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Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy

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Abstract

Objective

To determine incidence of increased levels of alanine transferase (ALT) >2× upper limit of normal (ULN) in patients receiving methotrexate (MTX), treated according to a dynamic strategy, and to identify predictors of ALT of >2× ULN.

Methods

Data of 508 recent-onset rheumatoid arthritis (RA) patients from the BeSt study, randomized to initial monotherapy or combination therapy, were used. Treatment was dynamic, aiming at a disease activity score = ≤ 2.4. ALT was measured every three months. With logistic regression analyses, baseline variables predictive of first ALT of >2× ULN were identified and the association between use of concomitant antirheumatic drugs, the actual and cumulative dose of MTX and ALT of >2× ULN was determined.

Results

In total, 498 patients ever initiated MTX, with a total duration on MTX of 1,416 patient-years. In 89 patients, a first incidence of ALT of >2× ULN occurred. Incidence rate was 6.3 per 100 patient-years and cumulative incidence 18 %. ACPA positivity and baseline ALT of >1× ULN were independent predictors of later ALT of >2× ULN (OR 1.8 (95 % CI, 1.1–3.1) and OR 3.1 (95 % CI, 1.6–6.2), respectively). Smoking showed a trend (OR 1.6 (95 % CI, 0.98–2.7)). Mean MTX dosage over time was higher in patients with an ALT of >2× ULN. Patients who did not have an ALT of >2× ULN used more concomitant disease-modifying antirheumatic drugs and longer.

Conclusions

In RA patients treated with MTX according to a dynamic strategy resembling daily clinical practice, incidence of increased ALT of >2× ULN was lower than previously reported, and also without treatment adjustments, persistence was rare. The recommendations for ALT monitoring may be reevaluated.

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Acknowledgments

We would like to thank all patients as well as the following rheumatologists (other than the authors) who participated in the Foundation for Applied Rheumatology Research (all locations are in The Netherlands): W.M. de Beus, MD (Medical Center Haaglanden, Leidschendam); C. Bijkerk, MD (Reinier de Graaf Gasthuis, Delft); M.H.W. de Bois, MD (Medical Center Haaglanden, The Hague); F.C. Breedveld, Prof (Leiden University Medical Center, Leiden); G. Collée, MD (Medical Center Haaglanden, The Hague); J.A.P.M. Ewals, MD (Haga Hospital, The Hague); A.H. Gerards, MD (Vlietland Hospital, Schiedam); B.A.M. Grillet, MD (De Honte Hospital, Terneuzen); K.H. Han, MD (Medical Center Rijnmond-Zuid, Rotterdam); J.M.W. Hazes (Erasmus University Medical Center, Rotterdam); H.M.J. Hulsmans, MD (Haga Hospital, The Hague); M.H. de Jager, MD (Albert Schweitzer Hospital, Dordrecht); J.M. de Jonge-Bok, MD (retired); M.V. van Krugten, MD (Walcheren Hospital, Vlissingen); H. van der Leeden, MD (retired); M.F. van Lieshout-Zuidema, MD (Spaarne Hospital, Hoofddorp); A. Linssen, MD (retired); P.A.H.M. van der Lubbe, MD (Vlietland Hospital, Schiedam); C. Mallée, MD (Kennemer Gasthuis, Haarlem); E.T.H. Molenaar, MD (Groene Hart Hospital, Gouda); H.C. van Paassen, MD (Sint Franciscus Gasthuis, Rotterdam); A.J. Peeters, MD (Reinier de Graaf Gasthuis, Delft); H.K. Markusse, MD (deceased); R.M. van Soesbergen, MD (retired); I. Speyer, MD (Bronovo Hospital, The Hague); K.S.S. Steen, MD (Kennemer Gasthuis, Haarlem); J.Ph. Terwiel, MD (Spaarne Hospital, Hoofddorp); A.E. Voskuyl, MD (VU Medical Center, Amsterdam); M.L. Westedt, MD (Bronovo Hospital, The Hague); S. ten Wolde, MD (Kennemer Gasthuis, Haarlem); J.M.G.W. Wouters, MD (Sint Franciscus Gasthuis, Rotterdam); and D. van Zeben, MD (Sint Franciscus Gasthuis, Rotterdam). We would also like to thank all other rheumatologists and trainee rheumatologists who enrolled patients in this study and all research nurses for their contributions.

Funding

The BeSt study was supported by the Dutch College of Health Insurances. Schering–Plough and Centocor provided additional funding. The authors were responsible for the study design, the collection, analysis and interpretation of all data, the writing of this article, and the decision to publish.

Disclosures

None.

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Authors and Affiliations

  1. Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300, Leiden, The Netherlands

    L. Dirven, N. B. Klarenbeek, M. van den Broek, T. W. J. Huizinga & C. F. Allaart

  2. Department of Rheumatology, Franciscus Hospital, Roosendaal, The Netherlands

    J. H. L. M. van Groenendael

  3. Department of Rheumatology, Admiraal de Ruyter Hospital, Goes, The Netherlands

    P. B. J. de Sonnaville

  4. Department of Rheumatology, Jan van Breemen Research Institute|Reade, Amsterdam, The Netherlands

    P. J. S. M Kerstens, B. A. C. Dijkmans & W. F. Lems

  5. Department of Rheumatology, VUMC, Amsterdam, The Netherlands

    B. A. C. Dijkmans & W. F. Lems

Authors
  1. L. Dirven
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  2. N. B. Klarenbeek
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  3. M. van den Broek
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  4. J. H. L. M. van Groenendael
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  5. P. B. J. de Sonnaville
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  6. P. J. S. M Kerstens
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  7. T. W. J. Huizinga
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  8. B. A. C. Dijkmans
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  9. W. F. Lems
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  10. C. F. Allaart
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Corresponding author

Correspondence to L. Dirven.

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Dirven, L., Klarenbeek, N.B., van den Broek, M. et al. Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy. Clin Rheumatol 32, 585–590 (2013). https://doi.org/10.1007/s10067-012-2136-8

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  • DOI: https://doi.org/10.1007/s10067-012-2136-8

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