Rheumatology International

, Volume 27, Issue 1, pp 11–17 | Cite as

Adenosine and cytokine levels following treatment of rheumatoid arthritis with dipyridamole

  • Caroline M. ForrestEmail author
  • Nicholas Stoy
  • Trevor W. Stone
  • Gillian Harman
  • Gillian M. Mackay
  • Lynn Oxford
  • L. Gail Darlington
Original Article


Adenosine can suppress the release of tumour necrosis factor-α (TNF-α) from activated monocytes and macrophages, and may contribute to the anti-inflammatory activities of methotrexate and sulphasalazine. Dipyridamole inhibits the cellular uptake and metabolism of adenosine and we have, therefore, examined the effects of dipyridamole in patients with rheumatoid arthritis in an attempt to alleviate their symptoms. Forty patients aged 18–75 years were randomised to receive dipyridamole 400 mg/day or placebo. Blood samples were taken at baseline and at monthly intervals for 6 months. Purines were determined by HPLC and cytokines by ELISA. After 3 months of treatment there were significant reductions in neopterin levels and in the modified Health Assessment Questionnaire score, but these were not maintained. Dipyridamole had no effect on disease severity or the levels of purine metabolites, interleukin-1β (IL-1β), IL-6, TNF-α, lipid peroxidation products, erythrocyte sedimentation rate or C-reactive protein. In conclusion, rheumatoid arthritis patients showed no clinical improvement following treatment with dipyridamole for 6 months.


Adenosine Dipyridamole Rheumatoid arthritis TNF-α IL-1β IL-6 



We are grateful to the NHS R&D Levy, the Peacock Foundation and the Denbies Trust for financial support. We would like to thank Rosalind McMillan and Nicole Packham for technical assistance.


  1. 1.
    Feldmann M (1996) The cytokine network in rheumatoid arthritis: definition of TNF-α as a therapeutic target. J R Coll Phys Lond 30:560–570Google Scholar
  2. 2.
    Choy EHS, Panayi GS (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. New Engl J Med 344:907–916PubMedCrossRefGoogle Scholar
  3. 3.
    Cohen SB, Woolley JM, Chan W (2003) Interleukin 1 receptor antagonist anakinra improves functional status in patients with rheumatoid arthritis. J Rheumatol 30:225–231PubMedGoogle Scholar
  4. 4.
    Cronstein BN, Bouma MG, Becker BF (1996) Purinergic mechanisms in inflammation. Drug Dev Res 39:426–435CrossRefGoogle Scholar
  5. 5.
    Cronstein BN, Rosenstein ED, Kramer SB Weissmann G, Hirschhorn R (1985) Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. Adenosine acts via an A2 receptor on human neutrophils. J Immunol 135:1366–1371PubMedGoogle Scholar
  6. 6.
    Gessi S, Varani K, Merighi S, Ongini E, Borea PA (2000) A(2A) adenosine receptors in human peripheral blood cells. Br J Pharmacol 129:2–11PubMedCrossRefGoogle Scholar
  7. 7.
    Bshesh K, Zhao B, Spight D, Biaggioni I, Feokistov I, Denenberg A, Wong HR, Shanley TP (2002) The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells. J Leuk Biol 72:1027–1036Google Scholar
  8. 8.
    Hasko G, Kuhel DG, Chen JF, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabo C (2000) Adenosine inhibits IL-12 and TNF-alpha production via adenosine A(2a) receptor-dependent and independent mechanisms. FASEB J 14:2065–2074PubMedCrossRefGoogle Scholar
  9. 9.
    Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP, Wilder RL, Elenkov IJ (2000) Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 164:436–442PubMedGoogle Scholar
  10. 10.
    Revan S, Montesinos MC, Naime D, Landau S, Cronstein BN (1996) Adenosine A2 receptor occupancy regulates stimulated neutrophil function via activation of a serine/threonine protein phosphatase. J Biol Chem 271:17114–17118PubMedCrossRefGoogle Scholar
  11. 11.
    Hannon JP, Bray-French KM, Phillips RM, Fozard JR (1998) Further Pharmacological characterization of the adenosine receptor subtype mediating inhibition of oxidative burst in human isolated neutrophils. Drug Develop Res 43:214–224CrossRefGoogle Scholar
  12. 12.
    Xaus J, Mirabet M, Lloberas J, Soler C, Lluis C, Franco R, Celada A (1999) IFN-gamma up-regulates the A(2B) adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. J Immunol 162:3607–3614PubMedGoogle Scholar
  13. 13.
    Mirabet M, Herrera C, Cordero OJ, Mallol J, Lluis C, Franco R (1999) Expression of A(2B) adenosine receptors in human lymphocytes: their role in T cell activation. J Cell Sci 112:491–502PubMedGoogle Scholar
  14. 14.
    Sajjadi FG, Takabayashi K, Foster AC, Domingo RC, Firestein GS (1996) Inhibition of TNF-alpha expression by adenosine—role of A3 adenosine receptors. J Immunol 156:3435–3442PubMedGoogle Scholar
  15. 15.
    Bouma MG, Jeunhomme TMMA, Boyle DL, Dentener MA, Voitenok NN, vandenWildenberg FAJM, Buurman WA (1997) Adenosine inhibits neutrophil degranulation in activated human whole blood—involvement of adenosine A2 and A3 receptors? J Immunol 158:5400–5408PubMedGoogle Scholar
  16. 16.
    Salmon HE, Cronstein BN (1990) Fcγ receptor-mediated functions in neutrophils are modulated by adenosine receptor occupancy: A1 receptors are stimulatory and A2 receptors are inhibitory. J Immunol 145L:2235–2240Google Scholar
  17. 17.
    Straub RH, Pongratz G, Gunzler C, Michna A, Baier S, Kees F, Falk W, Scholmerich J (2002) Immunoregulation of IL-6 secretion by endogenous and exogenous adenosine and by exogenous purinergic agonists in splenic tissue slices. J Neuroimmunol 125:73–81PubMedCrossRefGoogle Scholar
  18. 18.
    Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF, Cooper NS, healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG (1988) The American-rheumatism-association 1987 revised criteria for the classification of rheumatoid-arthritis. Arthritis Rheum 31:315–324PubMedGoogle Scholar
  19. 19.
    Huskisson EC (1982) Measurement of pain. J Rheumatol 9:768–769PubMedGoogle Scholar
  20. 20.
    Arvidson NG, Gudbjornsson B, Elfman L, Ryden A-C, Totterman TH, Hallgren R (1994) Circadian rhythm of serum interleukin-6 in rheumatoid arthritis. Ann Rheum Dis 53:521–524PubMedCrossRefGoogle Scholar
  21. 21.
    ICSH (1933) ICSH Recommendations for measurement of erythrocyte sedimentation rate. Clin Pathol 46:198–200Google Scholar
  22. 22.
    Westergren A (1921) Studies of the suspension stability of the blood in pulmonary tuberculosis. Med Scand 54:247–250Google Scholar
  23. 23.
    Cronstein BN (1994) Adenosine, an endogenous antiinflammatory agent. J Appl Physiol 76:5–13PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Caroline M. Forrest
    • 1
    Email author
  • Nicholas Stoy
    • 2
  • Trevor W. Stone
    • 1
  • Gillian Harman
    • 2
  • Gillian M. Mackay
    • 1
  • Lynn Oxford
    • 1
  • L. Gail Darlington
    • 2
  1. 1.Institute of Biomedical and Life Sciences, West Medical BuildingUniversity of GlasgowGlasgowUK
  2. 2.Epsom General HospitalEpsomUK

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