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Abstract: Combination of methotrexate (MTX) with hydroxychloroquine (HCQ) is one of the most effective therapies used for treatment of rheumatoid arthritis. The aim of the study was to more complexly examine the effect of combination HCQ and MTX on disease progression in arthritic rats focusing on inflammatory markers. Adjuvant arthritis (AA) was induced by intradermal injection of Mycobacterium butyricum in incomplete Freund´s adjuvant in Lewis rats and the disease was monitored 28 days. The experiment included healthy animals, control AA animals, AA animals with administration of HCQ (40 mg/kg b.w. daily, p.o.), AA animals with administration of MTX (0.4 mg/kg b.w. twice a week, p.o.), and AA animals treated with the combination of HCQ + MTX. HCQ in monotherapy reduced only the plasmatic level of IL-1β (day 28). On day 14, MTX + HCQ significantly decreased the plasmatic levels of IL-1β, IL-17 and combination was more effective than MTX in reduction of IL-17. On day 28, combination significantly decreased the plasmatic levels of CRP and IL-1β and it was more effective than MTX in reduction of IL-1β. Expression of IL-1β and inducible NO-synthase total mRNA in lung were most effectively reduced by MTX + HCQ. Combination of MTX + HCQ reduced hind paw volume, arthritic score and increased body mass of animals very effectively (days 14, 21, and 28). In summary, MTX + HCQ were much better than MTX in correcting inflammatory and clinical markers. This study showed in more details that the anti-arthritic effect of MTX + HCQ is particularly due to reduction of the levels of inflammatory cytokines.Graphical Abstract: [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the morphological changes in the spleen, the thymus and the knee joints of rats with experimental adjuvant arthritis induced by Mycobacterium butyricum in the incomplete Freund's adjuvant and the effect of treatment with methotrexate (MTX). Particular attention was aimed on the redistribution of granulocytes in the tissues during the inflammatory process. Clinical parameters, e.g., joint edema, body weight and of gamma glutamyl transferase (GGT) activity as an inflammatory marker, have also been determined. Induction of adjuvant arthritis caused a significant decrease in granulocyte number in the spleen and vice versa a significant increase in the knee joints, but without significant changes in the thymus. Treatment with methotrexate reversed this phenomenon by increasing the granulocyte number in the spleen and decreasing it in knee joints. MTX decreased the joint edema as well as the activity of GGT in the spleen, modified the size of the white pulp of the spleen and increased the cortex/medulla ratio in the thymus. The observed changes support the anti-inflammatory and immunomodulatory properties of MTX supporting its use as the first-line medication in patients with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]