA study. Interaction analysis based on an additive model was performed to understand the combined effect of two risk factors in the disease and treatment response. Two out of three genes from pathway analysis that were RXRA and NR3C1, pointed to ACPA-positive RA related important pathways including vitamin D receptor (VDR) pathway and adipocytokine signaling pathway. The replication analysis in SRQ-case-control study showed 2.627% of the evaluated SNPs insignificant additive interaction with HLA-DRB1 SE alleles. No interactions were significant in relation to the response to MTX monotherapy after 3 and 6 months follow-up. This project provides new insights into the gene-gene interactions in the study of ACPA-positive RA and suggests candidate genes for future functional studies.