Nocturnal baricitinib administration leads to rapid drug responses in rheumatoid arthritis: a multicenter non-randomized controlled study

Abstract

Background: Inflammatory cytokine levels exhibit a circadian rhythm in sera, peaking from late night to early morning in patients with rheumatoid arthritis (RA). This cytokine kinetics is a recognized therapeutic target. This clinical study aimed to evaluate the effectiveness of night-time baricitinib administration based on cytokine secretion.

Methods: In this 52-week multicenter non-randomized controlled study, 122 patients with RA were assigned to four groups: baricitinib 2 mg morning (BAR2MORN), 2 mg evening (BAR2EVE), 4 mg morning (BAR4MORN), or 4 mg evening (BAR4EVE). The primary endpoint was assessed using the 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. The secondary endpoints were ACR20/50/70 and changes in the clinical disease activity index (CDAI) through 52 weeks. The results were evaluated using the propensity score inverse probability of treatment weighted to reduce selection bias in patient background.

Results: BAR4EVE resulted in better primary endpoint improvement than BAR4MORN (78.2 vs. 43.3%; p < 0.001). No difference in improvement was observed in the primary endpoint between BAR2EVE and BAR2MORN (75.5 vs. 60.6%; p = 0.10). However, BAR2EVE demonstrated higher ACR20 at weeks 4, 24, and 52 and ACR50 at weeks 4 and 12 than BAR2MORN. BAR4EVE demonstrated higher ACR20/50 at weeks 4, 8, and 12 and ACR70 at weeks 8, 12, and 24 than BAR4MORN. CDAI changes were significantly reduced in BAR4EVE than in BAR4MORN at weeks 4 and 8.

Conclusion: Chronotherapy targeting cytokine secretion resulted in rapid drug response, proposing a new potential application for JAK inhibitors.

Trial registration: UMIN000040094, July 1, 2020.

Keywords: Baricitinib; Chronotherapy; JAK inhibitor; Rheumatoid arthritis.

Fig. 1

Participant recruitment flow chart. BAR, baricitinib

Fig. 2

Primary and secondary endpoints: (A) proportion of patients who achieved ACR20 at week 12. Baricitinib 4 mg in the evening resulted in better improvement than baricitinib 4 mg in the morning (p < 0.001). (B) Proportion of patients who achieved ACR20, (C) ACR50, and (D) ACR70 at weeks 4, 8, 12, 24, and 52. (i) Baricitinib 2 mg in the morning vs. baricitinib 2 mg in the evening, n = 50, 51 (ii) Baricitinib 4 mg in the morning vs. baricitinib 4 mg in the evening, n = 52, 53, respectively. Error bars represented a 95% confidence interval. ACR20, ACR50, and ACR70: 20%, 50%, and 70% improvement in American College of Rheumatology criteria

Fig. 3

Change in ACR components from baseline to weeks 4, 8, 12, 24, and 52: (A) SJC, (B) TJC, (C) PtGA VAS, (D) patient pain VAS, (E) PGA VAS, (F) HAQ-DI, (G) CRP, and (H) ESR. Results are presented as the mean ± 95% confidence interval: (i) baricitinib 2 mg in the morning vs. baricitinib 2 mg in the evening, n = 50, 51, (ii) baricitinib 4 mg in the morning vs. baricitinib 4 mg in the evening, n = 52, 53, respectively

Fig. 4

Change in DAS28-ESR and CDAI from baseline to weeks 4, 8, 12, 24, and 52. DAS28-ESR (A) improved in baricitinib 4 mg in the evening compared with baricitinib 4 mg in the morning at week 8. Similarly, CDAI (C) significantly improved in baricitinib 4 mg in the evening at weeks 4 and 8. Results are presented as the mean ± 95% confidence interval. (i) Baricitinib 2 mg in the morning vs. baricitinib 2 mg in the evening n = 50, 51, (ii) Baricitinib 4 mg morning vs. baricitinib 4 mg in the evening, n = 52, 53, respectively. Proportion of patients achieving (B) DAS28-ESR < 2.6, (D) CDAI ≤ 2.8 at weeks 12, 24, and 52. Baricitinib 4 mg in the evening has a higher rate of patients achieving DAS28 remission at weeks 12 and 24 and CDAI remission at weeks 12, 24, and 52. Error bars represented 95% confidence interval; n = 50, 51, 52, and 53 for baricitinib 2 mg in the morning, 2 mg in the evening, 4 mg in the morning, and 4 mg in the evening, respectively

Fig. 5

MTX (A) and prednisolone (B) doses at weeks 0, 24, and 52. MTX dose was significantly decreased in baricitinib 2 mg in the evening and 2 mg in the morning groups at weeks 24 and 52 as compared with baseline. The prednisolone dose also decreased in baricitinib 2 mg in the morning, baricitinib 2 mg in the evening, and baricitinib 4 mg in the evening groups at weeks 24 and 52 as compared to that at the baseline. Results are expressed as the mean ± 95% confidence interval; n = 50, 51, 52, and 53 for baricitinib 2 mg baricitinib in the morning, 2 mg in the evening, 4 mg in the morning, and 4 mg in the evening, respectively, paired Wilcoxon signed-rank test