In this real-world, observational study of baricitinib for Chinese patients with moderate-to-severe active RA, the safety profile was generally consistent with previous reports from clinical trials [17, 24, 25] and no new safety signals were observed. Baricitinib treatment demonstrated effectiveness in the treatment of Chinese patients with RA, with notable proportions of patients able to achieve remission per DAS28-CRP, SDAI, and CDAI scales.

Notably, use of prior bDMARDs was lower in our study (4.9%) than in the Japanese PMSS (71%) [26], reflecting the difference in bDMARD access and approvals between China and global populations [19]. Indeed, the majority of patients in our study (87.0%) received the 2-mg dose of baricitinib, and not the 4-mg dose used in previous clinical trials of baricitinib and the Japanese PMSS [25, 26]. As this PMSS was conducted from 2020 onwards, prescribing physicians followed Chinese recommendations for dosage at the time, which required patients to initiate baricitinib at 2 mg QD as the only approved dosage. However, the study protocol was amended in March 2021 to reflect the additional approval of the 4-mg dose in China, which is indicated for patients with an inadequate response to the 2-mg dose for at least 3 months or to TNF inhibitors.

With appropriate caution for cross-trial comparisons, baseline characteristics were generally comparable between our study and previous clinical trials or post-marketing studies [17, 24,25,26]. The mean age in our study was 53.2 years, slightly older than the 48.0 years reported in Chinese patients in RA-BALANCE [24], but younger than the 64 years reported in a 24-week Japanese baricitinib PMSS for RA [26]. The mean BMI was 22.3 kg/m2 in our study similar to the Japanese PMSS, but lower than that of patients enrolled in clinical trials (mean BMI 27.7 kg/m2) [27]. Finally, in our study, baseline DAS28-CRP, SDAI, and CDAI remission rates were 12.7, 4.8, and 4.7%, respectively, similar to the Japanese PMSS, which reported baseline remission rates of 12.6, 3.1, and 2.9% for each scale, respectively [26].

In our study, AEs were reported in 37.5% of patients at 24 weeks (EAIR [95% CI], 125.9 [110.8–142.5] per 100 PY), which is higher than in the Japanese PMSS (26.9%; incidence rate [IR], 99.7 [95.1–104.2] per 100 PY) [26]; however, the incidence of AEs did not increase from 12 to 24 weeks (EAIR [95% CI], 172.5 [150.2–197.3] per 100 PY). Serious AE incidences were similar to those reported in the 24-week Japanese PMSS [26].

Two patients died in this study; both had multiple concomitant diseases and received the 2-mg dose of baricitinib. One 73-year-old patient died of treatment-related pneumonia (receiving multiple concomitant medications, including the immunomodulatory leflunomide, methotrexate, and Tripterygium wilfordii) and one 69-year-old patient died of an unknown cause, not considered related to treatment. The EAIR for death in this study of 0.77 (95% CI, 0.1–2.8) per 100 PY was similar to global data: 0.0 [95% CI, not available–1.9] and 0.6 [95% CI, 0.1–1.8] per 100 PY in the 2- and 4-mg dose groups to week 24, respectively [25], and the incidence rate of 0.56 (95% CI, 0.45–0.70) per 100 PY in a long-term extension study [17]. The EAIR for death in this study is also comparable to the Japanese PMSS (0.85 [0.46–1.24] per 100 PY) [26].

In our study, a total of eight patients (1.2%) had serious infections, which was similar to the proportion reported for Chinese patients in the RA-BALANCE study (0.9%) and in the Japanese PMSS (1.9%) [24, 26]. The EAIR for serious infections in our study was similar to the incidence rate reported in both the 2-mg and 4-mg cohorts in the 3-year integrated analysis of clinical trials to week 24 [25].

The incidence of hepatotoxicity was slightly higher in this study than the EAIR reported in the Japanese 24-week PMSS (7.15 per 100 PY) [26] and the EAIR for abnormal hepatic function (6.5 per 100 PY) in a Japanese integrated analysis of nine clinical trials of baricitinib in RA with a median of 1.6 years on treatment [28]. However, the incidences of ALT and AST changes in our study were comparable to previous reports [26, 28] and no patients met laboratory criteria for Hy’s law [29], suggesting that hepatocellular injury was unlikely to occur with baricitinib treatment.

In the phase 3b/4 ORAL Surveillance study, which included patients with RA who were ≥ 50 years old with at least one additional cardiovascular risk factor, increased risks of MACE, malignancy, and serious infections were observed in patients who received tofacitinib compared with TNF inhibitors after a median follow-up of 4.0 years [10, 11]. In an observational study using propensity-matched data from multiple databases in the US, Europe, and Japan, there was a statistically significant increase in the incidence of VTE with baricitinib compared with TNF inhibition, but not with MACE or serious infection [30]. However, no VTE or MACE occurred among patients who received baricitinib in the two Japanese databases, though these patients were relatively few in number (n = 384) [30]. In the Japanese baricitinib PMSS, the IR of malignancy (including lymphoma) was 0.91 per 100 PY, IR of MACE was 0.38 per 100 PY, and IR of VTE was 0.38 per 100 PY [26]. These were generally similar to the IRs in the global integrated safety analysis:, IR, 0.9 per 100 PY, IR, 0.5 per 100 PY, and IR, 0.5 per 100 PY for malignancy, MACE, and deep vein thrombosis events of special interest, respectively, in all patients who received baricitinib [17]. In a Korean real-world study, JAK inhibition did not increase the risk of MACE or cancer compared with TNF inhibition in patients with RA [31]. In our study, no MACE or VTE were observed and malignancy (deemed unrelated to baricitinib by the investigator) was observed in one patient. However, the exposure (24-week observation period) and the sample size of our study limits the ability to observe AEs with a long latency time. In addition, it should be noted that patients in our study had a relatively low mean baseline BMI of 22.3 kg/m2, as well as low proportions of patients who had ever smoked (12.3%), which may have been protective against MACE and VTE events. Together, there were differences in those previous studies, it is crucial to assess the long-term safety profile of baricitinib, and further studies are required.

Changes from baseline in hematological or other laboratory parameters were observed in our study; however, clinically meaningful events (grade ≥ 3 change) were uncommon, consistent with a pooled analysis of eight clinical trials of baricitinib in which hematological changes were evaluated for up to 128 weeks [32]. In that pooled analysis, grade ≥ 3 neutrophil count decreases were seen in < 1% of patients who received baricitinib [32]; grade ≥ 3 decreased lymphocyte count was seen in 1.3% with baricitinib 2 mg and 0.8% with baricitinib 4 mg [32]; and drug discontinuation due to hematological abnormalities occurred in a low proportion (< 1%) of patients [32]. This is consistent with our study, wherein no discontinuations due to hematological abnormalities occurred.

While our study was designed to assess the real-world safety of baricitinib, it is notable that 52.4% of patients achieved DAS28-CRP remission at 24 weeks. This proportion is comparable to the Japanese PMSS (61.3%) [26], which is higher than in clinical trials [16, 18]. In our study, the LS mean change from baseline to week 24 for DAS28-CRP, SDAI, and CDAI was − 1.9, − 19.3, and − 17.7, respectively. In the Spanish ORBIT-RA real-world study of patients with refractory RA, the mean (SD) change from baseline in SDAI and CDAI at 6 months was − 13.4 (11.6) and − 13.0 (11.4), respectively [33]. However, caution is warranted when interpreting any comparisons due to differences in patient populations and methodological differences between the studies. For example, patients in our study who received baricitinib for < 10 weeks were excluded from the effectiveness analysis, while patients in clinical trials who received rescue therapy or discontinued were defined as non-responders [13, 16].

In our study, there was some discrepancy between the DAS28-CRP and SDAI/CDAI measures of effectiveness. This may be expected, as previous studies, including an observational study using the Chinese CREDIT database with 30,501 patients, have found that that the proportion of discordance was lowest between SDAI and CDAI (8.7%) and highest between DAS28-CRP and CDAI (32.8%) [34]. This suggests that despite high correlation between indices, they are not interchangeable [34]. Clinical trials have also found differences: in the RA-BEAM trial at week 24, 34% of patients who received baricitinib achieved DAS28-CRP remission, compared with 16% by SDAI/CDAI [5].

Patients reported reductions from baseline in both mean scores of duration of MJS and pain VAS in our study. While this observational study was not designed for statistical comparison of PROs, these results are in line with those reported in analyses of clinical trials wherein statistically significant improvements in PROs with baricitinib treatment were reported compared with placebo [5, 18, 35].

Limitations of this study include its single-arm, observational design, precluding robust conclusions regarding the safety or effectiveness of baricitinib treatment for RA in Chinese patients. Additionally, the 24-week maximum observation period limits safety conclusions drawn from these data for patients who receive baricitinib for longer than 24 weeks. However, EAIRs for AEs, treatment-related AEs, serious AEs, AEs leading to discontinuation, and AESIs did not increase from 12 to 24 weeks of observation, suggesting that a longer duration of baricitinib treatment does not lead to an increased risk of AEs. Taken together with previous studies of baricitinib treatment [5, 14,15,16,17,18], including long-term safety data, the results of this study do not suggest an increased risk of AEs with 24 weeks of baricitinib treatment. In our study, the majority of patients (86.8%) received concomitant csDMARDs. This is in line with the approval of baricitinib in China, where the approval of baricitinib is in combination with csDMARDs. However, due to the observational nature of this study which was designed to provide real-world data on safety and effectiveness of baricitinib, data regarding baricitinib monotherapy or other concomitant treatment patterns are not available.