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Purine enzymes in patients with rheumatoid arthritis treated with methotrexate

A E van Ede¹, R F J M Laan¹, R A De Abreu², A B J Stegeman², L B A van de Putte¹

¹ Department of Rheumatology, University Medical Centre St Radboud, Nijmegen, The Netherlands
² Laboratory of Paediatrics and Neurology, University Medical Centre St Radboud, Nijmegen, The Netherlands

Correspondence to:
Correspondence to:
Dr R F J M Laan, Department of Rheumatology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands;
R.Laan{at}reuma.azn.nl

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/10<sup>6</sup> 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/10<sup>6</sup> 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/10<sup>6</sup> mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10<sup>6</sup> mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10<sup>6</sup> 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.

Keywords: purine enzymes; methotrexate; rheumatoid arthritis

Abbreviations: ADA, adenosine deaminase; AICAR, amino-imidazolcarboxamide ribosyl-5-phosphate; ALT, alanine aminotransferase; DAS, disease activity score; ESR, erythrocyte sedimentation rate; HGPRT, hypoxanthine-guanine- phosphoribosyltransferase; MTX, methotrexate; 5`NT, 5`-nucleotidase; PNP, purine-nucleoside-phosphorylase; RA, rheumatoid arthritis; THF, 5,10-methylene-tetrahydrofolate

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