Abstract
AimTo explore the circadian rhythm of serum interleukin (IL)-6 in collagen-induced arthritis (CIA) rats and compare the safety and effectiveness of methotrexate (MTX) administered traditionally and via chronotherapy.MethodsCIA rat models were immunized with bovine type II collagen. Serum IL-6 levels in normal and CIA rats were measured at 2, 6, 10, 14, 18, or 22 h after the light was turned on (HALO). MTX was administered to 6 HALO/18 HALO experimental groups of Wistar rats once daily according to the IL-6 rhythm. The control groups (positive, negative, and normal) were given MTX or an equal volume of phosphate buffered saline (PBS) once a week simultaneously. Arthritis score, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C reactive protein (CRP) levels in the serum were measured by enzyme-linked immunosorbent assay (ELISA). Histological changes in the ankle joint were analyzed.ResultsAfter 6 weeks of treatment, arthritis scores in the experimental group were lower than in the control group. The expression of TNF-α, IL-6, and CRP was lower in the 18 HALO group than in the control or 6 HALO groups. Histopathology scores in the experimental groups were lower than in the control group (p < 0.05).ConclusionThe plasma IL-6 levels in CIA rats were higher than in normal rats and showed significant circadian rhythm. Daily administration of MTX is more potent than weekly administration. The therapeutic index of rheumatoid arthritis (RA) may be improved with MTX therapy based on the IL-6 circadian rhythm.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology
The results showed that selection of the optimal dosage associated with a circadian rhythm of RA symptoms resulted in an effective treatment for RA
We found that the level of interleukin 6 (IL-6) showed a clear 24-hour rhythm, with higher levels at 6 hours after the light was turned on (HALO) and lower levels at 18 HALO in the collagen-induced arthritis (CIA) rats (
Summary
Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology. Rheumatoid arthritis affects 0.5–1.0% of adults, with 5–50 new cases per 100,000 annually [1]. The development of an effective therapeutic strategy focusing on prevention and treatment of the disease, its complications, and associated disorders is imperative. Methotrexate (MTX), which has been used for more than 40 years in the treatment of rheumatoid arthritis, has an antiinflammatory cytotoxic and immunosuppressive effect. The therapeutic mechanisms of MTX in RA have yet to be fully elucidated. The plasma halflife of MTX was 7 to 10 h, onset time 6 to 8 weeks, and the optimal therapeutic effect was seen after 2 to 3 months [3, 4]. An uncontrolled trial conducted by To et al suggested that
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