DISCUSSION
gastrointestinal motility, TNF-α, dyspepsia, inflammation, gastrointestinal tract, hair loss, muscle pain, nausea,, IBD
INFLAMMATION, SECONDARY, HAIR LOSS, MUCOSAL DISEASE
The primary aim of our study was to determine whether a simple intervention of changing drug delivery times of AZA and 6-MP would affect key metabolite levels that are clearly associated with efficacy and side effects. A secondary aim of this study was to determine whether these outcomes were dependent on host's circadian rhythm. The reason we selected AZA/6-MP for chronotherapy in IBD was the metabolites 6-TG and 6-MMP which are well-established and clearly associated with clinical outcomes. Indeed, we found that morning delivery of AZA and 6-MP resulted in optimizing metabolite profiles with a statistically significant increase in 6-TG levels and decrease in 6-MMP levels by paired analysis. In addition, host chronotype did affect the optimal time of therapy, with a late host chronotype being associated with more optimal metabolite levels during the evening dosage.We did not find that chronotherapy of AZA/6-MP significantly affected clinical outcomes—HBI or SIBDQ or markers of subclinical inflammation (serum cytokines TNF-α and IL-6). This is not surprising because this study had a short follow-up (10 weeks) and was not powered to find a clinical difference. Furthermore, it included only an inactive group of participants with IBD who were on a stable dose of medication and had no recent flares in the last 4 months making detecting a clinical difference or difference in subclinical inflammation very unlikely.Overall, our approach of increasing 6-TG level through optimizing time of drug delivery (i.e., chronotherapy) with AZA/6-MP should be preferred compared with simply increasing the dose of AZA/6-MP. This is because increasing the dose of AZA/6-MP will increase the 6 TG level but will also be associated with a higher level of toxic metabolites, such as 6-MMP. Furthermore, this strategy would avoid dose-dependent side effects of AZA/6-MP, such as nausea, dyspepsia, hair loss, and muscle pain (To our knowledge, there have been no previous studies evaluating chronotherapy in IBD. Circadian rhythms are known to control various functions in the gastrointestinal tract, including intestinal barrier function, gastrointestinal motility, and the secretion of mucus and digestive enzymes (In addition to assessing the central circadian clock or chronotype, the time of food consumption which is the main entertainer or zeitgeber of the peripheral clock in the gastrointestinal tract may also be important. Although we did not access the peripheral circadian clock in this study, we did recently develop a food timing questionnaire for this purpose, which could be used as a covariate in future studies (There were several limitations in this study. First, this was a single-center study with an overall limited number of participants with IBD that focused on metabolite levels and not clinical efficacy. As the first study conducted on chronotherapy of AZA and 6-MP, this was a “proof-of-concept” pilot study, and larger multicenter studies are needed to confirm the importance of chronotherapy of AZA/6-MP on clinical end points such as mucosal disease activity. Second, the overall dose of AZA/6-MP used in this study was low because it was frequently used in combination with a biologic for its immunogenicity properties. Therefore, the dose of AZA or 6-MP was infrequently increased to the dosage typical of monotherapy (2.0 mg/kg for AZA or 1.5 mg/kg for 6-MP). Third, the study design relied on patient compliance with medication timing and did not use a medication monitoring system to ensure compliance with the intervention. Finally, circadian rhythms were assessed only by a questionnaire (MCTQ and MEQ) and not directly measured in the laboratory by DLMO.In conclusion, chronotherapy of AZA/6-MP can optimize metabolite levels associated with increased efficacy and decreased side effects without changing the dose of the medication. In addition, host chronotype can help to determine the optimal timing for AZA or 6-MP therapy. Recently, there has been an increased understanding of the importance of incorporating a fourth dimension in medicine–time. In future IBD studies, the time of IBD medications needs to be carefully monitored along with the host circadian rhythms to achieve the goals of personalized medicine and to optimize medical therapy for each patient.