Multifactorial Risk in Rheumatoid Arthritis: Genetic, Environmental, and Lifestyle Factors and Their Conceptual Implications for Genetic Counseling: A Narrative Review

Rheumatoid arthritis (RA) refers to a chronic inflammatory disorder which damages the joints and affects a person’s quality of life. According to recent global burden studies, the incidence and prevalence of RA have become higher in the last few decades, with women having a higher burden than men. RA is an autoimmune disorder that is now better understood as multifactorial. The condition is the result of an interaction of a multiplicity of genetic as well as environmental factors that interact over time. Some of the key genetic factors responsible for the etiology of RA include human leukocyte antigen-DRB1 (HLA) shared epitope alleles, and the many non-HLA risk loci identified through genome-wide association studies (GWAS). Similarly, a number of environmental and lifestyle determinants, such as exposure to cigarette smoke, excess adiposity, and mucosal microbial exposures, further shape risk. As a result of these findings, polygenic risk scores are being developed to stratify risk and guide treatment in RA, although their use in the clinic is not routine. People with RA are also at increased risk of clinical depression and anxiety. Qualitative studies with patients and first-degree relatives indicate that risk information is often filtered through preexisting beliefs and worry about family responsibility. Genetic counseling helps individuals and families understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. This communication process is better defined for multifactorial disorders but is not yet clearly defined for RA. This narrative review synthesizes evidence published between 2015 and 2025 on genetic, environmental, and psychosocial risk factors for RA and uses this evidence to conceptualize possible roles for genetic counseling in this disease. It used nonsystemic PubMed and Google Scholar searches for English-language human studies published between 2015 and 2025, using terms related to RA genetic susceptibility, PRS, environmental risks, lifestyle risks, psychological influences, and genetic counseling.