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. 2002 Dec;61(12):1060–1064. doi: 10.1136/ard.61.12.1060

Purine enzymes in patients with rheumatoid arthritis treated with methotrexate

A E van Ede 1, R Laan 1, R A De Abreu 1, A Stegeman 1, L B A van de Putte 1
PMCID: PMC1753961  PMID: 12429535

Abstract

Objectives: To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment.

Methods: One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5`-nucleotidase (5`NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment.

Results: Baseline values of 5`NT and PNP (16.9 and 206.8 nmol/106 mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/106 mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/106 mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/106 mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/106 mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5`NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity.

Conclusion: MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5`NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.

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Figure 1 .

Figure 1

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Simplified metabolic scheme illustrating folate metabolism and its relation to purine and homocysteine metabolism. Known inhibition of enzymes by methotrexate is indicated by two short lines across an arrow. DHF, dihydrofolate; dhfr, dihydrofolate-reductase; THF, tetrahydrofolate; 5,10-CH2-THF, 5,10-methylene tetrahydrofolate; 5,10-CH-THF, 5,10-methenyl tetrahydrofolate; 10-CHO-THF, 10-formyl tetrahydrofolate; mthfr, methylene-tetrahydrofolate reductase; 5-CH3-THF, 5-methyl tetrahydrofolate; 5-CHO-THF, 5-formyl tetrahydrofolate (folinic acid); Met, methionine; SAM, S-adenosyl- L -methionine; ms, methionine synthetase; Hcy, homocysteine; SAH, S-adenosyl- L -homocysteine; R, methyl acceptor; PRPP, 5-phosphoribosyl-1-pyrophosphate; PRA, phosphoribosylamine; GAR, glycinamide ribosyl-5-phosphate; FGAR, form-glycinamide ribosyl-5-phosphate; AICAR, amino-imidazolcarboxamide ribosyl-5-phosphate; FAICAR, form-amino-imidazolcarboxamide ribosyl-5-phosphate; IMP, inosine monophosphate; s-AMP, succinyl-adenosine monophosphate; AMP, adenosine monophosphate; GMP, guanosine monophosphate; XMP, xanthine monophosphate; 5`nt, purine-5`nucleotidase; pnp, purine nucleoside phosphorylase; hgprt, hypoxanthine-guanine phosphoribosyl transferase; ada, adenosine deaminase; ak, adenosine kinase.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Appelboom T., Mandelbaum I., Vertongen F. Purine enzyme levels in rheumatoid arthritis. J Rheumatol. 1985 Dec;12(6):1075–1078. [PubMed] [Google Scholar]
  2. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Carapella-de Luca E., Aiuti F., Lucarelli P., Bruni L., Baroni C. D., Imperato C., Roos D., Astaldi A. A patient with nucleoside phosphorylase deficiency, selective t-cell deficiency, and autoimmune hemolytic anemia. J Pediatr. 1978 Dec;93(6):1000–1003. doi: 10.1016/s0022-3476(78)81237-2. [DOI] [PubMed] [Google Scholar]
  4. Cronstein B. N. The mechanism of action of methotrexate. Rheum Dis Clin North Am. 1997 Nov;23(4):739–755. doi: 10.1016/s0889-857x(05)70358-6. [DOI] [PubMed] [Google Scholar]
  5. Edwards N. L., Magilavy D. B., Cassidy J. T., Fox I. H. Lymphocyte ecto-5'-nucleotidase deficiency in agammaglobulinemia. Science. 1978 Aug 18;201(4356):628–630. doi: 10.1126/science.27864. [DOI] [PubMed] [Google Scholar]
  6. Fries J. F., Spitz P. W., Williams C. A., Bloch D. A., Singh G., Hubert H. B. A toxicity index for comparison of side effects among different drugs. Arthritis Rheum. 1990 Jan;33(1):121–130. doi: 10.1002/art.1780330117. [DOI] [PubMed] [Google Scholar]
  7. Giblett E. R., Ammann A. J., Wara D. W., Sandman R., Diamond L. K. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet. 1975 May 3;1(7914):1010–1013. doi: 10.1016/s0140-6736(75)91950-9. [DOI] [PubMed] [Google Scholar]
  8. Giblett E. R., Anderson J. E., Cohen F., Pollara B., Meuwissen H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067–1069. doi: 10.1016/s0140-6736(72)92345-8. [DOI] [PubMed] [Google Scholar]
  9. Johnson S. M., North M. E., Asherson G. L., Allsop J., Watts R. W., Webster A. D. Lymphocyte purine 5'-nucleotidase edficiency in primary hypogammaglobulinaemia. Lancet. 1977 Jan 22;1(8004):168–170. doi: 10.1016/s0140-6736(77)91765-2. [DOI] [PubMed] [Google Scholar]
  10. Kerstens P. J., Stolk J. N., Boerbooms A. M., De Abreu R. A., Van de Putte L. B. Purine enzymes in rheumatoid arthritis. A clue to the prediction of the response to azathioprine? Review and hypothesis. Clin Exp Rheumatol. 1995 Jan-Feb;13(1):107–111. [PubMed] [Google Scholar]
  11. Kerstens P. J., Stolk J. N., Boerbooms A. M., Lambooy L. H., de Graaf R., De Abreu R. A., van de Putte L. B. Purine enzymes in rheumatoid arthritis: possible association with response to azathioprine. A pilot study. Ann Rheum Dis. 1994 Sep;53(9):608–611. doi: 10.1136/ard.53.9.608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kerstens P. J., Stolk J. N., De Abreu R. A., Lambooy L. H., van de Putte L. B., Boerbooms A. A. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum. 1995 Jan;38(1):142–145. doi: 10.1002/art.1780380122. [DOI] [PubMed] [Google Scholar]
  13. Levinson D. J., Chalker D., Arnold W. J. Reduced purine nucleoside phosphorylase activity in preparations of enriched T-lymphocytes from patients with systemic lupus erythematosus. J Lab Clin Med. 1980 Sep;96(3):562–569. [PubMed] [Google Scholar]
  14. Marinello E., Carlucci F., Tabucchi A., Leoncini R., Pizzichini M., Pagani R. The purine nucleotide content of lymphocytes from patients with rheumatoid arthritis. Int J Clin Pharmacol Res. 1994;14(2):57–63. [PubMed] [Google Scholar]
  15. Markert M. L. Purine nucleoside phosphorylase deficiency. Immunodefic Rev. 1991;3(1):45–81. [PubMed] [Google Scholar]
  16. Rich K. C., Arnold W. J., Palella T., Fox I. H. Cellular immune deficiency with autoimmune hemolytic anemia in purine nucleoside phosphorylase deficiency. Am J Med. 1979 Jul;67(1):172–176. doi: 10.1016/0002-9343(79)90100-1. [DOI] [PubMed] [Google Scholar]
  17. Ritchie D. M., Boyle J. A., McInnes J. M., Jasani M. K., Dalakos T. G., Grieveson P., Buchanan W. W. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med. 1968 Jul;37(147):393–406. [PubMed] [Google Scholar]
  18. Sandman R., Ammann A. J., Grose C., Wara D. W. Cellular immunodeficiency associated with nucleoside phosphorylase deficiency. Immunologic and biochemical studies. Clin Immunol Immunopathol. 1977 Sep;8(2):247–253. doi: 10.1016/0090-1229(77)90114-3. [DOI] [PubMed] [Google Scholar]
  19. Stolk J. N., Boerbooms A. M., De Abreu R. A., Kerstens P. J., de Koning D. G., de Graaf R., Mulder J., van de Putte L. B. Purine enzyme activities in recent onset rheumatoid arthritis: are there differences between patients and healthy controls? Ann Rheum Dis. 1996 Oct;55(10):733–738. doi: 10.1136/ard.55.10.733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Stolk J. N., De Abreu R. A., Boerbooms A. M., de Koning D. G., de Graaf R., Kerstens P. J., van de Putte L. B. Purine enzyme activities in peripheral blood mononuclear cells: comparison of a new non-radiochemical high-performance liquid chromatography procedure and a radiochemical thin-layer chromatography procedure. J Chromatogr B Biomed Appl. 1995 Apr 7;666(1):33–43. doi: 10.1016/0378-4347(94)00571-l. [DOI] [PubMed] [Google Scholar]
  21. Stolk J. N., de Koning D. G., Pennings A. H., De Abreu R. A., van de Putte L. B., Boerbooms A. M. Reduced purine 5'-nucleotidase activity in lymphocytes of patients with systemic lupus erythematosus: results of a pilot study. Ann Rheum Dis. 1999 Feb;58(2):122–125. doi: 10.1136/ard.58.2.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. van Ede A. E., Laan R. F., Blom H. J., De Abreu R. A., van de Putte L. B. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum. 1998 Apr;27(5):277–292. doi: 10.1016/s0049-0172(98)80049-8. [DOI] [PubMed] [Google Scholar]
  23. van Ede A. E., Laan R. F., Rood M. J., Huizinga T. W., van de Laar M. A., van Denderen C. J., Westgeest T. A., Romme T. C., de Rooij D. J., Jacobs M. J. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001 Jul;44(7):1515–1524. doi: 10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  24. van Gestel A. M., Prevoo M. L., van 't Hof M. A., van Rijswijk M. H., van de Putte L. B., van Riel P. L. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996 Jan;39(1):34–40. doi: 10.1002/art.1780390105. [DOI] [PubMed] [Google Scholar]
  25. van der Heijde D. M., van 't Hof M. A., van Riel P. L., Theunisse L. A., Lubberts E. W., van Leeuwen M. A., van Rijswijk M. H., van de Putte L. B. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990 Nov;49(11):916–920. doi: 10.1136/ard.49.11.916. [DOI] [PMC free article] [PubMed] [Google Scholar]

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