A new insight into effects of a clinically proved combination of methotrexate and hydroxychloroquine

  • Silvester Poništ
  • Viera Kuncírová
  • Ľudmila Pašková
  • Lukáš Slovák
  • Danica Mihalová
  • Viera Jančinová
  • Radomír Nosáľ
  • Katarína Bauerová
Original Paper
  • 17 Downloads

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

Keywords

Drug research Immunoassay Alkaloids Rheumatoid arthritis Cytokines Anti-rheumatic therapy 

Notes

Acknowledgements

This work was supported by grants APVV-0052-10, APPV-15-308, and VEGA 2/0045/11.

References

  1. 1.
    Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y (2012) Clin Rev Allergy Immunol 42:145CrossRefGoogle Scholar
  2. 2.
    Kalia S, Dutz JP (2007) Dermatol Ther 20:160CrossRefGoogle Scholar
  3. 3.
    Ohkuma S, Poole B (1978) Proc Natl Acad Sci USA 75:3327CrossRefGoogle Scholar
  4. 4.
    Ziegler HK, Unanue ER (1982) Proc Natl Acad Sci USA 79:175CrossRefGoogle Scholar
  5. 5.
    Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L (1993) J Rheumatol 20:803Google Scholar
  6. 6.
    Loffler BM, Bohn E, Hesse B, Kunze H (1985) Biochim Biophys Acta 835:448CrossRefGoogle Scholar
  7. 7.
    Manku MS, Horrobin DF (1976) Lancet 2:1115CrossRefGoogle Scholar
  8. 8.
    Cohen SN, Yielding KL (1965) J Biol Chem 240:3123Google Scholar
  9. 9.
    Goldman FD, Gilman AL, Hollenback C, Kato RM, Premack BA, Rawlings DJ (2000) Blood 95:3460Google Scholar
  10. 10.
    Lesiak A, Narbutt J, Sysa-Jedrzejowska A, Lukamowicz J, McCauliffe DP, Wozniacka A (2010) Lupus 19:683CrossRefGoogle Scholar
  11. 11.
    Kyburz D, Brentano F, Gay S (2006) Nat Clin Pract Rheumatol 2:458CrossRefGoogle Scholar
  12. 12.
    Tian H, Cronstein BN (2007) Bull NYU Hosp Jt Dis 65:168Google Scholar
  13. 13.
    Montesinos MC, Desai A, Delano D, Chen JF, Fink JS, Jacobson MA, Cronstein BN (2003) Arthritis Rheumatol 48:240CrossRefGoogle Scholar
  14. 14.
    Baggott JE, Morgan SL, Vaughn WH (1994) Biochem J 300:627CrossRefGoogle Scholar
  15. 15.
    Montesinos MC, Takedachi M, Thompson LF, Wilder TF, Fernández P, Cronstein BN (2007) Arthritis Rheumatol 56:1440CrossRefGoogle Scholar
  16. 16.
    Montesinos MC, Yap JS, Desai A, Posadas I, McCrary CT, Cronstein BN (2000) Arthritis Rheumatol 43:656CrossRefGoogle Scholar
  17. 17.
    Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP (1998) J Clin Invest 102:322CrossRefGoogle Scholar
  18. 18.
    Bernini JC, Fort DW, Griener JC, Kane BJ, Chappell WB, Kamen BA (1995) Lancet 345:544CrossRefGoogle Scholar
  19. 19.
    Mirabet M, Herrera C, Cordero OJ, Mallol J, Lluis C, Franco R (1999) J Cell Sci 112:491Google Scholar
  20. 20.
    Kuncirova V, Ponist S, Mihalova D, Drafi F, Nosal R, Acquaviva A, Gardi C, Harmatha J, Hradkova I, Bauerova K (2014) Fundam Clin Pharmacol 28:616CrossRefGoogle Scholar
  21. 21.
    Dale J, Alcorn N, Capell H, Madhok R (2007) Nat Clin Pract Rheumatol 3:450CrossRefGoogle Scholar
  22. 22.
    Connolly KM, Stecher VJ, Danis E, Pruden DJ, LaBrie T (1988) Int J Immunopharmacol 10:717CrossRefGoogle Scholar
  23. 23.
    Trnavský K, Gatterová J, Lindusková M, Pelisková Z (1993) Z Rheumatol 52:292Google Scholar
  24. 24.
    Ridker PM (2001) Eur Heart J 22:2135CrossRefGoogle Scholar
  25. 25.
    Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA (2002) J Pathol 198:220CrossRefGoogle Scholar
  26. 26.
    Dayer JM (2003) Rheumatology (Oxford) 42:3CrossRefGoogle Scholar
  27. 27.
    DiMartino MJ, Johnson WJ, Votta B, Hanna N (1987) Agents Actions 21:348CrossRefGoogle Scholar
  28. 28.
    Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, Baggiolini M, Gerber NJ (1995) Br J Rheumatol 34:602CrossRefGoogle Scholar
  29. 29.
    Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K (2015) Arch Immunol Ther Exp 63:435CrossRefGoogle Scholar
  30. 30.
    Stolina M, Bolon B, Middleton S, Dwyer D, Brown H, Duryea D, Zhu L, Rohner A, Pretorius J, Kostenuik P, Feige U, Zack D (2009) J Clin Immunol 29:158CrossRefGoogle Scholar
  31. 31.
    Hayashida K, Nanki T, Girschick H, Yavuz S, Ochi T, Lipsky PE (2001) Arthritis Res 3:118CrossRefGoogle Scholar
  32. 32.
    Lopez-Castejon G, Brough D (2011) Cytokine Growth Factor Rev 22:189CrossRefGoogle Scholar
  33. 33.
    Hymowitz SG, Filvaroff EH, Yin JP, Lee J, Cai L, Risser P, Maruoka M, Mao W, Foster J, Kelley RF, Pan G, Gurney AL, de Vos AM, Starovasnik MA (2001) EMBO J 20:5332CrossRefGoogle Scholar
  34. 34.
    Thompson D, Pepys MB, Wood SP (1999) Structure 7:169CrossRefGoogle Scholar
  35. 35.
    Yunt ZX, Solomon JJ (2015) Rheum Dis Clin North Am 41:225CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Silvester Poništ
    • 1
  • Viera Kuncírová
    • 1
  • Ľudmila Pašková
    • 2
  • Lukáš Slovák
    • 1
  • Danica Mihalová
    • 1
  • Viera Jančinová
    • 1
  • Radomír Nosáľ
    • 1
  • Katarína Bauerová
    • 1
    • 2
  1. 1.Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of SciencesBratislavaSlovak Republic
  2. 2.Department of Cell and Molecular Biology of Drugs, Faculty of PharmacyComenius UniversityBratislavaSlovak Republic

Personalised recommendations