Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor-α in collagen-induced arthritic rats and mice

Abstract

Our findings suggest that choosing an optimal dosing time associated with the 24-h cycling of TNF-alpha could lead to effective treatment of rheumatoid arthritis by methotrexate.

Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats

“…The aggravation of arthritis was not inhibited in any of the dosing schedule groups even though MTX (14.0 mg/kg per week) was administered from day 11 after the first sensitization (). The MTX‐treated groups did not exhibit any antirheumatic effects over the control group even though the dosage administered in the present study was 10‐fold higher than that in a previous study . This may have been because the dose selected was insufficient to inhibit fulminant arthritis because the administration of MTX was initiated in CIA rats from a few days after the onset of arthritis.…”

“…This may have been because the dose selected was insufficient to inhibit fulminant arthritis because the administration of MTX was initiated in CIA rats from a few days after the onset of arthritis. In a previous study, MTX was administered from the next day after the first sensitization . Therefore, we estimated the influence of the dosing schedule on antirheumatic effects during the administration of MTX from the next day after the first or second sensitization.…”

Circadian Use of Glucocorticoids in Rheumatoid Arthritis

“…Chronotherapy with night-time GC availability optimizes the use of low-dose GCs in RA patients, and also possibly of DMARDs and NSAIDs (at least at bedtime), through a more efficient targeting of the mediators of the immune/inflammatory reaction during their night rising time [43,53,54,55]. These results were anticipated almost 30 years ago by the direct night administration of prednisone to RA patients; however, the system was not introduced to clinical practice because it was not practical to administer GCs to patients at 3-4 a.m. [56,57,58].…”

“…might follow the same concepts of GC chronotherapy [2]. This hypothesis was recently tested in an in vivo investigation using an animal model of arthritis, which showed that the optimal dosing time, associated with the 24-hour cycling of TNF-α, could lead to optimization of methotrexate anti-inflammatory action (and decrease of TNF-α) [43]. A further clinical study confirmed that bedtime methotrexate chronotherapy (3 times a week once a day) can improve RA symptoms compared to the current usual weekly dosing methods [44].…”

Mechanism of the 24-hour rhythm of tumor necrosis factor-alpha formed by onset of rheumatoid arthritis

“…Cytokines are also known to be an important target for RA therapy due to the development of biological disease-modifying anti-rheumatic drugs (Gabay, 2002;Olsen & Stein, 2004) and evidence of chronotherapy with anti-rheumatic drugs such as methotrexate, tacrolimus and mizoribine (Kanasaki et al, 2012;Obayashi et al, 2011;To et al, 2009To et al, , 2011. Although an increase in cytokine levels has been observed in inflammatory diseases, RA is interesting because of the variations observed in cytokine concentrations.…”