Background Among the several available DMARDs, Methotrexate (MTX) is currently the most widely used drug in clinical practice. About 30-40% of the patients could experience an adequate response to MTX alone; thus, it might not be necessary to start intensive combination therapy for all newly diagnosed RA patients. Given ACR20 response rate of MTX monotherapy is only 46% ∼65%, it is possible that a significant number of early RA patients could suffer from a failure of monotherapy. Therefore, it is important to identify biomarkers predictive of non-response to MTX monotherapy. In the past, using microarray genome-wide analysis of gene expression profile of peripheral blood mononuclear cells (PBMCs), we have discovered a small set of discriminative transcripts between MTX- responsive and MTX-resistant RA patients. In this set, the Haptoglobin (HP, OMIM:140100) expression signal was 5.1 fold increased in MTX resistant RA patients. These observations prompted us to investigate whether serum HP levels are able to predict the efficacy of MTX treatment over a period of 3 months.
Objectives To investigate whether serum levels of Haptoglobin (HP) could predict responsiveness to methotrexate (MTX) at the 12th week of treatment in patients with recent-onset RA.
Methods A total of 69 patients with newly diagnosed and active RA were treated with MTX (initiated at a dosage of 10 mg/week and increased to 20 mg/week after 4-6 weeks). Clinical variables associated with disease activity were recorded at week 0 and week 12. Levels of HP mRNA in PBMCs and serum levels of circulating HP protein at week 0 and week 12 were determined using Real-time PCR and ELISA, respectively.
Results After 12 weeks of MTX treatment, 39.1% (n=27) and 60.9% (n=42) of all 69 evaluable patients were classified as responders or non-responders, respectively, according to the DAS-28-ESR score. The baseline HP mRNA expression in PBMCs from non-responders is significantly higher than those in responders (p<0.05). Similar to mRNA expression, non-responders who had inadequate response to 12 weeks MTX therapy showed significantly elevated HP levels at baseline (369.9±159.8 mg/dl) compared to those in responders (255.3±143.9 mg/dl) (p =0.01). Serum HP levels decreased significantly from 255.3±143.9 mg/dl at baseline to 186.4±108.5 mg/dl at week 12 (p =0.04) in responders, but remained at high levels in non-responders (369.9±159.8 mg/dl at baseline vs. 309.6±183.9 mg/dl at week 12; p=0.71).
Conclusions Serum levels of HP might predict response to MTX treatment in recent-onset RA patients.
Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363(9410):675-81
Ranganathan P, Eisen S, Yokoyama WM, McLeod HL. Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis? Ann Rheum Dis 2003; 62(1):4-9.
Disclosure of Interest None Declared