Clinical Rheumatology

, Volume 31, Issue 1, pp 29–34 | Cite as

Tryptophan degradation and neopterin levels in treated rheumatoid arthritis patients

  • Yesim Ozkan
  • Guray Mete
  • Aylin Sepici-Dincel
  • Vesile Sepici
  • Bolkan Simsek
Original Article


Increased kynurenine/tryptophan—reflects trytophan degradation—and neopterin levels have been regarded as a biochemical marker of cell-mediated immune response and inflammation. This study was designed to evaluate the usefulness of tryptophan degradation and neopterin levels in active rheumatoid arthritis patients under therapy. In this case–control study, kynurenine and tryptophan levels were determined by HPLC; neopterin and tumor necrosis factor-α levels were measured with ELISA in 32 active rheumatoid arthritis patients and 20 healthy controls. Although mean values of tryptophan, kynurenine, ratio of kynurenine to tryptophan, neopterin, and tumor necrosis factor-α levels did not show statistically significant differences between patient and control groups, neopterin levels correlated positively with kynurenine (r = 0.582, p < 0.02), kynurenine/tryptophan (r = 0.486, p < 0.05), erythrocyte sedimentation rate (r = 0.472, p < 0.05) and RF (r = 0.478, p < 0.05) in the rheumatoid arthritis group. CRP levels of the patient group correlated with kynurenine levels (r = 0.524, p < 0.03). Determination of tryptophan degradation and neopterin levels in chronic inflammatory disease may provide a better understanding of progression of the disease.


Indoleamine 2,3-dioxygenase Kynurenine Neopterin Rheumatoid arthritis Tryptophan 


  1. 1.
    Sweeney SE, Firestein GS (2004) Rheumatoid arthritis: regulation of synovial inflammation. Int J Biochem Cell Biol 36:372–378PubMedCrossRefGoogle Scholar
  2. 2.
    Richard DM, Dawes MA, Mathias CW, Acheson A, Hill-Kapturczak N, Dougherty DM (2009) L-Tryptophan: basic metabolic functions, behavioral research and therapeutic indications. Int J Tryptophan Res 2:45–60PubMedGoogle Scholar
  3. 3.
    King JCN, Thomas SR (2007) Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol 39:2167–2172PubMedCrossRefGoogle Scholar
  4. 4.
    Szántó S, Koreny T, Mikecz K, Glant TT, Szekanecz Z, Varga J (2007) Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice. Arthritis Res Ther 9:1–7CrossRefGoogle Scholar
  5. 5.
    Xu H, Oriss TB, Fei M et al (2008) Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation. Proc Natl Acad Sci USA 105:6690–6695PubMedCrossRefGoogle Scholar
  6. 6.
    Schroecksnadel K, Murr C, Winkler C, Wirleitner B, Fuith LC, Fuchs D (2004) Neopterin to monitor clinical pathologies involving interferon-γ production. Pteridines 15:75–90Google Scholar
  7. 7.
    Hamerlinck EFV (1999) Neopterin: a review. Exp Dermatol 8:167–176PubMedCrossRefGoogle Scholar
  8. 8.
    Berdowska A, Zwirska-Korczala K (2001) Neopterin measurement in clinical diagnosis. J Clin Pharm Ther 26:319–329PubMedCrossRefGoogle Scholar
  9. 9.
    Werner ER, Werner-Felmayer G, Fuchs D et al (1991) Biochemistry and function of pteridine synthesis in human and murine macrophages. Pathobiology 59:276–279PubMedCrossRefGoogle Scholar
  10. 10.
    Pascual C, Karzai W, Meier-Hellmann A et al (1998) Total plasma antioxidant capacity is not always decreased in sepsis. Crit Care Med 26:705–709PubMedCrossRefGoogle Scholar
  11. 11.
    Wagner R, Hayatghebi S, Rosenkranc M, Reinwein D (1993) Increased serum neopterin levels in patients with Graves' disease. Exp Clin Endocrinol 101:249–254PubMedCrossRefGoogle Scholar
  12. 12.
    Reibnegger G, Krainer M, Herold M, Ludwig H, Wachter H, Huber H (1991) Predictive value of interleukin-6 and neopterin in patients with multiple myeloma. Cancer Res 51:6250–6253PubMedGoogle Scholar
  13. 13.
    Oda K, Arai T, Nagase M (1999) Increased serum and urinary neopterin in nephrotic syndrome indicate cell-mediated immune dysfunction. Am J Kidney Dis 34:611–617PubMedCrossRefGoogle Scholar
  14. 14.
    Weiss G, Willeit J, Kiechl S et al (1994) Increased concentrations of neopterin in carotid atherosclerosis. Atherosclerosis 106:263–271PubMedCrossRefGoogle Scholar
  15. 15.
    Reibnegger G, Aichberger C, Fuchs D et al (1991) Posttransplant neopterin excretion in renal allograft recipients - a reliable diagnostic aid for acute rejection and a predictive marker of long-term graft survival. Transplantation 52:58–63PubMedCrossRefGoogle Scholar
  16. 16.
    Schroecksnadel K, Winkler C, Duftner C, Wirleitner B, Schimer M, Fuchs D (2006) Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin Rheumatol 25:334–337PubMedCrossRefGoogle Scholar
  17. 17.
    Schroecksnadel K, Kaser S, Ledochowski M et al (2003) Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J Rheumatol 30:1935–1939PubMedGoogle Scholar
  18. 18.
    Scott GN, DuHadaway J, Pigott E et al (2009) The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J Immunol 182:7509–7517PubMedCrossRefGoogle Scholar
  19. 19.
    Chavele KM, Shukla D, Keteepe-Arachi T et al (2010) Regulation of myeloperoxidase-specific T cell responses during disease remission in antineutrophil cytoplasmic antibody-associated vasculitis: the role of Treg cells and tryptophan degradation. Arthritis Rheum 62:1539–1548PubMedGoogle Scholar
  20. 20.
    Arnelt FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324CrossRefGoogle Scholar
  21. 21.
    Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48PubMedCrossRefGoogle Scholar
  22. 22.
    Laich A, Neurauter G, Widner B, Fuchs D (2002) More rapid method for simultaneous measurement of tryptophan and kynurenine by HPLC. Clin Chem 48:579–581PubMedGoogle Scholar
  23. 23.
    Thackray SJ, Mowat CG, Chapman SK (2008) Exploring the mechanism of tryptophan 2,3-dioxygenase. Biochem Soc Trans 36:1120–1123PubMedCrossRefGoogle Scholar
  24. 24.
    Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5:2516–2522PubMedGoogle Scholar
  25. 25.
    Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473PubMedCrossRefGoogle Scholar
  26. 26.
    Mellor AL, Munn DH (2003) Tryptophan catabolism and regulation of adaptive immunity. J Immunol 170:5809–5813PubMedGoogle Scholar
  27. 27.
    Al M, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774CrossRefGoogle Scholar
  28. 28.
    Zhu L, Ji F, Wang Y et al (2006) Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition. J Immunol 177:8226–8233PubMedGoogle Scholar
  29. 29.
    Spiera H, Vallarıno R (1969) Serum kynurenine in rheumatoid arthritis. J Clin Invest 48:856–859PubMedCrossRefGoogle Scholar
  30. 30.
    Igari T, Tsuchizawa M, Shimamura T (1987) Alteration of tryptophan metabolism in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. Tohoku J Exp Med 153:79–86PubMedCrossRefGoogle Scholar
  31. 31.
    Rider LG, Schiffenbauer AS, Zito M et al (2002) Neopterin and quinolinic acid are surrogate measures of disease activity in the juvenile idiopathic inflammatory myopathies. Clin Chem 48:1681–1688PubMedGoogle Scholar
  32. 32.
    Murr C, Hainz U, Asch E, Berger P, Jenewein B, Saurwein-Teissl M, Grubeck-Loebenstein B, Fuchs D (2003) Association of increased neopterin production with decreased humoral immunity in the elderly. Exp Gerontol 38:583–587PubMedCrossRefGoogle Scholar
  33. 33.
    Frick B, Schroecksnadel K, Neurauter G, Leblhuber F, Fuchs D (2004) Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin Biochem 37:684–687PubMedCrossRefGoogle Scholar
  34. 34.
    Hagihara M, Nagatsu T, Ohhashi M, Miura T (1990) Concentration of neopterin and biopterin in serum from patients with rheumatoid arthritis or systemic lupus erythematosus and in synovial fluid from patients with rheumatoid or osteoarthritis. Clin Chem 36:705–706PubMedGoogle Scholar
  35. 35.
    Altındağ ZZ, Şahin G, İnancı F, Hasçelik Z (1998) Urinary neopterin excretion and dihydropteridine reductase activity in rheumatoid arthritis. Rheumatol Int 18:107–111PubMedCrossRefGoogle Scholar
  36. 36.
    Hannonen P, Tikanoja S, Hakola M, Möttönen T, Viinikka L, Oka M (1986) Urinary neopterin index as a measure of rheumatoid activity. Scand J Rheumatol 15:148–152PubMedCrossRefGoogle Scholar
  37. 37.
    Espersen GT, Vestergaard M, Ernst E, Grunnet N (1991) Tumor necrosis factor alpha and interleukin-2 in plasma from rheumatoid arthritis patients in relation to disease activity. Clin Rheumatol 10:374–376PubMedCrossRefGoogle Scholar
  38. 38.
    Gaffo A, Saag KG, Curtis JR (2006) Treatment of rheumatoid arthritis. Am J Health Syst Pharm 63:2451–2465PubMedCrossRefGoogle Scholar
  39. 39.
    McLean-Tooke A, Aldridge C, Waugh S, Spickett GP, Kay L (2009) Methotrexate, rheumatoid arthritis and infection risk-what is the evidence? Rheumatology 48:867–871PubMedCrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2011

Authors and Affiliations

  • Yesim Ozkan
    • 1
  • Guray Mete
    • 1
  • Aylin Sepici-Dincel
    • 2
  • Vesile Sepici
    • 3
  • Bolkan Simsek
    • 1
  1. 1.Department of Biochemistry, Faculty of PharmacyGazi UniversityAnkaraTurkey
  2. 2.Health Research and Practice Center, Faculty of MedicineGazi UniversityAnkaraTurkey
  3. 3.Department of Physical Medicine and Rehabilitation, Faculty of MedicineGazi UniversityAnkaraTurkey

Personalised recommendations