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Rheumatology Advance Access published online on March 9, 2005
Rheumatology, doi:10.1093/rheumatology/keh583
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received February 13, 2004
Accepted January 26, 2005

Original Papers

Down-regulation of activating Fc{gamma} receptors on monocytes of patients with rheumatoid arthritis upon methotrexate treatment

S. Wijngaarden 1, J. A. G. van Roon 2*, J. G. J. van de Winkel 3, J. W. J. Bijlsma 1, and F. P. J. G. Lafeber 1

1 Rheumatology and Clinical Immunology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
2 Rheumatology and Clinical Immunology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands; Immunotherapy Laboratory, Department of Immunology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
3 Immunotherapy Laboratory, Department of Immunology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands; Genmab, P.O. Box 85500, 3508 GA Utrecht, The Netherlands

* To whom correspondence should be addressed.
J. A. G. van Roon, E-mail: J.vanRoon{at}azu.nl


  Abstract

Objective. To determine the effect of methotrexate (MTX) on expression levels of activating receptors for IgG (Fc{gamma} Rs) on monocytes of rheumatoid arthritis (RA) patients in relation to changes in disease activity.

Methods. The effect of MTX on Fc{gamma} Rs on monocytes of RA patients was evaluated ex vivo as well as in vitro. Recently diagnosed, disease-modifying antirheumatic drug (DMARD)-naive RA patients were treated with low-dose MTX. At baseline and 16 weeks after the start of MTX treatment, changes in Fc{gamma} R expression levels on peripheral blood monocytes were evaluated by fluorescence-activated cell sorting analysis and were correlated to changes in disease parameters. To study the direct effects of MTX on monocytes, these cells were isolated from peripheral blood monocytes of healthy controls and cultured with MTX. Other monocyte surface molecules (CD40, CD80, CD86, MHC class II) were also determined to test the specificity of the effect on Fc{gamma} R expression levels.

Results. Eleven out of 15 patients improved clinically (mean disease activity score before 6.2 ± 0.8 vs 4.3 ± 1.7 after). Sixteen weeks after the start of MTX therapy, the expression levels of Fc{gamma} RI and IIa on monocytes were significantly decreased, whereas the decreases in Fc{gamma} RIIIa expression levels on monocytes were less marked. The percentage decrease in Fc{gamma} RI expression correlated with the percentage decrease in CRP and well-being. In vitro MTX selectively decreased Fc{gamma} RI and Fc{gamma} RIIa expression levels of isolated monocytes, in contrast to other surface molecules.

Conclusion. The disease-modifying effect of MTX in the treatment of RA is accompanied by down-regulation of activating Fc{gamma} RI and IIa on monocytes, which could be a direct effect of MTX on monocytes. This down-regulation represents a new mode of action of MTX which should be considered in RA patients, especially during conditions that could give rise to monocyte activation by IgG-containing immune complexes, e.g. during antibody-based therapy of RA.

Keywords: Fc{gamma}; receptor; Methotrexate; Rheumatoid arthritis; Monocytes/macrophages.
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