be differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. Bacterial arthritis (such as by Streptococcus) is usually asymmetric, while RA usually involves both sides of the body symmetrically. Gonococcal arthritis (a bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles. Sometimes arthritis is in an undifferentiated stage (i.e. none of the above criteria is positive), even if synovitis is witnessed and assessed with ultrasound imaging. Difficult-to-treat Rheumatoid arthritis (D2T RA) is a specific classification RA by the European League against Rheumatism (EULAR).<ref>{{cite journal | vauthors = Roodenrijs NM, Welsing PM, van der Goes MC, Jacobs JW, van der Heijde D, van Laar JM, Nagy G | title = Response to: 'Correspondence on 'EULAR definition of difficult-to-treat rheumatoid arthritis by Novella-Navarro et al | journal = Annals of the Rheumatic Diseases | pages = annrheumdis–2020–219535 | date = December 2020 | pmid = 33277239 | doi = 10.1136/annrheumdis-2020-219535 | s2cid = 227275679 }}</ref> Signs of illness: Persistence of signs and symptoms Drug resistance Does not respond on two or more biological treatments Does not respond on anti-rheumatic drugs with different mechanism of action Factors contributing to difficult-to-treat disease: Genetic risk factors Environmental factors (diet, smoking, physical activity) Overweight and obese Genetic factors Genetic factors such as HLA-DR1B1, TRAF1, PSORS1C1 and microRNA 146a are associated with difficult to treat rheumatoid arthritis, other gene polymorphisms seem to be correlated with response to biologic modifying anti-rheumatic drugs (bDMARDs). Next one is FOXO3A gene region been reported as associated with worst disorder. The minor allele at FOXO3A summon a differential response of monocytes in RA patients. FOXO3A can provide an increase of pro-inflammatory cytokines, including TNFα. Possible gene polymorphism: STAT4, PTPN2, PSORS1C1 and TRAF3IP2 genes had been correlated with response to TNF inhibitors. HLA-DR1 and HLA-DRB1 gene The HLA-DRB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex is the human version of the major histocompatibility complex (MHC). Currently, have been identified at least 2479 different versions of the HLA-DRB1 gene. The presence of HLA-DRB1 alleles seems to predict radiographic damage, which may be partially mediated by ACPA development, and also elevated sera inflammatory levels and high swollen joint count. HLA-DR1 is encoded by the most risk allele HLA-DRB1 which share a conserved 5-aminoacid sequence that is correlated with the development of anti-citrullinated protein