Pharmacotherapy for rheumatoid arthritis: new strategy, new targets

Rheumatoid arthritis (RA) is a chronic immunoinflammatory (autoimmune) disease manifested by progressive joint destruction, systemic inflammation of the internal organs, and a wide range of comorbidities associated with chronic inflammation and frequently with adverse drug reactions. However, despite the major advances in the early diagnosis and treatment of RA, which have led to the radical improvement of prognosis in many patients, the problem of pharmacotherapy for RA is far from being solved. This is determined by a lack of sensitive and specific diagnostic and prognostic biomarkers in the early stage of the disease and, most importantly, by the heterogeneity of immunopathogenesis mechanisms in both at the onset of RA and during its progression, which make the personalization of therapy difficult in the patients. Selective block of inflammatory mediators with innovative medicines is frequently associated with primary inefficiency, secondary drug resistance, the development of generalized immunosuppression, the paradoxical activation of an autoimmune process, and the aggravation of comorbidities. At the same time, it is difficult to search for new RA pharmacotherapy targets since the nature of immunopathological disorders in patients can be substantially different from the inflammatory process that takes place when simulating arthritis in laboratory animals. The paper discusses the novel drugs that are used in rheumatology to treat RA or tested in different phases of preclinical or clinical trials, such as tumor necrosis factor-а inhibitors, interleukin-6 (IL-6), IL-17, anti-B cell therapy, bispecific antibodies, blockers of JAK (and other signaling molecules), bioelectronic vagus nerve activation, dendritic cell-based immunotherapy, and other therapies, as well as approaches to secondary prevention of RA in patients with undifferentiated arthritis and clinically suspect arthralgia, who are at high risk for RA. Decoding the mechanisms underlying the pathogenesis of RA and a chronic inflammatory process as a whole has created preconditions for the design of novel medications for the prevention and treatment of this disease, the introduction of which into clinical practice should lead to a radical improvement of prognosis in this disease.