Etiology and Risk Factors for Rheumatoid Arthritis: A State-of-the-Art Review

Abstract

Rheumatoid arthritis (RA) is the most common systemic inflammatory rheumatic disease. It is associated with significant burden at the patient and societal level. Extensive efforts have been devoted to identifying a potential cause for the development of RA. Epidemiological studies have thoroughly investigated the association of several factors with the risk and course of RA. Although a precise etiology remains elusive, the current understanding is that RA is a multifactorial disease, wherein complex interactions between host and environmental factors determine the overall risk of disease susceptibility, persistence and severity. Risk factors related to the host that have been associated with RA development may be divided into genetic; epigenetic; hormonal, reproductive and neuroendocrine; and comorbid host factors. In turn, environmental risk factors include smoking and other airborne exposures; microbiota and infectious agents; diet; and socioeconomic factors. In the present narrative review, aimed at clinicians and researchers in the field of RA, we provide a state-of-the-art overview of the current knowledge on this topic, focusing on recent progresses that have improved our comprehension of disease risk and development.

Keywords: etiology; pathogenesis; pre-RA; pre-rheumatoid arthritis; rheumatoid arthritis; risk factors.

Figure 1

Summary of risk factors for the development of rheumatoid arthritis. Factors that are associated with decreased risk are represented in brackets. Factors for which evidence is conflicting and uncertainty remains are followed by a question mark. AI, aromatase inhibitors; COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr virus; FLS, fibroblast-like synoviocyte: GI, gastrointestinal; GU, genitourinary; HCV, hepatitis C virus; HDAC, histone deacetylases; HLA, human leukocyte antigen; HPA, hypothalamic-pituitary-adrenal; IBD, inflammatory bowel disease; lncRNA, long non-coding RNA; miRNA, micro RNA; MS, multiple sclerosis; OC, oral contraceptives; PBMCs, peripheral blood mononuclear cells; PTSD, post-traumatic stress disorder; SE, shared epitope.