Rheumatoid arthritis (RA) is a defective post-translational modification of citrullinated peptides which cause synovial inflammation in joints. The present review elaborates the basic mechanisms of RA and the root causes of molecular mechanisms. The gender-based differentiation and probabilitiesof RA causes were discussed. Many report studies supporting that females are more prone to RA than males maybe suspected that circulating estrogen hormones 16a-hydroxy estrone, 2-hydroxy estrogens involvement in the RA pathogenicity. Other important aspects like environmental factors and air pollutants like (SO2 and NO2) were also impacted and enhances the risk of RA were discussed. The root cause of pathomechanisms of peptidylarginine deiminase (PAD) enzymes in RA and autoimmunity factors were poorly understood, however, Ati-citrullinated peptides (ACP) are the powerful markers to diagnose the RA disease. This review discusses three main risk factors of RA to understand the RA pathogenesis and disease-modifying mechanisms, may provide a unique opportunity to determine disease prevalence and RA associations.