https://orcid.org/0000-0002-4624-0777
Figures
Abstract
Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19–1.52) and opportunistic (RR 2.69; 95% CI: 1.22–5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05–1.39), peficitinib (RR 1.40; 95% CI: 1.05–1.86) and upadacitinib (RR 1.30; 95% CI: 1.09–1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.
Citation: Ouranos K, Avila DV, Mylona EK, Vassilopoulos A, Vassilopoulos S, Shehadeh F, et al. (2024) Cumulative incidence and risk of infection in patients with rheumatoid arthritis treated with janus kinase inhibitors: A systematic review and meta-analysis. PLoS ONE 19(7): e0306548. https://doi.org/10.1371/journal.pone.0306548
Editor: Benjamin M. Liu, Children’s National Hospital, George Washington University, UNITED STATES
Received: April 10, 2024; Accepted: June 18, 2024; Published: July 31, 2024
Copyright: © 2024 Ouranos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
Disease-modifying antirheumatic drugs (DMARDs) are currently the first-line treatment option for patients with rheumatoid arthritis (RA) [1]. Among the available DMARDs, conventional synthetic DMARDs, including methotrexate and leflunomide, are first-line agents due to their proven efficacy and favorable safety profile [2]. In patients with inadequate response or contraindications to conventional synthetic DMARD monotherapy, treatment escalation to targeted synthetic DMARDs, such as biologic DMARDs and Janus kinase (JAK) inhibitors (JAKi), is recommended, either alone or in combination with conventional synthetic DMARDs [3].
Landmark phase III clinical trials have established the effectiveness of JAKi compared with placebo in methotrexate-naïve patients or patients with inadequate response to methotrexate or other DMARDs [4]. Tofacitinib, baricitinib, and upadacitinib are currently approved by the Food and Drug Administration for use in patients with RA. Each approved JAKi has varying specificity for different JAK isoforms, thus impacting distinct downstream pathways involved in the pathophysiology of RA [5].
Patients with RA are at increased risk of infection due to disease pathophysiology and the use of immunomodulatory therapy [6]. The use of JAKi has also been associated with an increased risk of infection, including opportunistic infections [7]. The infection risk profile of these agents has been attributed to the blockade of cytokines that use the JAK-Signal Transduction and Activator of Transcription (STAT) signaling pathway and are the primary drivers of host cellular and humoral immune responses against infection [8].
Although JAKi have been associated with a heightened risk of infection, their risk profile in patients with RA is not thoroughly described. The goal of our systematic review and meta-analysis was to estimate the pooled cumulative incidence and infection risk in patients with RA receiving JAKi compared with patients with RA receiving placebo or treatment regimen that was similar with that of participants in the treatment group, with the exception of JAKi.
2. Materials and methods
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist [9] to perform this systematic review and meta-analysis, and we registered the study on PROSPERO (CRD42024507846).
2.1 Data sources and search strategies
PubMed and EMBASE databases were queried for studies in English, spanning from database inception to October 30, 2023, using the following search terms: (“rheumatoid arthritis” AND (tofacitinib OR baricitinib OR upadacitinib OR peficitinib OR filgotinib OR “JAK inhibitor*”). In order to find additional articles that would meet our inclusion criteria, we also manually checked the reference lists of extracted articles, as well as previously published meta-analyses, to consistently include all eligible papers in our manuscript.
2.2 Criteria for study inclusion in the analysis
We considered randomized controlled trials for inclusion in the analysis if they met the following criteria: a) Randomization of study participants to a treatment or control group occurred; b) Participants in the treatment group had a diagnosis of RA and received JAKi; c) Participants in the control group had a diagnosis of RA and received placebo or treatment regimen that was similar with that of participants in the treatment group, with the exception of JAKi; d) The diagnosis of RA was based on the 1987 American College of Rheumatology (ACR) Revised Criteria [10] or the ACR/European League Against Rheumatism (EULAR) 2010 classification criteria [11]; and e) included studies had available data for at least one of our pre-defined outcomes. Studies in which patients with RA were receiving concurrent therapy with agents other than JAKi were also included in the analysis. We excluded studies that were not randomized controlled trials, including case-control and/or cohort studies, review articles, and case reports. An abstract presentation was considered for inclusion in our analysis only if the results were not already published in full text manuscripts.
2.3 Study endpoints
Our primary study endpoint was to measure the relative risk (RR) of any-grade and severe infection in patients with RA receiving JAKi (treatment group), as compared with patients with RA receiving placebo or treatment regimen that was similar with that of participants in the treatment group, with the exception of JAKi (control group).
Our secondary study endpoints were the pooled cumulative incidence of any-grade and severe infection during two study periods in each included study: the first spanned the period from study initiation until primary outcome assessment, and the second was the follow-up period, extending beyond the primary outcome assessment until the end of each study. After primary outcome assessment, significant crossover between treatment and control groups occurred. As such, pooled cumulative incidences of infection were calculated at two separate periods to account for the differences in study population under examination.
Next, we measured the cumulative incidence and risk of opportunistic infections, including herpes zoster infection, in the treatment group compared with the control group. We harnessed the definitions proposed by Winthrop et al. [12] to calculate the number of opportunistic infections in our analysis. Lastly, we aimed to measure the RR and pooled cumulative incidence of different types of infections reported in the included studies. Such an analysis was carried out only when data were of sufficient quantity to run these analyses, in the treatment group compared with the control group. We used the National Cancer Institute’s Common Terminology Criteria for Adverse Events [13] to assign the grade of infectious complications.
2.4 Extraction of data and assessment of quality of included studies
Two reviewers (K.O. and D.A.) conducted an independent evaluation of study eligibility by reviewing titles and abstracts, and then conducted a full text review of the chosen studies. Data extracted from the selected studies included information regarding study design, demographic characteristics of study participants, medication history in addition to the use of JAKi, the specific JAKi used, information regarding primary and secondary outcome assessments, and infection-attributed mortality rate.
We independently evaluated (K.O. and D.A.) the included studies’ quality by harnessing the revised Cochrane risk-of-bias assessment tool for randomized trials (RoB 2) [14]. This tool assesses study quality against five domains: process of randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selection of the reported results. Each individual study and all outcomes within those studies were categorized as having low risk, some concerns, or high risk of bias.
2.5 Statistical analysis
Random-effects meta-analysis using the restricted maximum likelihood method [15] was implemented to estimate the RR of infections in patients with RA in the treatment group compared with the controls. Additionally, we measured the pooled cumulative incidence of infections during the two study periods under consideration, as described above, and we harnessed the Freeman-Tukey double-arcsine transformation to stabilize the variances [16, 17]. We reported study outcomes using 95% confidence intervals (CI). We also used the I2 statistic to determine study heterogeneity. Low, moderate, and high heterogeneity was defined as an I2 value of 25, 50, and 75%, respectively [18]. In order to assess for publication bias and small study effects, the Egger’s test was used. [19]. For all data analysis and interpretation, we set statistical significance at α = 0.05.
In order to account for multiple extracted variables that could confound the association between JAKi administration and infection risk, we conducted a meta-regression analysis [20] by taking into consideration the following variables: mean age of patients’ in the intervention and control group, percentage of female study participants in each group, and concurrent use of methotrexate and/or glucocorticoids.
To perform all data analysis, we used the Stata v17 (Stata Corporation, College Station, TX) software.
3. Results
3.1 Database search results
We found 4,795 studies in our literature search in PubMed and EMBASE. We removed 989 duplicates and assessed 3,806 studies against our inclusion criteria. A total of 3,659 studies were excluded after careful review of their title and abstract, and, as such, we reviewed 147 publications in full text. We included 35 randomized controlled trials from 35 publications for the quantitative synthesis of the study. Details regarding the number of studies retrieved from each database, and reasons for excluding ineligible studies are presented in Fig 1.
3.2 Baseline characteristics of included studies and overview of study results
Out of the 35 studies, eight examined upadacitinib [21–28], seven examined baricitinib [29–35], five examined filgotinib [36–40], ten examined tofacitinib [41–50], and five examined peficitinib [51–55]. S1 Table displays the characteristics of the studies analyzed.
The included randomized controlled trials included data on 10,730 patients with RA in the treatment group and 4,628 patients with RA in the control group. Mean age of the patients in the treatment and control groups was 53.6 and 53.1 years, respectively. Additionally, 8,853 (82.5%) patients in the treatment group and 3,551 (76.7%) patients in the control group were female. Data regarding concomitant methotrexate use at study entry and for the duration of the study were available in 9,512 patients in the treatment group and 4,153 patients in the control group, of whom 7,975 (74.3%) and 3,623 (78.3%), respectively, were receiving methotrexate. Data regarding concomitant corticosteroid use at study entry and for the duration of the study were available in 8,226 patients in the treatment group and 3,732 patients in the control group, of whom 4,224 (51.3%) and 1,948 (52.2%), respectively, were receiving glucocorticoids. Overall, analysis based on type of infection during the period from study initiation until the time of primary outcome assessment for each study revealed that 2,213 out of 10,519 (16.70%) patients in the intervention arm developed any-grade infection, 133 out of 10,730 (1.24%) patients developed severe infection, and 115 out of 10,519 (1.09%) patients developed opportunistic infections (S2 Table). During follow-up, 1,880 out of 6,835 (27.51%) patients developed any-grade infection, 143 out of 6,835 (2.09%) patients developed severe infection, and 132 out of 6,835 (1.93%) patients developed opportunistic infections (S3 Table).
3.3 Primary and secondary study endpoints
3.3.1 Risk of any-grade infection in patients with RA receiving JAKi compared with control subjects.
The overall RR of any-grade infection in patients with RA in the treatment group compared with the control group was 1.25 (95% CI: 1.17–1.35, I2 = 6.50%), as shown in Table 1 and Fig 2. Out of eight studies [21–28] that assessed patients with RA who were treated with upadacitinib, 374 out of 1,743 patients (21.5%) in the treatment group and 126 out of 782 (16.1%) control subjects developed any-grade infection [RR 1.30 (95% CI: 1.09–1.56, I2 = 0.00%)].
The size of the square is representative of the weight assigned to the respective study for outcome analysis. The 95% CI for each study is represented by the horizontal lines. The diamond shape represents the pooled estimate of the analysis. Abbreviations: CI: confidence interval; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis; RR: relative risk.
Six studies [29–31, 33–35] assessed patients with RA who were treated with baricitinib, in which 675 out of 1,953 (34.6%) patients in the treatment group and 371 out of 1,394 (26.6%) control subjects developed any-grade infection [RR 1.34 (95% CI: 1.19–1.52, I2 = 19.81%)].
Three [36–38] studies assessed patients with RA who were treated with filgotinib, in which 502 out of 1,878 (26.7%) patients in the treatment group and 230 out of 1,039 (22.1%) control subjects developed any-grade infection [RR 1.21 (95% CI: 1.05–1.39, I2 = 0.00%)].
Out of ten studies [41–50] that assessed patients with RA who were treated with tofacitinib, 421 out of 3,114 (13.5%) patients in the treatment group and 113 out of 891 (12.7%) control subjects developed any-grade infection [RR 1.01 (95% CI: 0.81–1.25, I2 = 12.94%)].
Three studies [52–54] assessed peficitinib in patients with RA, in which 174 out of 779 (22.3%) patients in the treatment group and 50 out of 327 (15.3%) control subjects developed any-grade infection [RR 1.40 (95% CI: 1.05–1.86, I2 = 0.00%)].
3.3.2 Pooled cumulative incidence of any-grade infection in patients with RA receiving JAKi.
Among 9,975 patients with RA receiving JAKi, the pooled cumulative incidence of any-grade infection from study initiation until primary outcome assessment, over a mean duration of 18.2 weeks, was 21.59% (95% CI: 18.10%-25.71%, I2 = 94.6%) (Table 2 and S1 Fig). The pooled cumulative incidence of any-grade infection during follow-up, over a mean duration of 30.8 weeks, in 6,835 patients with RA treated with JAKi was 32.44% (95% CI: 21.04%-45.01%, I2 = 99.1%) (S2 Fig). The pooled cumulative incidence of any-grade infection from study initiation until primary outcome assessment, as well as during follow-up, for every JAKi under consideration, is presented in the S1 File
3.3.3 Relative risk of severe infection in patients with RA receiving JAKi compared with control subjects.
The overall RR for severe infection in patients with RA in the treatment group compared with control subjects was 1.13 (95% CI: 0.81–1.57, I2 = 0.00%), as shown in Fig 3. Out of eight studies [21–28] that assessed patients with RA who received upadacitinib, 22 out of 1,743 (1.26%) in the treatment group and 2 out of 782 (0.26%) control subjects developed severe infection [RR 2.05 (95% CI: 0.76–5.55, I2 = 0.00%)].
The size of the square is representative of the weight assigned to the respective study for outcome analysis. The 95% CI for each study is represented by the horizontal lines. The diamond shape represents the pooled estimate of the analysis. Abbreviations: CI: confidence interval; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis; RR: relative risk.
Six studies [29–31, 33–35] assessed patients with RA who received baricitinib, in which 36 out of 1,953 (1.84%) patients in the treatment group and 26 out of 1,394 (1.87%) control subjects developed severe infection [RR 0.90 (95% CI: 0.54–1.51, I2 = 0.00%)].
Four studies [36–38, 40] assessed patients with RA who received filgotinib, in which 34 out of 2,089 (1.62%) patients in the treatment group and 15 out of 1,111 (1.35%) control subjects developed severe infection [RR 1.19 (95% CI: 0.64–2.19, I2 = 0.00%)].
Out of ten studies [41–50] that assessed tofacitinib in patients with RA, 26 out of 3,114 (0.83%) patients in the treatment group and 3 out of 891 (0.34%) control subjects developed severe infection [RR 1.19 (95% CI: 0.48–2.95, I2 = 0.00%)].
Five studies [51–55] assessed peficitinib in patients with RA, in which 8 out of 1,323 (0.60%) patients in the treatment group and 0 out of 450 (0.00%) control subjects developed severe infection [RR 1.23 (95% CI: 0.29–5.12, I2 = 0.00%)].
3.3.4 Pooled cumulative incidence of severe infection in patients with RA receiving JAKi.
The pooled cumulative incidence of severe infection from study initiation until primary outcome assessment, over a mean duration of 17.5 weeks, in 10,730 patients with RA receiving JAKi was 0.92% (95% CI: 0.65%-1.23%, I2 = 43.8%) (S3 Fig). The pooled cumulative incidence of severe infection during follow-up, over a mean duration of 30.8 weeks, in 6,835 patients with RA treated with JAKi was 2.02% (95% CI: 1.22%-3.01%, I2 = 84.3%) (S4 Fig). The pooled cumulative incidence of severe infection from study initiation until primary outcome assessment, as well as during follow-up, for every JAKi under consideration, is presented in the S1 File.
3.3.5 Relative risk and pooled cumulative incidence of opportunistic infections in patients with RA receiving JAKi compared with control subjects.
The RR of opportunistic infections in patients with RA in the treatment group compared control subjects was 1.52 (95% CI: 1.01–2.27, I2 = 0.00%), as shown in Fig 4. Information about the pooled cumulative incidence of opportunistic infections in patients with RA treated with JAKi from study initiation until primary outcome assessment is provided in Table 2 and S5 Fig. The pooled cumulative incidence of opportunistic infections during follow-up in 6,835 patients with RA treated with JAKi, over a mean duration of 30.8 weeks, was 1.74% (95% CI: 0.71%-3.16%, I2 = 92.8%) (S6 Fig). The RR and pooled cumulative incidence of opportunistic infections from study initiation until primary outcome assessment, as well as during follow-up, for every JAKi under consideration, are presented in the S1 File.
The size of the square is representative of the weight assigned to the respective study for outcome analysis. The 95% CI for each study is represented by the horizontal lines. The diamond shape represents the pooled estimate of the analysis. Abbreviations: CI: confidence interval; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis; RR: relative risk.
3.3.6 Relative risk and pooled cumulative incidence of herpes zoster in patients with RA receiving JAKi compared with control subjects.
The RR of herpes zoster in patients with RA in the treatment group compared with control subjects was 1.50 (95% CI: 0.99–2.27, I2 = 0.00%), as shown in Fig 5. Information about the pooled cumulative incidence of herpes zoster in patients with RA treated with JAKi from study initiation up until primary outcome assessment is provided in Table 2 and S7 Fig. The pooled cumulative incidence of herpes zoster during follow-up in 6,835 patients with RA treated with JAKi, over a mean duration of 30.8 weeks, was 1.56% (95% CI: 0.59%-2.92%, I2 = 92.8%) (S8 Fig). The RR and pooled cumulative incidence of herpes zoster from study initiation until primary outcome assessment, as well as during follow-up, for every JAKi under consideration, are presented in the S1 File.
The size of the square is representative of the weight assigned to the respective study for outcome analysis. The 95% CI for each study is represented by the horizontal lines. The diamond shape represents the pooled estimate of the analysis. Abbreviations: CI: confidence interval; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis; RR: relative risk.
3.3.7 Relative risk and pooled cumulative incidence of pneumonia in patients with RA receiving JAKi compared with control subjects.
The RR of pneumonia in patients with RA in the treatment group compared with control subjects was 0.80 (95% CI: 0.47–1.37, I2 = 0.00%; Fig 6). Information about the pooled cumulative incidence of pneumonia in patients with RA treated with JAKi from study initiation up until primary outcome assessment is provided in Table 2 and S9 Fig. The pooled cumulative incidence of pneumonia during follow-up in 6,835 patients with RA treated with JAKi, over a mean duration of 30.8 weeks, was 0.49% (95% CI: 0.20%-0.89%, I2 = 69.1%) (S10 Fig). The RR and pooled cumulative incidence of pneumonia from study initiation until primary outcome assessment, as well as during follow-up, for every JAKi under consideration, are presented in the S1 File.
The size of the square is representative of the weight assigned to the respective study for outcome analysis. The 95% CI for each study is represented by the horizontal lines. The diamond shape represents the pooled estimate of the analysis. Abbreviations: CI: confidence interval; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis; RR: relative risk.
3.4 Results of meta-regression analysis
When assessing the risk of any-grade, severe, or opportunistic infections in patients with RA treated with JAKi, there was no statistically significant relationship between any type of infection and increasing age, female sex, or concurrent use of glucocorticoids and/or methotrexate (S4 Table).
3.5 Quality control of studies included in the analysis
Based on the RoB 2 tool, all included randomized controlled trials had a low risk of bias. Detailed assessment of the included studies’ quality metrics is detailed in S5 Table. There was no evidence of publication bias in our analysis (bias = 0.46, p = 0.4716).
4. Discussion
Treatment with JAKi has been shown to slow disease progression and provide symptom relief in patients with RA [56]. However, safety concerns, including a heightened risk of infection, have been reported [57]. In this systematic review and meta-analysis, we found that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19–1.52) and opportunistic (RR 2.69; 95% CI: 1.22–5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05–1.39), peficitinib (RR 1.40; 95% CI: 1.05–1.86) and upadacitinib (RR 1.30; 95% CI: 1.09–1.56) was associated with increased risk of any-grade infection only.
The JAK-STAT pathway is involved in antiviral and antibacterial host immune responses by modifying type I interferon and interferon-gamma responses as well as effector pathways of major inflammatory interleukins [58]. From our analysis, we found that there was a statistically significant difference in the risk of any-grade but not severe infection in patients with RA in the treatment group receiving baricitinib, filgotinib, peficitinib or upadacitinib, compared to the control group. Consistent with our findings, Bechman et al. [59] conducted a meta-analysis of 21 studies to evaluate the incidence of severe infections in patients with RA receiving tofacitinib, baricitinib, or upadacitinib and found that the incidence rate ratio of severe infections in patients receiving JAKi compared to placebo was statistically non-significant. Overall, the incidence rate ratio of severe infections in that study [59] was low (1.97–3.02 per 100 patient-years), which is in line with the cumulative incidence of severe infection in our study, which was approximately 2% during the follow-up period. Similarly, a long-term extension study assessing the safety of tofacitinib over 8.5 years pooled data from 19 clinical trials and reported an incidence rate of severe infections of 2.7 per 100 patient-years [60]. Other long-term extension studies have also reported low long-term severe infection incidence rates [61–63]. Notably, pharmacovigilance studies could provide additional real-world data regarding the infection risk profile of these agents, especially for newly licensed JAKi, such as upadacitinib and filgotinib, which are not extensively studied compared to older JAKi [57].
In our analysis, patients receiving the JAKi baricitinib were significantly more likely to develop opportunistic infections compared to patients in the control group. The increased risk of opportunistic infections in patients receiving JAKi has been attributed to down-modulation of cytokines responsible for mounting T-cell specific responses against pathogens [64], impaired granuloma formation necessary for containment of infections, such as tuberculosis [65], and diminished interferon-mediated antiviral responses that protect against viral infections [66]. The most common infections as a result of JAKi therapy reported in our analysis and other published studies, in addition to herpes zoster, include Candida spp., followed by infections from cytomegalovirus, Cryptococcus spp., Pneumocystis jirovecii, and tuberculosis [57, 67]. The pooled cumulative incidence of these opportunistic infections in our study was below 2%. Winthrop et al. [68] pooled the results of 12 clinical trials and two long-term extension studies including 5,671 patients treated with tofacitinib and reported 60 opportunistic infections, translating to an incidence rate of 0.46 per 100 patient-years. Other long-term extension studies have reported a low incidence of opportunistic infections as well [62, 69], reinforcing the favorable long-term infection risk profile of JAKi.
In our analysis, patients treated with any JAKi had a higher risk of herpes zoster compared to controls, but the difference in risk was not statistically significant, except for baricitinib. A previous meta-analysis conducted by Wang et al. [70] assessed the safety of JAKi and found that treatment with any JAKi increased herpes zoster risk, whereas a subgroup analysis according to specific JAKi revealed that only baricitinib was associated with a heightened herpes zoster risk. Failure to reveal a significantly increased risk of infection with JAKi other than baricitinib in our and previous studies might be due to confounding variables that are not accounted for, such as area of residence, race/ethnicity, prior history of herpes zoster and vaccination against herpes zoster. Of note, increasing age and concomitant glucocorticoid use, which have been associated with heightened herpes zoster risk [71], were included in our meta-regression analysis and did not affect the association between JAKi use and risk of herpes zoster. Also, during the follow-up period of the included studies, the pooled cumulative incidence of herpes zoster was 1.56%, while the cumulative incidence from study initiation until primary outcome assessment was 0.74%. Due to the lack of a true comparator group during follow-up, the failure to include herpes zoster cases that occurred during the follow-up period in our comparative risk analysis between intervention and control groups might account for the lack of significant findings. Nevertheless, since herpes zoster was the most frequent opportunistic infection in our analysis and has been clearly established as a complication of JAKi therapy, both in terms of pathophysiology [72] and based on previous study experiences [73], it is imperative for clinicians to remain vigilant for this complication.
Our study has certain limitations. First, there was noticeable cross-over of patients in the treatment and control groups after primary outcome assessment in each included study, so we were unable to estimate the long-term infection risk profile of JAKi. Next, due to insufficient data, we could not estimate whether concomitant medications, other than methotrexate and glucocorticoids, as well as prior use of biologic DMARDs or JAKi, could confound the association between current JAKi use and infection risk. Furthermore, the number of patients receiving antibiotic prophylaxis was not available in the included studies, and, as such, the impact of antibiotics on the risk and frequency of infections cannot be evaluated. Also, the diagnostic methods used to identify infections may have been different in the included studies, resulting in variability in the detection rate of infections, including opportunistic infections such as Pneumocystis jirovecii [74], Cryptococcus spp. [75] and tuberculosis [76]. Finally, information on race/ethnicity was available for the entire population entering each individual study, and no information was provided for participants who developed infections. As such, although geographic residence and race/ethnicity have been associated with varying risk of opportunistic infections, including herpes zoster [71], we could not estimate their impact on infection risk in our analysis.
In summary, patients with RA treated with baricitinib, filgotinib, peficitinib or upadacitinib were at increased risk of any-grade, but not severe, infection compared to patients in the control group. Risk of herpes zoster was increased in the intervention compared to the control group, but the difference in risk was not statistically significant, likely due to the lack of data on long-term follow-up. Well-designed prospective studies and registries should evaluate the effect of vaccination and prophylactic antibiotic regimens on the incidence and outcomes of infection in patients with RA receiving JAKi. Also, as our work focused on elucidating the infection risk profile of JAKi in patients with RA, we did not include information on other aspects of JAKi, including treatment efficacy and non-infection risk profile. In the future, research could focus on covering different aspects of this drug class, including treatment efficacy, safety profile beyond infections, and identification on immune markers that could predict treatment response.
Supporting information
S1 Fig. Pooled cumulative incidence of any-grade infection in patients with RA treated with JAKi, from study initiation until primary study outcome assessment, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of any-grade infection in patients treated with JAKi from study initiation until primary study outcome assessment, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s003
(TIF)
S2 Fig. Pooled cumulative incidence of any-grade infection in patients with RA treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of any-grade infection in patients treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s004
(TIF)
S3 Fig. Pooled cumulative incidence of severe infection in patients with RA treated with JAKi, from study initiation until primary study outcome assessment, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of severe infection in patients treated with JAKi from study initiation until primary study outcome assessment, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s005
(TIF)
S4 Fig. Pooled cumulative incidence of severe infection in patients with RA treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of severe infection in patients treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s006
(TIF)
S5 Fig. Pooled cumulative incidence of opportunistic infections in patients with RA treated with JAKi, from study initiation until primary study outcome assessment, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of opportunistic infections infection in patients treated with JAKi from study initiation until primary study outcome assessment, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s007
(TIF)
S6 Fig. Pooled cumulative incidence of opportunistic infections in patients with RA treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of opportunistic infections infection in patients treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s008
(TIF)
S7 Fig. Pooled cumulative incidence of herpes zoster in patients with RA treated with JAKi, from study initiation until primary study outcome assessment, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of herpes zoster in patients treated with JAKi from study initiation until primary study outcome assessment, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s009
(TIF)
S8 Fig. Pooled cumulative incidence of herpes zoster in patients with RA treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of herpes in patients treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s010
(TIF)
S9 Fig. Pooled cumulative incidence of pneumonia in patients with RA treated with JAKi, from study initiation until primary study outcome assessment, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of pneumonia in patients treated with JAKi from study initiation until primary study outcome assessment, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s011
(TIF)
S10 Fig. Pooled cumulative incidence of pneumonia in patients with RA treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, with 95% CI.
The red dotted line represents the overall pooled estimate of the cumulative incidence of pneumonia in patients treated with JAKi, during follow-up extending from the time of primary study outcome assessment until the end of the study, while the weight percentages correspond to the contribution of each study to the pooled estimate. Abbreviations: CI: confidence interval; ES: effect size; JAKi: Janus-activated kinase inhibitor; RA: rheumatoid arthritis.
https://doi.org/10.1371/journal.pone.0306548.s012
(TIF)
S1 Table. Characteristics of the randomized controlled trials included in the analysis.
https://doi.org/10.1371/journal.pone.0306548.s013
(PDF)
S2 Table. Number and type of infections in patients with RA treated with JAKi from study initiation until primary study outcome assessment compared to patients in the control group.
https://doi.org/10.1371/journal.pone.0306548.s014
(PDF)
S3 Table. Number and type of infections in patients with RA treated with JAKi during follow-up, extending from the time of primary study outcome assessment until the end of the study compared to patients in the control group.
https://doi.org/10.1371/journal.pone.0306548.s015
(PDF)
S4 Table. Random-effects meta-regression analysis for age, sex, current use of MTX and/or corticosteroids and risk of any-grade, severe, or opportunistic infection in patients with RA treated with JAKi compared to patients in the control group.
https://doi.org/10.1371/journal.pone.0306548.s016
(PDF)
S5 Table. Quality assessment of the included studies using the RoB 2 tool.
https://doi.org/10.1371/journal.pone.0306548.s017
(PDF)
References
- 1. Tanaka Y. Recent progress in treatments of rheumatoid arthritis: an overview of developments in biologics and small molecules, and remaining unmet needs. Rheumatology (Oxford). 2021;60: vi12–vi20. pmid:34951925
- 2. Smolen JS, Landewé RBM, Bergstra SA, Kerschbaumer A, Sepriano A, Aletaha D, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82: 3–18. https://doi.org/10.1136/ard-2022-223356 pmid:36357155
- 3. Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021;73: 1108–1123. pmid:34101376
- 4. Shams S, Martinez JM, Dawson JRD, Flores J, Gabriel M, Garcia G, et al. The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions. Front Pharmacol. 2021;12: 680043. pmid:34122106
- 5. Angelini J, Talotta R, Roncato R, Fornasier G, Barbiero G, Dal Cin L, et al. JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future. Biomolecules. 2020;10: 1002. pmid:32635659
- 6. Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford). 2013;52: 53–61. pmid:23192911
- 7. Olivera PA, Lasa JS, Bonovas S, Danese S, Peyrin-Biroulet L. Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis. Gastroenterology. 2020;158: 1554–1573.e12. pmid:31926171
- 8. Tanaka Y, Luo Y, O’Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol. 2022;18: 133–145. pmid:34987201
- 9. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372: n71 pmid:33782057
- 10. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31: 315–324. pmid:3358796
- 11. Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford). 2012;51: vi5–vi9. pmid:23221588
- 12. Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 2015;74: 2107–2116. pmid:26395500
- 13.
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf.
- 14. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366: l4898. pmid:31462531
- 15.
The Handbook of Research Synthesis and Meta-analysis. Available from: https://www.daneshnamehicsa.ir/userfiles/files/1/9-%20The%20Handbook%20of%20Research%20Synthesis%20and%20Meta-Analysis.pdf.
- 16. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7: 177–188. pmid:3802833
- 17. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health. 2014;72: 39. pmid:25810908
- 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21: 1539–1558. pmid:12111919
- 19. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295: 676–680. pmid:16467236
- 20. Harbord RM, Higgins JPT. Meta-Regression in Stata. The Stata Journal. 2008;8: 493–519. https://doi.org/10.1177/1536867X0800800403
- 21. Fleischmann R, Friedman A, Drescher E, Singhal A, Cortes-Maisonet G, Doan T, et al. Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial. Lancet Rheumatol. 2022;4: e395–e406. pmid:38293957
- 22. Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, Zhou Y, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391: 2503–2512. pmid:29908669
- 23. Kameda H, Takeuchi T, Yamaoka K, Oribe M, Kawano M, Zhou Y, et al. Efficacy and safety of upadacitinib in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE): a placebo-controlled phase IIb/III study. Rheumatology (Oxford). 2020;59: 3303–3313. pmid:32277824
- 24. Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol. 2016;68: 2867–2877. pmid:27389975
- 25. Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016;68: 2857–2866. pmid:27390150
- 26. Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018;391: 2513–2524. pmid:29908670
- 27. Zeng X, Zhao D, Radominski SC, Keiserman M, Lee CK, Meerwein S, et al. Upadacitinib in patients from China, Brazil, and South Korea with rheumatoid arthritis and an inadequate response to conventional therapy. Int J Rheum Dis. 2021;24: 1530–1539. pmid:34779576
- 28. Tanaka Y, Takeuchi T, Yamaoka K, Oribe M, Kawano M, Zhou Y, et al. SAT0257 A phase 2b/3 randomised, placebo-controlled, double-blind study of upadacitinib, a selective jak1 inhibitor, in japanese patients with active rheumatoid arthritis and inadequate response to conventional synthetic dmards. Ann Rheum Dis. 2018;77: 991–992
- 29. Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, Beattie S, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76: 88–95. pmid:27689735
- 30. Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, et al. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis Rheumatol. 2017;69: 506–517. pmid:27723271
- 31. Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74: 333–340. https://doi.org/10.1136/annrheumdis-2014-206478
- 32. Li Z, Hu J, Bao C, Li X, Li X, Xu J, et al. Baricitinib in patients with rheumatoid arthritis with inadequate response to methotrexate: results from a phase 3 study. Clin Exp Rheumatol. 2020;38: 732–741 pmid:32452344
- 33. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374: 1243–1252. pmid:27028914
- 34. Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017;376: 652–662. pmid:28199814
- 35. Tanaka Y, Emoto K, Cai Z, Aoki T, Schlichting D, Rooney T, et al. Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J Rheumatol. 2016;43: 504–511. https://doi.org/10.3899/jrheum.150613
- 36. Combe B, Kivitz A, Tanaka Y, van der Heijde D, Simon JA, Baraf HSB, et al. Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial. Ann Rheum Dis. 2021;80: 848–858. pmid:33504485
- 37. Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, Bartok B, Matzkies F, et al. Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial. JAMA. 2020;322: 315–325. https://doi.org/10.1001/jama.2019.9055
- 38. Westhovens R, Rigby WFC, van der Heijde D, Ching DWT, Stohl W, Kay J, et al. Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial. Ann Rheum Dis. 2021;80: 727–738. pmid:33452004
- 39. Westhovens R, Taylor PC, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis. 2017;76: 998–1008. pmid:27993829
- 40. Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis. 2017;76: 1009–1019. pmid:27993828
- 41. Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015;74: 1311–1316. pmid:25398374
- 42. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381: 451–460. pmid:23294500
- 43. van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65: 559–570. pmid:23348607
- 44. Kremer JM, Kivitz AJ, Simon-Campos JA, Nasonov EL, Tony HP, Lee SK, et al. Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. Arthritis Res Ther. 2015;17: 95. pmid:25889308
- 45. Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159: 253–261. pmid:24026258
- 46. Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60: 1895–1905. pmid:19565475
- 47. Strand V, Mysler E, Moots RJ, Wallenstein GV, DeMasi R, Gruben D, et al. Patient-reported outcomes for tofacitinib with and without methotrexate, or adalimumab with methotrexate, in rheumatoid arthritis: a phase IIIB/IV trial. RMD Open. 2019;5: e001040. pmid:31673419
- 48. Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH. Tofacitinib Study Investigators. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011;63: 1150–1158. https://doi.org/10.1002/acr.20494
- 49. Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015;25: 514–521. pmid:25496464
- 50. van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367: 508–519. pmid:22873531
- 51. Kivitz AJ, Gutierrez-Ureña SR, Poiley J, Genovese MC, Kristy R, Shay K, et al. Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2017;69: 709–719. pmid:27748083
- 52. Takeuchi T, Tanaka Y, Iwasaki M, Ishikura H, Saeki S, Kaneko Y. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016;75: 1057–1064. pmid:26672064
- 53. Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Iwasaki M, Katayama K, et al. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan. Ann Rheum Dis. 2019;78: 1305–1319. pmid:31350269
- 54. Tanaka Y, Takeuchi T, Tanaka S, Kawakami A, Iwasaki M, Song YW, et al. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3). Ann Rheum Dis. 2019;78: 1320–1332. pmid:31350270
- 55. Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, et al. Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease-Modifying Antirheumatic Drugs in the Treatment of Moderate-to-Severe Rheumatoid Arthritis. Arthritis Rheumatol. 2017;69: 932–942. pmid:28118538
- 56. Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79: 685–699. pmid:31969328
- 57. Adas MA, Alveyn E, Cook E, Dey M, Galloway JB, Bechman K. The infection risks of JAK inhibition. Expert Rev Clin Immunol. 2022;18: 253–261. pmid:34860621
- 58. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13: 234–243. pmid:28250461
- 59. Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, et al. A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford). 2019;58: 1755–1766. pmid:30982883
- 60. Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017;76: 1253–1262. https://doi.org/10.1136/annrheumdis-2016-210457
- 61. Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, et al. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open. 2020;6: e001395. pmid:33127856
- 62. Wollenhaupt J, Silverfield J, Lee EB, Curtis JR, Wood SP, Soma K, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41: 837–852. pmid:24692527
- 63. Taylor PC, Takeuchi T, Burmester GR, Durez P, Smolen JS, Deberdt W, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81: 335–343. pmid:34706874
- 64. Chen Y, Gong FY, Li ZJ, Gong Z, Zhou Z, Ma SY, et al. A study on the risk of fungal infection with tofacitinib (CP-690550), a novel oral agent for rheumatoid arthritis. Sci Rep. 2017;7: 6779. pmid:28754958
- 65. Kraaijvanger R, Ambarus CA, Damen J, van der Vis JJ, Kazemier KM, Grutters JC, et al. Simultaneous Assessment of mTORC1, JAK/STAT, and NLRP3 Inflammasome Activation Pathways in Patients with Sarcoidosis. Int J Mol Sci. 2023;24: 12792. pmid:37628972
- 66. Mahjoor M, Mahmoudvand G, Farokhi S, Shadab A, Kashfi M, Afkhami H. Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy. Cell Commun Signal. 2023;21: 272. pmid:37784164
- 67. Winthrop K, Isaacs J, Calabrese L, Mittal D, Desai S, Barry J, et al. Opportunistic infections associated with Janus kinase inhibitor treatment for rheumatoid arthritis: A structured literature review. Semin Arthritis Rheum. 2023;58: 152120. pmid:36347212
- 68. Winthrop KL, Park SH, Gul A, Cardiel MH, Gomez-Reino JJ, Tanaka Y, et al. Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75: 1133–1138. pmid:26318385
- 69. W Winthrop KL, Harigai M, Genovese MC, Lindsey S, Takeuchi T, Fleischmann R, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. 2020;79: 1290–1297. pmid:32788396
- 70. Wang F, Tang X, Zhu M, Mao H, Wan H, Luo F. Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis. J Clin Med. 2022;11: 4459. pmid:35956078
- 71. Winthrop KL, Nash P, Yamaoka K, Mysler E, Khan N, Camp HS, et al. Incidence and risk factors for herpes zoster in patients with rheumatoid arthritis receiving upadacitinib: a pooled analysis of six phase III clinical trials. Ann Rheum Dis. 2022;81: 206–213. pmid:34615638
- 72. Sunzini F, McInnes I, Siebert S. JAK inhibitors and infections risk: focus on herpes zoster. Ther Adv Musculoskelet Dis. 2020;12: 1759720X20936059. pmid:32655703
- 73. Xu Q, He L, Yin Y. Risk of herpes zoster associated with JAK inhibitors in immune-mediated inflammatory diseases: a systematic review and network meta-analysis. Front Pharmacol. 2023;14: 1241954. pmid:37614317
- 74. Liu B, Totten M, Nematollahi S, Datta K, Memon W, Marimuthu S, et al. Development and Evaluation of a Fully Automated Molecular Assay Targeting the Mitochondrial Small Subunit rRNA Gene for the Detection of Pneumocystis jirovecii in Bronchoalveolar Lavage Fluid Specimens. J Mol Diagn. 2020;22: 1482–1493. pmid:33069878
- 75. Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: What do we know now. Fungal Genet Biol. 2015;78: 49–54. pmid:25312862
- 76. Gill CM, Dolan L, Piggott LM, McLaughlin AM. New developments in tuberculosis diagnosis and treatment. Breathe (Sheff). 2022;18: 210149. pmid:35284018