Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients

Abstract

Weekly pulsed low-dose methotrexate (MTX) is a standard regimen for rheumatoid arthritis (RA). Severe adverse reactions to MTX, such as pneumonia and cytopenia, sometimes occur; however, it is difficult to predict the development of these adverse reactions. In this article, we examine the serum concentrations of orally administered MTX of 69 Japanese patients with RA in the clinical setting. The maximum serum concentration (C (max)) after the first dose of the weekly administration and the time at which C (max) was obtained (T (max)) were analyzed. C (max) correlated with the administered dose before measurement. The average T (max) was 2.0 +/- 0.8 h, and none of the patients showed a T (max) of more than 4 h. In addition, we demonstrated that the weekly MTX dosage and the mean dosage of steroids were significantly higher in patients with adverse reactions than in those without them, and the C (max) after the first dose of the weekly administration particularly correlated with the incidence of adverse reactions (P < 0.001). In fact, the cut-off point of C (max) (0.16 micromol/l) was a sensitive predictor of the adverse reactions (sensitivity 81% and specificity 67%). We concluded that C (max) after the first dose of weekly administration is a useful parameter for predicting the development of adverse reactions to MTX.

Elevated level of serum cystatin-C concentration is a useful predictor for myelosuppression induced by methotrexate for treatment of rheumatoid arthritis

“…Nonetheless, MTX-induced myelosuppression also develops in Japanese patients at a certain frequency independently of MTX dosage. In fact, Wyeth Corporation announced that MTX-related fatalities excluding those related to generics were 319 from 12 March 12 1999 to 31 December 2008 in Japan, and among them, the percentage of myelotoxicity was 36.7% (117 patients) [3]. As with other studies, the results of our study suggest that MTX may induce myelotoxicity more frequently than noted in the literature listed in references described later, which has supposedly underreported the prevalence of myelotoxicity [4].…”

“…It has been reported that patients with the maximum level of serum MTX concentration suffer ILD and liver dysfunction, the prevalence of the adverse events being higher in these patients than in patients with no adverse events [31]. The correlation may be observed between renal insufficiency and these events, although it is considered incidental for these reasons: (1) identified risk factors of MTX-induced ILD are hypoalbuminemia prior to DMARD administration, diabetes, and older age [32]; (2) our logistic regression analysis demonstrated that renal insufficiency did not contribute to these events.…”

Risk factors of gastrointestinal and hepatic adverse drug reactions in the treatment of rheumatoid arthritis with biomedical combination therapy and Chinese medicine

“…There had been reported that some factors are probably correlated with ADRs in RA patients, such as a higher body mass index (BMI) (Verstappen et al, 2010), the maximum serum concentration -C after the first dose of the weekly MTX administration (Shoda et al, 2007), increasing age (McKendry and Dale, 1993), the IgG, IgA, and IgM, and lymphocyte count reductions and reduction ratios (Inokuma et al, 2000), genetic variation within ADORA2a (Hider et al, 2008). All these factors showed significantly association with MTX-related ADRs in different studies.…”

Cytopenia and autoimmune diseases: A vicious cycle fueled by mTOR dysregulation in hematopoietic stem cells

“…It is generally agreed that autoreactive antibodies may cause elimination of leukocytes and thus contribute to immune deficiency [4, 13]. Methotrexate and occasionally, prednisone, the popular drug for autoimmune diseases, are known to cause cytopenia [14–18]. On the other hand, lymphopenia has been shown to cause homeostatic proliferation (HP) of T cells [19–22].…”

“…A well-established autoimmune disease in both adults and children is autoimmune hemolytic anemia, in which autoreactive antibodies are abnormally produced and mediate elimination of both erythrocytes and/or leukocytes [4, 13]. In addition, it is increasingly clear that drugs frequently used for autoimmune patients, such as methotrexate and occasionally prednisone, may have cytopenia as a major adverse event [14–18]. A largely overlooked issue is whether autoimmune diseases may cause defective hematopoiesis.…”