Correlation between serum methotrexate concentrations and disease remission status in rheumatoid arthritis patients on triple disease-modifying antirheumatic drug therapy

Prasanna Kumar T Subbanna¹, Sujith J Chandy¹, Debashish Danda², Binu S Mathew¹,  
¹ Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore - 632 002, India
² Department of Rheumatology, Christian Medical College, Vellore - 632 002, India

Correspondence Address:
Prasanna Kumar T Subbanna
Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore - 632 002
India

Full Text

The therapeutic goals in rheumatoid arthritis (RA) are the induction of remission of symptoms involving the joints, a return of full function and the maintenance of remission with disease-modifying antirheumatic drugs (DMARDs). The current strategy is initial aggressive treatment with a combination of DMARDs to prevent substantial disability and premature mortality. One such synthetic DMARD, methotrexate (MTX), is known to induce a long-term response. [1] Low-dose methotrexate (LDMTX), 5-17.5 mg/week, [1] is given in combination with sulfasalazine and/or hydroxychloroquine. Even with combination therapy, more than one third of the patients fail to achieve remission due to unknown reasons. Thus, it seems to be possible to individualise LDMTX therapy according to the results of pharmacokinetic and pharmacodynamic analysis.

Based on these observations, we decided to conduct an initial pilot study to estimate serum MTX concentrations and their effect on disease remission status in RA patients on triple DMARD therapy. As the measurement of serum MTX is expensive (Rs. 630/sample in our institution), we planned to conduct our study in two phases, a pilot followed by (if necessary) a definitive phase in case the pilot study revealed a correlation between disease remission and serum drug concentrations. At this juncture, we would like to acknowledge that correlating serum MTX concentration alone with disease remission status in patients taking many drugs, is a limitation in our study. However, given that MTX is the chief component of the triple regimen and that it has both toxicity and interindividual variability in bioavailability, it continues to be a very important aspect of LDMTX therapy

The study was conducted at Christian Medical College, Vellore, India between April 2005 to October 2005. Twelve female RA patients attending the Rheumatology Clinic were recruited after obtaining their written informed consent and approval from the institutional ethics committee. All patients fulfilled the American College of Rheumatology (ACR) criteria for RA but without any significant systemic involvement secondary to RA (e.g., Vasculitis, Pulmonary fibrosis etc.). Six patients had DAS28-3 2.66 (3.99 ± 0.99). All patients received triple DMARD therapy, i.e., Tab Methotrexate 10 mg/week, Tab Sulfasalazine 1 gm bid and Tab Hydroxychloroquine 200 mg hs od on an out patient basis. The patients were also taking proton pump inhibitors, folinic acid and naproxen. Patient characteristics are given in [Table 1]. To assess the remission status, disease activity scores (DAS28-3) were calculated using the results of the 28 tender joint count (TJC 28), 28 swollen joint count (SJC 28) and erythrocyte sedimentation rate (ESR, 60 min) based on the formula given by Fransen et al . [2]

DAS28-3 [2]

Two blood samples were collected, before and 1.5 hrs after 10 mg Tab Methotrexate intake. Serum was extracted and stored at -70 C until analysis. The cycle of methotrexate intake by the patients was unaltered during the study. Serum methotrexate concentrations were estimated based on the enzyme-multiplied immunoassay technique (EMIT) as described by Oellerich et al . [3] EMIT was performed using the Hitachi 912 auto analyzer and MTX kits were purchased from Syva Company, Dade Boehring Inc., GmbH. The assay was optimized for measuring MTX with a standard curve ranging from 0.1-2.0 µmol/liter.

The Mann Whitney test was used for statistical analysis. P value 2.66 were 0.26 ± 0.15 µmol/L and 0.20 ± 0.89 µmol/L, respectively. Analysis with the Pearson correlation test showed an insignificant ( P = 0.4) correlation coefficient of -0.235 between DAS28.3 and serum methotrexate concentrations. All the patients experienced minor side effects like abdominal pain, nausea and vomiting. None of them presented with any serious side effects. Serum liver enzyme levels and blood cell counts were within the normal range.

Interindividual variability of MTX pharmacokinetics is very high. [1] Oral absorption of doses between 10 and 25 mg may be as low as 25% and as high as 100% (mean 70%). [1] This results in variable systemic and variable therapeutic / toxic effects in patients. Routine therapeutic monitoring of plasma MTX concentrations is advocated in patients receiving high doses of methotrexate. Even though a few studies on populations in western countries reported a lack of correlation between serum MTX concentrations and disease activity status, [4],[5] the data is still not enough to fully accept or refute therapeutic drug monitoring of MTX in LDMTX regimens in RA. Our study shows an insignificant correlation between serum methotrexate concentrations and disease remission status. Genetic polymorphisms are predicted to influence the clinical response to LDMTX. [1] Hence, it is possible that there will be an interracial difference in the clinical efficacy of LDMTX. To the best of our knowledge, inspite of seven million Indians reported to be suffering from RA and a large number of RA patients receiving LDMTX due to its efficacy and low cost, no pharmacokinetics data on LDMTX in Indian RA patients is available. Thus, although our study has been conducted in a small number of Indian patients (twelve), it strengthens the view that routine monitoring of MTX concentrations in RA patients on LDMTX are not essential as they are expensive and not commonly available and provides some preliminary data for MTX PK in Indian RA patients.

 Acknowledgments

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