Korean J Intern Med The Korean Journal of Internal Medicine 1226-3303 2005-6648 Korean Association of Internal Medicine 10.3904/kjim.2022.369 kjim-2022-369 Original Article Rheumatology Comparative effectiveness of JAK inhibitors and biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis ChoSoo-Kyung1 KimHyoungyoung1 SongYeo-Jin1 KimHye Won1 NamEunwoo1 LeeShin-Seok2 LeeHye-Soon3 ParkSung-Hoon4 LeeYeon-Ah5 ParkMin-Chan6 ChangSung Hae7 KimHyoun-Ah8 KwokSeung-Ki9 KimHae-Rim10 KimHyun-Sook11 YoonBo Young12 UhmWan-Sik13 KimYong-Gil14 KimJae Hoon15 LeeJisoo16 ChoiJeongim17 http://orcid.org/0000-0001-6691-8939 SungYoon-Kyoung1 Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases and Hanyang University Institute for Rheumatology Research, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea Division of Rheumatology, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea Uhm’s Rheumatism Clinic, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea Division of Rheumatology, Department of Internal Medicine, Busan Saint Mary’s Hospital, Busan, Korea Correspondence to: Yoon-Kyoung Sung, M.D., Ph.D., M.P.H., Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea, Tel: +82-2-2290-9250, Fax: +82-2-2298-8231, E-mail: sungyk@hanyang.ac.kr 7 2023 20 06 2023 38 4 546 556 28 11 2022 15 03 2023 25 04 2023 Copyright © 2023 The Korean Association of Internal Medicine 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background/Aims

We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease-modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs.

 Methods

A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)–28– erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs).

 Results

Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups.

 Conclusions

Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

 Janus kinase inhibitor Tumor necrosis factor inhibitors Comparative effectiveness research Safety Rheumatoid arthritis GRAPHICAL ABSTRACT

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that primarily affects the joints [1]. Recent improvements in the understanding of RA pathogenesis have led to the development of targeted disease-modifying antirheumatic drugs (DMARDs) for modifying inflammatory cells and cytokines [2]. These include biologic DMARDs (bDMARDs), such as tumor necrosis factor inhibitors (TNFi), non-TNF inhibitors (non-TNFi) including abatacept and tocilizumab; and targeted synthetic DMARDs (tsDMARDs), including Janus kinase inhibitors (JAKi) [3]. With these various targeted DMARDs, treatment strategies suggest early diagnosis and early initiation of effective therapy aimed at remission or, at the least, low disease activity (LDA) [4].

The 2019 European Alliance of Associations for Rheumatology (EULAR) recommendations and 2021 American College of Rheumatology (ACR) guidelines for RA treatment place JAKi at the same level as the bDMARDs, being used for patients who experienced treatment failure with csDMARDs, and no preference is given to any of these agents [4,5]. Previous clinical trials have shown that tofacitinib is effective and generally well tolerated in the treatment of active RA, both as monotherapy and in combination with methotrexate (MTX) [6–8] or other csDMARDs [9]. Additionally, in patients naïve to bDMARDs, tofacitinib combination therapy with MTX has been shown to have similar efficacy to adalimumab and MTX combination therapy [10,11].

There are many factors to consider when selecting drugs in the real world, unlike in clinical trials wherein drug selection is randomized. These factors include patient characteristics (demographic and clinical characteristics, for example), as well as information about side effects, drug effectiveness, and medication logistics (such as frequency and route of administration) [12]. In terms of these aspects, compared with bDMARD, JAKi have a different route of administration and different supporting evidence regarding safety issues: bDMARDs are injectable (subcutaneous or intravenous), while JAKi is an oral medication, and there is more long-term information about the safety in bDMARDs. The latter consideration is because JAKi has only been recently approved for use. Furthermore, physician seemed to consider patients’ disease severity and comorbidities [13], as well as facility-related factors, such as the presence of space or assistants to explain medications to patients. Furthermore, shared decision-making (SDM) for the choice of treatment between patients and their physicians has been emphasized. Given the growing number of treatment options, recent guidelines have recommended the treat-to-target strategy and SDM as the first principles for creating RA treatment plans [5]. Therefore, a comparative effectiveness study between JAKi and bDMARDs–considering various factors for drug selection in clinical practice–is needed.

This study aimed to evaluate the effectiveness and safety of JAKi compared with bDMARDs in patients with RA in real-world practice.

 METHODS Protocol of the full study

A quasi-experimental, multicenter, prospective, nonrandomized study of RA patients initiated on targeted therapy was conducted to compare the effectiveness and safety of two treatments. RA patients who started JAKi or bDMARDs were recruited by rheumatologists from 17 centers across the Republic of Korea, including 15 tertiary academic hospitals and 2 primary/secondary hospitals from April 2020 through August 2022. Disease activity is being assessed by well-trained health professionals, and participants completed patient-reported outcomes (PROs) at weeks 0, 12, 24, and 48 (Supplementary Fig. 1). All data are being entered into web-based case report forms.

The primary endpoint is the proportion of patients achieving LDA based on disease activity score (DAS)–28–erythroid sedimentation rate (ESR) (DAS28-ESR, <3.2) at 24 weeks after treatment initiation. The secondary endpoints are the proportion of patients achieving remission rate at 24 weeks, as well as the LDA and remission rates at 48 weeks. Disease activity is also being assessed using the DAS28–C-reactive protein (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and EULAR response criteria. The EULAR response criteria classify individual patients as nonresponders, moderate responders, or good responders, depending on the extent of change and the level of disease activity reached. Quality of life (QOL) and disability are being assessed using the EuroQol-5 dimension (EQ-5D) and Health Assessment Questionnaire–Disability Index (HAQ-DI) tools, respectively. Global Health assessment using Visual Analogue Scale (GH VAS) data are being collected by patients and their physicians.

The safety assessment includes capturing data on the development of adverse events (AEs) and abnormal laboratory tests for 52 weeks after treatment initiation. Severe AEs (SAEs) are also being identified. AE severity is being classified according to a five-grade scale (mild, moderate, severe, life-threatening, or death) according to definitions from the Common Terminology Criteria for Adverse Events. Serious AEs are defined as grade-3 to grade-5 AEs.

To participate in the study, RA patients must have met all of the following inclusion criteria: (1) > 19 years old; (2) moderate to severe active RA with an inadequate response or intolerance to MTX; (3) started on JAKi such as baricitinib, tofacitinib, or upadacitinib; or bDMARDs, including TNFi (etanercept, adalimumab, golimumab) or non-TNFi (abatacept, tocillizumab); (4) provided written informed consent to participate. Patients who did not provide written informed consent to participate were excluded.

The sample size was calculated for performing noninferiority testing of JAKi vs. bDMARDs using the proportion of patients achieving LDA based on DAS28-ESR at 24 weeks. The noninferiority margin was set to 13%, which is estimated by 50% of the effect of bDMARDs, i.e., 50% of the difference in the proportions of LDA achievement between bDMARD (36%) and placebo groups in previous studies [14–17]. With an assumption of a 1:1 allocation between the JAKi and bDMARD groups, the sample size was calculated as 215 patients for each group at a significance level, α, of 0.025 to acquire more than 80% of test power. Finally, with a predicted dropout rate of 15%, the total sample size was calculated as 506 patients for both groups.

 Study population and outcomes of interim analysis

For this interim analysis, out of all the recruited patients, patients enrolled between April 2020 and October 2021 were extracted to evaluate outcomes at 24 weeks.

We evaluated the patients achieving LDA and remission at 12 weeks and 24 weeks after treatment with JAKi or bDMARDs. PROs at 12 weeks and 24 weeks were also compared between the two treatment groups. Additionally, the frequency of AEs at 24 weeks was determined.

 Statistical analysis

Demographic and clinical features of JAKi and bDMARD users were compared using the chi-square analysis or Fisher’s exact test for categorical variables and the Mann–Whitney U test for continuous variables.

As the primary analysis, noninferiority testing using the proportion of patients achieving LDA based on DAS28-ESR at 24 weeks was performed, with a noninferiority margin of 13% representing 50% of the effect of bDMARDs, which is the active control. If the entire 95% confidence interval (CI) of the difference in proportions of LDA patients between the JAKi and bDMARD groups is above ~13%, we can conclude that JAKi is noninferior to bDMARDs.

In the secondary analysis, the proportions of patients achieving LDA at 12 weeks or remission at 12 weeks and 24 weeks (based on DAS28-ESR after treatment with JAKi or bDMARDs) were assessed as an intention-to-treat analysis. Proportions were compared between the two groups using the chi-square test. As a per-protocol analysis, PROs were compared between the two groups using the Mann–Whitney U test after treatment. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). Results were considered statistically significant when p values were < 0.05.

 Ethical considerations

The study protocol was approved by the Institutional Review Boards of each participating hospital (IRB file No. HYUN 2019-11-031) or public IRB (https://public.irb.or.kr/). Additionally, this study is registered in the US ClinicalTrials.gov database (no. NCT04449224).

 RESULTS Baseline characteristics of the study population

This interim analysis included 346 patients enrolled from April 2020 through October 2021 because at least 24 weeks had passed after follow-up initiation for these patients; this included patients treated with bDMARDs (n = 150) and patients treated with JAKi (n = 196) (Fig. 1). Among bDMARD users, more than half (58.2%) were treated with TNFi (n = 87), and 42.0% of patients were treated with non-TNFi (n = 63). Among JAK inhibitor users, 58.2% of patients were treated with baricitinib (n = 114), and the others were treated with tofacitinib (n = 51) and upadacitinib (n = 31) (Table 1). There were no differences in demographic characteristics between bDMARD and JAKi users. The baseline clinical characteristics of the study participants included in the interim analysis are summarized in Table 1.

 Effectiveness

The rate of LDA achievement at 24 weeks was not significantly different between the two treatment groups (48.7% for bDMARDs and 49.0% for JAKi, p = 0.954). The difference between the groups was estimated to be 0.3% (95% CI, −10.6% to 11.3%), which was above −13% and implied that JAKi is not inferior to bDMARDs. The LDA rates at 12 weeks were also similar between the two groups (44.7% with bDMARDs and 46.9% with JAKi, p = 0.674). There were no statistically significant differences between the treatment groups in the remission rates at 12 weeks (32.0% with bDMARDs vs. 31.6% with JAKi, p = 0.942) and 24 weeks (31.3% with bDMARDs vs. 30.1% with JAKi, p=0.806).

The LDA and remission rates, based on DAS28-CRP, CDAI, and SDAI, were not significantly different between the treatment groups (Fig. 2, 3).

We compared PROs between two groups after treatment as per protocol at 12 and 24 weeks after treatment initiation. Changes in GH VAS, HAQ-DI, and EQ5D ratings were similar between the groups (Supplementary Fig. 2).

 Safety

The frequency of AEs reported in the JAKi group was higher than that in the bDMARD group, but this difference was not statistically significant (75 of 196 patients [38.3%] vs. 43 of 150 patients [28.73%], p = 0.105). In the JAKi group, gastrointestinal disorders (n = 10, 5.1%) and skin disorders (n = 9, 4.6%) were most common, while infection (n = 9, 6.0%) and skin disorders (n = 8, 5.3%) were the most common in the bDMARDs group (Table 2). In terms of infection, herpes zoster was diagnosed in 5 patients (2 in the bDMARD and 3 in the JAKigroup), and 5 patients developed respiratory tract infections (2 in the bDMARD group and 3 in the JAKi group). Tuberculosis, malignancy, and thromboembolic events were not reported in either group. Two patients in the JAKi group experienced cardiac AEs: cardiac arrest (n = 1) and palpitations (n = 1), while no patients in the bDMARD group had cardiac AEs. There was no intergroup difference in the frequencies of SAE (Supplementary Table 1) or serious AEs (SAEs, 4.0% vs. 4.6% in the bDMARD and JAKi groups, respectively, p = 0.789; serious AEs, 3.3% vs. 3.6% in the bDMARD and JAKi groups, respectively, p = 0.905) (Table 3).

 DISCUSSION

In the interim analysis of this ongoing quasi-experimental, multicenter, prospective, nonrandomized study, we demonstrated JAKi to have comparable effectiveness with bDMARDs at 24 weeks after treatment initiation in RA patients with inadequate responses to csDMARDs. Half of the RA patients reached LDA (49.0% with JAKi and 48.7% with bDMARDs), and a third of the patients (30.1% with JAKi and 31.3% with bDMARDs) achieved remission. For 24 weeks, there were no significant intergroup differences in the rates of overall AEs between the two treatment groups. Our results are in line with evidence from recent observational studies that have determined similar response rates between JAKi and bDMARDs [18–20]. However, some observational studies have found tofacitinib to be associated with better improvements in disease activity than those associated with bDMARDs after 6 or 12 months of treatment in bDMARD-naïve RA patients [21–23]. Notably, in one study, this difference was not observed in bDMARD-failure RA patients [21]. Moreover, early introduction of tofacitinib has been associated with similar or better survival than that associated with bDMARD administration [23]. Therefore, the drug selection order is important because previous experience with bDMARDs may be a crucial factor affecting drug responses. In our interim analysis results, the LDA achievement rate at 12 weeks was numerically higher in the JAKi group than in the bDMARD group, but there was no statistical significance. Further follow-up is needed to determine the comparative effectiveness of both treatments.

The AE profile observed with JAKi was similar to that observed with bDMARDs. There was, however, a nonsignificant trend toward a higher frequency of AEs associated with JAKi compared with bDMARDs. This could be due to heightened concerns from physicians and patients, causing them potentially to be more careful with this newer treatment. The rates of infections, including herpes zoster, associated with drug administration were similar between the two treatment groups for 24 weeks after treatments. Neither venous thromboembolism nor malignancy was reported in either group. Only one patient treated with JAKi died, with cardiac arrest reported as the cause of death. Previous observational studies have reported higher incidences of herpes zoster infection among patients treated with JAKi [24,25]. A recent large observational study conducted in the United States using claims database data found tofacitinib to be associated with an increased risk of hospitalization for serious infection compared with bDMARDs [26]. Additionally, a recent randomized controlled trial demonstrated that the risks of major adverse cardiovascular events and cancers were higher in association with tofacitinib than with TNF inhibitors among patients with cardiovascular risk factors [27]. However, United States registry data have demonstrated tofacitinib to be associated with similar major adverse cardiovascular events, serious infection, malignancy, death, and venous thromboembolism rates compared with bDMARDs [28]. Long-term follow-up studies are needed to confirm the safety of JAKi.

The strength of our study lies in the provision of information on the real-world management of patients with RA. This study has good generalizability because the patients have been enrolled from multiple healthcare facility levels: tertiary hospitals, community hospitals, and private clinics. To the best of our knowledge, this is the only data set in Korea that includes bDMARD-naïve RA patients receiving targeted therapy at multiple healthcare facility levels. Additionally, this study included three JAKi approved for the treatment of RA in Korea. Therefore, we can compare the effectiveness and safety of each drug in the final analysis, which is important because drugs of the same class may have different effects.

In conclusion, our interim findings of this ongoing real-world, pragmatic, multicenter study revealed JAKi to be comparable with bDMARDs, in terms of effectiveness and safety, at 24 weeks after treatment initiation. We hope that the final analysis will present the effectiveness and safety of the two treatments in bDMARD-naïve patients with RA, as well as provide future research directions.

 KEY MESSAGE

1. Our interim findings of this ongoing real-world, pragmatic, multicenter study reveal that JAKi have had comparable effectiveness to bDMARDs at 24 weeks after treatment initiation in patients with RA naïve to targeted therapy.

2. The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups.

 Supplementary Information

Conflicts of interest

The authors disclose no conflicts.

CRedit authorship contributions

Soo-Kyung Cho: conceptualization, data curation, methodology, visualization, writing - original draft, writing - review & editing; Hyoungyoung Kim: data curation, formal analysis, visualization, writing - review & editing; Yeo-Jin Song: data curation, visualization, writing - review & editing; Hye Won Kim: formal analysis, methodology, writing - review & editing; Eunwoo Nam: formal analysis, methodology, writing - review & editing; Shin-Seok Lee: data curation, methodology, writing - review & editing; Hye soon Lee: data curation, methodology, writing - review & editing; Sung-Hoon Park: data curation, methodology, writing - review & editing; Yeon Ah Lee: data curation, methodology, writing - review & editing; Min-Chan Park: data curation, methodology, writing - review & editing; Sung Hae Chang: data curation, methodology, writing - review & editing; Hyoun-Ah Kim: data curation, methodology, writing - review & editing; Seung-Ki Kwok: data curation, methodology, writing - review & editing; Hae-Rim Kim: data curation, methodology, writing - review & editing; Hyun-Sook Kim: data curation, methodology, writing - review & editing; Bo Young Yoon: data curation, methodology, writing - review & editing; Wan-sik Uhm: data curation, methodology, writing - review & editing; Yong-Gil Kim: data curation, methodology, writing - review & editing; Jae Hoon Kim: data curation, methodology, writing - review & editing; Jisoo Lee: data curation, methodology, writing - review & editing; Jeongim Choi: data curation, methodology, writing - review & editing; Yoon-Kyoung Sung: conceptualization, data curation, funding acquisition, methodology, project administration, writing - review & editing

Funding

This research was supported by a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0481, HC19C0052).

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tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial Lancet 2017 390 457 68 Morrison T Foster E Dougherty J Barton J Shared decision making in rheumatology: a scoping review Semin Arthritis Rheum 2022 56 152041 Sung YK Jung SY Kim H Factors for starting biosimilar TNF inhibitors in patients with rheumatic diseases in the real world PLoS One 2020 15 e0227960 Smolen JS Burmester GR Combe B Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study Lancet 2016 388 2763 74 Taylor PC Keystone EC van der Heijde D Baricitinib versus placebo or adalimumab in rheumatoid arthritis N Engl J Med 2017 376 652 62 Weinblatt ME Baranauskaite A Niebrzydowski J Phase III randomized study of SB5, an adalimumab biosimilar, versus reference adalimumab in patients with moderate-to-severe rheumatoid arthritis Arthritis Rheumatol 2018 70 40 8 Lie E van der Heijde D Uhlig T Treatment strategies in patients with rheumatoid arthritis for whom methotrexate monotherapy has failed: data from the NOR-DMARD register Ann Rheum Dis 2011 70 2103 10 Lauper K Iudici M Mongin D Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the ‘JAK-pot’ collaboration Ann Rheum Dis 2022 81 1358 66 Barbulescu A Askling J Chatzidionysiou K Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data Rheumatology (Oxford) 2022 61 3952 62 Bird P Littlejohn G Butcher B Real-world evaluation of effectiveness, persistence, and usage patterns of monotherapy and combination therapy tofacitinib in treatment of rheumatoid arthritis in Australia Clin Rheumatol 2022 41 53 62 Mori S Urata Y Yoshitama T Ueki Y Tofacitinib 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after initiating tofacitinib versus biologic DMARDs in patients with rheumatoid arthritis: a multidatabase cohort study Lancet Rheumatol 2020 2 E84 98 Ytterberg SR Bhatt DL Mikuls TR ORAL Surveillance Investigators Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis N Engl J Med 2022 386 316 26 Kremer JM Bingham CO 3rd Cappelli LC Postapproval comparative safety study of tofacitinib and biological disease-modifying antirheumatic drugs: 5-year results from a United States-based rheumatoid arthritis registry ACR Open Rheumatol 2021 3 173 84 Figures and Tables

Patient selection flow. RA, rheumatoid arthritis; DMARD, disease modifying anti-rheumatic drug.

Percentage of patients achieving low disease activity in the bDMARD and JAKi groups. (A) DAS28-ESR low disease activity and (B) CDAI low disease activity. Bar presents the mean with a 95% confidence interval of percentage (%) for patients achieving low disease activity. bDMARD, biologic disease-modifying antirheumatic drug; JAKi, Janus kinase inhibitors; DAS, disease activity score; ESR, erythrocyte sedimentation rate; CDAI, Clinical Disease Activity Index.

Percentage of patients achieving remission in the bDRARD and JAKi groups. (A) DAS28-ESR disease remission and (B) CDAI disease remission. Bar represents the mean with a 95% confidence interval of percentage (%) for patients achieving disease remission. bDMARD, biologic disease-modifying antirheumatic drug; JAKi, Janus kinase inhibitors; DAS, disease activity score; ESR, erythrocyte sedimentation rate; CDAI, Clinical Disease Activity Index.

Patient characteristics at baseline

Variable Total (n = 346) JAKi (n = 196) bDMARDs (n = 150) p value
Sex, female 298 (86.1) 168 (85.7) 130 (86.7) 0.800
Age, yr 53.9 ± 13.1 54.9 ± 11.5 52.5 ± 15.0 0.163
Disease duration of RA, yr (n = 221, 90, 131) 8.5 ± 8.5 8.6 ± 8.8 8.4 ± 8.3 0.862
BMI, kg/m2 25.0 ± 33.4 26.3 ± 44.3 23.3 ± 4.2 0.953
Ever smoker 60 (17.3) 36 (18.4) 24 (16.0) 0.564
Comorbidities
 Myocardial infarction 1 (0.3) 0 (0.7) 1 (0.7) 0.434
 Congestive heart failure 1 (0.3) 0 (0.7) 1 (0.7) 0.434
 Peripheral vascular disease 1 (0.3) 0 (0.7) 1 (0.7) 0.434
 Cerebrovascular disease 3 (0.9) 2 (0.7) 1 (0.7) 0.999
 Chronic pulmonary disease 10 (2.9) 3 (4.7) 7 (4.7) 0.109
 Peptic ulcer disease 10 (2.9) 7 (2.0) 3 (2.0) 0.524
 Mild liver disease 22 (6.4) 13 (6.0) 9 (6.0) 0.811
 DM without complications 19 (5.5) 11 (5.3) 8 (5.3) 0.910
 DM with chronic complications 10 (2.9) 4 (4.0) 6 (4.0) 0.340
 Hemiplegia or paraplegia 1 (0.3) 0 (0.7) 1 (0.7) 0.434
 Renal disease 7 (2.0) 1 (4.0) 6 (4.0) 0.046
 Solid tumor, nonmetastatic 2 (0.6) 1 (0.7) 1 (0.7) 0.999
 Lymphoma 1 (0.3) 1 (0.0) 0 (0.0) 0.999
RA disease activity
 DAS28-ESR 6.0 ± 0.8 6.0 ± 0.8 6.1 ± 0.8 0.339
 DAS28-CRP 5.3 ± 0.8 5.2 ± 0.7 5.4 ± 0.8 0.091
 CDAI 31.5 ± 8.6 31.1 ± 9.5 32.0 ± 9.5 0.571
 SDAI 33.3 ± 8.9 32.8 ± 8.3 34.0 ± 9.6 0.334
 Physicians’ GH VAS (mm) 72.5 ± 14.1 70.8 ± 14.5 74.7 ± 14.5 0.005
 Patient’s GH VAS (mm) 76.0 ± 15.2 75.4 ± 15.5 76.8 ± 15.5 0.232
Patient-reported outcomes
 HAQ-DI 1.1 ± 0.7 1.0 ± 0.7 1.2 ± 0.7 0.046
 EQ-5D 0.6 ± 0.2 0.7 ± 0.2 0.6 ± 0.2 0.020
Laboratory test
 RF positivity (n = 221,89, 132) 278 (81.3) 150 (86.5) 128 (86.5) 0.031
 Anti-CCP positivity (n = 217, 86, 131) 284 (84.0) 160 (84.9) 124 (84.9) 0.691
 Either RF or anti-CCP positivity 312 (90.2) 174 (92.0) 138 (92.0) 0.318
 ESR, mm/h 47.8 ± 26.0 45.9 ± 27.1 50.3 ± 27.1 0.128
 CRP, mg/dL 1.8 ± 2.2 1.7 ± 2.3 1.9 ± 2.0 0.054
Medications
 History of csDMARDs use
  Methotrexate 335 (96.8) 191 (97.5) 144 (96.0) 0.542
  Leflunomide 175 (50.6) 115 (58.7) 60 (40.0) 0.001
  Hydroxychloroquine 221 (63.9) 126 (64.3) 95 (63.3) 0.855
  Sulfasalazine 175 (50.6) 89 (45.4) 86 (57.3) 0.028
  Tacrolimus 147 (42.5) 87 (44.4) 60 (40.0) 0.413
  Number of csDMARD, ever use 3.1 ± 1.1 3.2 ± 1.1 3.1 ± 1.1 0.295
Targeted therapy, current use
 bDMARDs 150 (43.4) 150 (100.0)
  Adalimumab 65 (18.8) 65 (43.3)
  Etanercept 22 (6.4) 22 (14.7)
  Abatacpet 40 (11.6) 40 (26.7)
  Tocilizumab 23 (6.7) 23 (15.3)
 Small molecular inhibitor 196 (56.6) 196 (100.0)
  Baricitinib 114 (32.9) 114 (58.2)
  Tofacitinib 51 (14.7) 51 (26.0)
  Upadacitinib 31 (9.0) 31 (15.8)
Concomitant medications
 Combination with csDMARDs 307 (88.7) 174 (88.8) 133 (88.7) 0.975
  Methotrexate 12.2 ± 3.2 12.1 ± 3.4 12.3 ± 3.0 0.946
   Methotrexate dose, mg/wk 21 (6.1) 8 (4.1) 13 (8.7) 0.123
  csDMARDs other than methotrexate 18 (5.2) 14 (7.1) 4 (2.7) 0.063
 NSAIDs 272 (78.6) 153 (78.1) 119 (79.3) 0.775
 Oral glucocorticoid 271 (78.3) 150 (76.5) 121 (80.7) 0.355
 Glucocorticoid doseb), mg/d 5.0 ± 2.6 4.8 ± 2.4 5.2 ± 2.8 0.346

Continuous data are represented as mean ± standard deviation and compared using the Mann–Whitney U test. Categorical data are represented as frequency (%) and compared using the chi-square or Fisher’s exact test.

JAKi, Janus kinase inhibitors; bDMARD, biologic disease-modifying antirheumatic drug; RA, rheumatoid arthritis; BMI, body mass index; DM, diabetes mellitus; DAS, disease activity score; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; CDAI, Clinical Disease Activity Index; SDAI, Simplified Disease Activity Index; GH VAS, Global Health assessment using Visual Analogue Scale; HAQ-DI, Health Assessment Questionnaire-Disability Index; EQ-5D, EuroQol-5 dimension; RF, rheumatoid factor; Anti-CCP, anticyclic citrullinated peptide antibody; csDMARD, conventional disease-modifying antirheumatic drug; NSAID, nonsteroidal anti-inflammatory drug; CCI, Charlson Comorbidity Index; TNF, tumor necrosis factor.

The number of comorbidities included in the calculation of CCI, except for rheumatoid arthritis, was presented, and connective tissue disease was excluded in the calculation of CCI.

TNF inhibitors include infliximab, etanercept, adalimumab, and golimumab, and non-TNF inhibitors include abatacept, tocilizumab, and rituximab.

Adverse events in RA patients who used targeted therapy for 24 weeks

Category JAKi (n = 196) bDMARD (n = 150) p value
Events, n Patients, n (%) Events, n Patients, n (%)
All AE 80 75 (38.3) 49 43 (28.7) 0.105
SAE 10 9 (4.6) 6 6 (4.0) 0.789
Serious AEa) 7 7 (3.6) 5 5 (3.3) 0.905
Blood and lymphatic system disorders 3 3 (1.5) 1 1 (0.7) 0.636
Cardiac disorders 3 2 (1.0) 0 0 (0.0) 0.507
Endocrine disorders 5 5 (2.6) 2 2 (1.3) 0.703
Gastrointestinal disorders 11 10 (5.1) 8 5 (3.3) 0.423
General disorders and administration site conditions 7 7 (3.6) 2 2 (1.3) 0.309
Hepatobiliary disorders 4 4 (2.0) 1 1 (0.7) 0.394
Infections and infestations 9 8 (4.1) 10 9 (6.0) 0.413
Injury, poisoning and procedural complications 3 3 (1.5) 2 2 (1.3) 0.999
Musculoskeletal and connective tissue disorders 8 7 (3.6) 3 3 (2.0) 0.524
Neoplasms benign, malignant and unspecified 0 0 (0.0) 2 2 (1.3) 0.187
Nervous system disorders 4 4 (2.0) 1 1 (0.7) 0.394
Reproductive system and breast disorders 5 4 (2.0) 0 0 (0.0) 0.136
Respiratory, thoracic and mediastinal disorders 3 3 (1.5) 9 7 (4.7) 0.109
Skin and subcutaneous tissue disorders 9 9 (4.6) 8 8 (5.3) 0.752
Others 6 6 (3.1) 0 0 (0.0) 0.038

RA, rheumatoid arthritis; JAKi, Janus kinase inhibitors; bDMARD, biologic disease modifying anti-rheumatic drugs; AE, adverse event; SAE, severe adverse event.

Serious AEs included AEs from grade 3 to grade 5.

Cardiovascular events in RA patients who used targeted therapy for 24 weeks

Category JAKi (n = 196) bDMARD (n = 150)
Events, n Patients, n (%) Events, n Patients, n (%)
Cardiac disorders 3 2 (1.0) 0 0 0
 Cardiac arrest 1 1 (0.5) 0 0 0
 Palpitation 2 1 (0.5) 0 0 0

RA, rheumatoid arthritis; JAKi, Janus kinase inhibitors; bDMARD, biologic disease modifying anti-rheumatic drugs.