Динамика уровней цитокинов на фоне терапии метотрексатом и адалимумабом у пациентов с ранним ревматоидным артритом (исследование ремарка)

Abstract

Objective: to estimate changes in cytokine profile versus disease activity in patients with early rheumatoid arthritis (RA) who use methotrexate (MTX) and adalimumab (ADA) in accordance with the treat-to-target concept. Subjects and methods. Forty-five patients (35 women; median age 53.5 [46; 59.5] years) with early RA (median dura- tion 7.0 [4.0; 11.5] months; DAS28 5.8 [4.9; 6.4]; rheumatoid factor positivity (RF+) 91%; anti-cyclic citrullinated peptide antibody positivity (ACCP) + 96%) were examined. In all the patients, MTX as the first agent was subcuta- neously used in a dose of 10 mg/week with its rapid escalation up to 20-25 mg/week. Serum cytokine concentrations were determined using the xMAP multiplexing technology before and 12 and 24 weeks after therapy. Results. Following 12 weeks of therapy, DAS28 mean value decreased to 4.33 [3.5; 5.2] (p < 0.05 vs baseline). Twenty- nine (64.4%) patients responded to treatment. It was decided to continue MTX monotherapy in 23 patients (a monotherapy group) and in 22 patients ADA was added to therapy due to its inadequate effect in accordance with the standard regimen (a combined therapy group). At 24 weeks, mean DAS28 was 2.9 [2.1; 3.6] and 19 (82.6%) patients responded to treatment in the monotherapy group. In the combined therapy group, DAS28 was 3.4 [3.2; 4.4]; nearly 30% of the patients achieved remission/low disease activity and the number of patients with the high activity of a pathological process also declined significantly (from 59.1 to 13.6%). At 12 weeks, the monotherapy group showed reduction of the level of proinflammatory (interleukin-6 (IL-6), IL-17, tumor necrosis factor- α (TNF- α )), anti-inflammatory (IL-4, IL-5, IL-9, IL-13) cytokines, chemokines (interferon induced protein-10 (IP-10)), and vascular endothelial growth factors (VEGF) (p<0.05); at 24 weeks, there were reductions in IL-6, IL-9, and IL-10, and transforming GF-bb and an increase in IL-10 concentration (p<0.05). At 12 weeks of MTX therapy, the combined therapy group displayed a reduction in IL-6, IL-1Pa, IP-10 (p<0.05); at 24 weeks of treatment (12-week ADA administration) there were decreases in proinflammatory (IL-12), anti-inflammatory (IL-9) cytokines, chemokines (IP-10, monocyte chemoattractant protein, and macrophageal inflammatory protein-1β), VEGF and an elevation of IL-10. Conclusion. Thus, the results of the investigation suggest the high clinical efficiency of therapy with subcutaneous MTX, which is associated with the lower levels of a number of proinflammatory cytokines, chemokines, and growth factors. ADA treatment is also accompanied by decreased disease activity and positive changes in the cytokine profile, by exerting a higher impact on the level of chemokines and growth factors.