Table 1.

Preclinical evidence for chronotherapy according to the results obtained in animal models of arthritis.

	Author, Year	Animal Model	Main Findings
MTX	To, 2009 [88]	CIA	Arthritis score was significantly lower in CIA mice/rats treated with a 22-HALO MTX regimen when compared to a 10-HALO group (p < 0.01).
	To, 2011 [91]	MRL/lpr mice	Plasma SAA levels were significantly lower in MRL/lpr mice treated with an 18-HALO MTX regimen when compared to a 6-HALO group (p < 0.01).
	Wang, 2018 [89]	CIA	Arthritis severity, CRP, TNF, and IL-6 were significantly lower in CIA rats treated to an 18-HALO MTX regimen when compared to a 6-HALO group (p < 0.01).
Baricitinib	Yaekura, 2020 [93]	CIA	Arthritis score (p < 0.01), TNF (p < 0.01) and IL-6 (p < 0.01) were significantly lower in CIA mice treated with BARI administered at ZT0 when compared to BARI administered at ZT12.
Tacrolimus	Obayashi, 2011 [94]	CIA, MRL/lpr	Arthritis score (p < 0.01) and leukocyte count (p < 0.01) were significantly lower in CIA and MRL/lpr mice treated with a 2-HALO TAC regimen when compared to a 14-HALO group.
Mizoribine	Kanasaki, 2012 [95]	CIA	Arthritis score (p < 0.01) and leukocyte count (p < 0.01) were significantly lower in CIA mice treated with a 22-HALO MZR regimen when compared to a 10-HALO group.

Legend: BARI, baricitinib; CIA, collagen-induced arthritis; CRP, C-reactive protein; HALO, hours after the light was turned on; IL-6, interleukin 6; MRL/lpr, homozygous for the lymphoprolifera-tion spontaneous mutation (Faslpr); MTX, methotrexate; MZR, mizoribine; SAA, serum amyloid A; TAC, tacrolimus; TNF, tumor necrosis factor; ZT, zeitgeber time.