User:Andrey Stoletov/sandbox

Definition
Difficult-to-treat Rheumatoid Arthritis is a multifactorial state, for each individual patient, different factors may be crucial determinants of persistence of signs and symptoms, which is rarely caused by drug resistance only. Patients with difficult to treat rheumatoid arthritis  doesn't answer on two or more biological treatments. Moreover, patients with difficult to treat rheumatoid arthritis dose not answer on anti-rheumatic drugs with different mechanism of action.

Factors contributing to difficult- to-treat RA
1.	Genetic risk factors 2.	Environmental factors (diet, smoking, physical activity) 3.     Overweight and obese

Genetic factors
Genetic factors such as HLA-DR1, 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).

HLA-DR1
This molecule encoded by the most risk allele HLA-DRB1 witch share a conserved 5-aminoacid sequence that is corelated with the development of anti-citrullinated protein antibodies.

MicroRNAs
Probably, microRNAs is most important factor in development of that type of disease. MicroRNAs usually operate as a negative regulator of the expression of target proteins and their increase concentration after biologic treatment (bDMARDs) or after anti-rheumatic drugs.

Diet
Diet may provide susceptibility to autoimmune disease by epigenetic mechanism. For example, diet with high salt concentration may play a role in development of autoimmune disease. Surprisingly, high sodium diet appears to interfere with the suppressive effects of Tregs and improve cellular displacement to the pro-inflammatory phenotypes T-helper and Th17.