Next Article in Journal
Multi-Layer Picture of Neurodegenerative Diseases: Lessons from the Use of Big Data through Artificial Intelligence
Next Article in Special Issue
S100A6, Calumenin and Cytohesin 2 as Biomarkers for Cutaneous Involvement in Systemic Sclerosis Patients: A Case Control Study
Previous Article in Journal / Special Issue
Sea-Buckthorn Seed Oil Induces Proliferation of both Normal and Dysplastic Keratinocytes in Basal Conditions and under UVA Irradiation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 11
Issue 4
10.3390/jpm11040279
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Application of Janus Kinase Inhibitors in Atopic Dermatitis: An Updated Systematic Review and Meta-Analysis of Clinical Trials

by
Hou-Ren Tsai
1,
Jing-Wun Lu
2,
Li-Yu Chen
3 and
Tai-Li Chen
1,4,*
1
Department of Medical Education, Medical Administration Office, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
2
Department of Physical Medicine and Rehabilitation, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
3
Library of Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
4
School of Medicine, Tzu Chi University, Hualien 970, Taiwan
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2021, 11(4), 279; https://doi.org/10.3390/jpm11040279
Submission received: 4 March 2021 / Revised: 1 April 2021 / Accepted: 4 April 2021 / Published: 7 April 2021
(This article belongs to the Special Issue Personalized Medicine in the Field of Inflammatory Skin Disorders)
Browse Figures
Versions Notes

Abstract

:
Janus kinase (JAK) inhibitors are promising treatments for atopic dermatitis (AD). The aim of this study was to assess the efficacy and safety of JAK inhibitors for AD treatment via the “Grading of Recommendations Assessment, Development, and Evaluation” approach. We identified 15 randomized controlled trials comparing oral or topical JAK inhibitors against placebo to treat AD. A random-effects meta-analysis was performed, and the numbers-needed-to-treat (NNTs)/numbers-needed-to-harm (NNHs) were calculated. Patients treated with JAK inhibitors were associated with higher rates of achieving eczema area and severity index-75 (rate ratio (RR): 2.84; 95% confidence interval (CI): 2.20–3.67; I2: 38.9%; NNT = 3.97), Investigator’s Global Assessment response (RR: 2.99; 95% CI: 2.26–3.95; I2: 0%; NNT = 5.72), and pruritus numerical rating scale response (RR: 2.52; 95% CI: 1.90–3.35; I2: 39.4%; NNT = 4.91) than those treated with placebo. Moreover, patients treated with JAK inhibitors had a higher risk of treatment-emergent adverse events (RR: 1.14; 95% CI: 1.02–1.28; I2: 52%; NNH = 14.80) but not adverse events leading to drug discontinuation. According to the evidence-based results, JAK inhibitors are potentially effective strategies (certainty of evidence: “moderate”) for treating AD with tolerable side effects (certainty of evidence: “low”). Nevertheless, long-term follow-up is required.

Graphical Abstract

1. Introduction

Atopic dermatitis (AD) is the most common inflammatory skin disease affecting approximately 20% of children and 10% of adults worldwide [1,2]. This chronic condition is characterized by intense pruritus and recurrent eczematous lesions and has a considerable negative impact on patients’ quality of life [3]. Moreover, AD patients may display different clinical patterns depending on their age, ethnicity, and underlying mechanisms [4]. There are three main types of AD patterns: the persistent form where AD appears in childhood and then persists into adulthood; the relapsing form, in which AD occurs in childhood and recurs in adulthood with a symptom-free interval; and the adult-onset AD, the most difficult type to detect, where the disease is firstly observed in adulthood [5]. Due to its various presentations, the diagnosis and treatment of AD remained a challenge for clinicians [6].
While topical interventions are the mainstay treatment of AD, systemic therapy is recommended for patients with inadequate treatment response [7,8,9]. Advances have been made in systemic AD therapy owing to an improved understanding of the molecular mechanism of AD [10]. Innovative treatment options are available, such as dupilumab (obstructing alpha subunit of the IL-4 receptors), crisaborole (blocking phosphodiesterase 4), and lebrikizumab (preventing IL-13Rα1/IL-4Rα heterodimerization) [11]. Of note, the upregulation of key cytokines (interleukin (IL)-4, IL-5, and IL-13) and subsequent activation of the Janus kinase/signal transducer and transcription (JAK/STAT) pathways play important roles in the complex mechanism of AD [12,13]. In a growing number of preclinical studies, the inhibition of intracellular JAK/STAT signal transmission has demonstrated therapeutic potential [14,15].
Since their first approval, JAK inhibitors have become a promising AD treatment option [16]. In randomized controlled trials (RCTs), several JAK inhibitors (oral/topical) have significantly improved the clinical outcomes of patients with inadequate responses to other therapies [17,18]. An integrated safety analysis indicated similar incidences of adverse events (AEs) between JAK inhibitor application and placebo [19]. An earlier meta-analysis showed that JAK inhibitors lowered the eczema area and severity index (EASI) and pruritus scores [20]. Nevertheless, the sample sizes of the enrolled studies were small, and no phase III RCTs were included [20]. Considering the rapid developments in this field of study, an updated literature review with a meta-analysis is warranted to improve statistical power and provide supporting evidence for current guidelines.
In the present study, we performed a systematic review and meta-analysis of RCTs to compile evidence on the application of JAK inhibitors in the management of AD. We also graded certainty of evidence (CoE) based on the “Grading of Recommendations Assessment, Development, and Evaluation” (GRADE) approach and calculated the numbers-needed-to-treat (NNTs) and numbers-needed-to-harm (NNHs) to facilitate decision-making in clinical practice.

2. Materials and Methods

This study was conducted in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (v. 6.2) [21] and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [22]. The methodology was prespecified and registered on the PROSPERO website (Registration No. CRD42020173098). Two reviewers (H.R. Tsai and J.W. Lu) independently searched for suitable records, extracted the data, and evaluated the quality of the included studies. In the event of any discrepancy, a third reviewer (T.L. Chen) provided consensus or contributed to the discussions.

2.1. Data Sources and Literature Search

Relevant publications indexed in electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) between database inception and 1 February 2021 were searched. The keywords “atopic dermatitis” and “Janus kinase inhibitor” and their synonyms and derivatives were used for the search. Details of the search strategies are described in Table S1 in the Supplementary Materials. No language restriction was applied. To identify unpublished or ongoing trials, the trial registries of the US National Institutes of Health (https://clinicaltrials.gov/ accessed on 2 February 2021), International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/ accessed on 2 February 2021), and European Union Drug Regulating Authorities Clinical Trials Database (https://eudract.ema.europa.eu/ accessed on 3 February 2021) were searched. The bibliographies of available review articles and meta-analyses were also examined to find additional candidate studies. The literature search was performed with the assistance of a librarian (L.Y. Chen) at Hualien Tzu Chi Hospital.

2.2. Study Selection and Eligibility

Only RCTs were enrolled to avoid potential selection and confounding bias [21,23]. Studies comparing oral/topical JAK inhibitors against placebo were included with no defined limitations on age, sex, ethnicity, AD severity, or treatment duration of participants. Case reports, letters, editorials, review articles, conference abstracts, and in vivo studies involving animals were excluded.

2.3. Data Extraction and Efficacy and Safety Outcomes

The extracted data comprised study information (first author, publication year, clinical trial identifier, study design, and study period), patient characteristics (sample size, age, definition criteria, and AD severity), details of the various JAK inhibitors and placebos used (administration route, dosage, frequency, mode of action, and endpoint), and outcomes (efficacy and safety). Potential conflicts of interest were also listed.
The efficacy outcomes included (1) a ≥ 75% decrease in EASI from baseline (EASI-75 response), (2) an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with a ≥ 2-point reduction from baseline (IGA response), and (3) a ≥ 4-point decrease from baseline in pruritus numerical rating scale response (pruritus-NRS response). The safety outcomes included the development of treatment-emergent AEs (TEAEs) and AEs that lead to drug discontinuation.

2.4. Risk of Bias Assessment

The methodological quality of the RCTs was appraised using the Cochrane Risk of Bias Tool (RoB v. 2.0, The Cochrane Collaboration) [24].

2.5. Data Synthesis and Statistical Analyses

Pooled estimates and their confidence intervals (CIs) were obtained with a random-effects meta-analysis model (DerSimonian–Laird estimator) [21] based on the assumption of substantial clinical heterogeneity. Rate ratios or relative risks (RRs) and 95% CIs were used to evaluate the efficacy and safety outcomes. If the desired effect estimates were inadequate for data synthesis, the corresponding authors were contacted to obtain relevant information. Statistical significance was indicated by p < 0.05 and a CI not containing 1. All statistical analyses were conducted using Stata v.16 (StataCorp, College Station, TX, USA).
A pairwise meta-analysis comparing the effect of JAK inhibitors against placebos was conducted. However, when a multiple-arm RCT was enrolled, a unit-of-analysis error may arise if the same group of participants is included twice in the same meta-analysis (for example, if “dose 1 vs. placebo” and “dose 2 vs. placebo” are both included in the same analysis, with the same placebo patients in both comparisons) [25]. Therefore, when an enrolled RCT included more than two arms, the reported results were combined to create a single pairwise comparison against placebos [21]. This method had been utilized in previous studies [26,27].
Between-study heterogeneity was quantified using Cochran’s Q and I2 statistics [28]. p < 0.01 and I2 ≥ 50% indicated substantial heterogeneity. To identify the potential sources of heterogeneity, several subgroup analyses were conducted according to the administration route, AD severity, participant age, mode of action, and different JAK inhibitors at different time points. Meta-regression analyses were also performed to explore potential effect modifiers, which refer to the explanatory variables of the overall effect estimates that may contribute to the heterogeneity [21]. Visual inspection of the funnel plot and Egger’s regression test were used to assess publication bias [21].
Concerning the possibility of producing false-positive results when using the DerSimonian–Laird method, we applied the Hartung–Knapp–Sidik–Jonkman (HKSJ) method for sensitivity analyses [29]. This method widens the CIs to reflect uncertainty in estimating between-study heterogeneity, especially when the study number is less than 20 [21,30]. The HKSJ method had been widely used in previous meta-analyses [31,32,33].
The GRADE approach was adopted to summarize the CoE at the outcome level [34] and judged by all authors. In the event of disagreement, discussions were undertaken to arrive at a consensus for each outcome. CoE, classified as high, moderate, low, or very low, refers to the confidence that the true effect lies in a particular range [34]. The CoE was downgraded by one level if a serious flaw was present in the domains of risk of bias, inconsistency, indirectness, imprecision, and publication bias [34]. The NNT and NNH were calculated to evaluate the evidence-based efficacy and safety of JAK inhibitors in the management of AD [34].

3. Results

3.1. Search Results

A PRISMA flowchart of the process of study selection is shown in Figure S1. Initially, a total of 1237 records were retrieved. After screening the titles, abstracts, and full texts, 14 original articles involving 15 RCTs were eligible for a quantitative meta-analysis. These comprised seven phase III trials [19,35,36,37,38,39], seven phase II trials [40,41,42,43,44,45,46], and one phase I trial [47].

3.2. Characteristics of Eligible Studies

The demographic data and relevant outcomes are summarized in Table 1. We included 4367 patients with AD in this meta-analysis and assessed seven different JAK inhibitors. Four of them (abrocitinib, baricitinib, gusacitinib, and upadacitinib) were orally administered, while the remaining three (delgocitinib, ruxolitinib, and tofacitinib) were topically administered. All eligible studies had participants with a documented history of inadequate treatment response to topical corticosteroids/calcineurin inhibitors. Guttman-Yassky et al. also recruited participants with a documented history of inadequate treatment response to systemic corticosteroids or immunosuppressants [42]. Most eligible studies did not report participants with failure of systemic treatment but a washout period for systemic steroid, immunosuppressive, and biologic treatments.
Most of the enrolled trials involved adult patients with moderate to severe AD. Three studies involved children or adolescents, while another three included patients with mild to moderate AD. All enrolled studies had declared their conflict of interest with an institution or a company.

3.3. Risk of Bias Assessment

We used the Risk-of-Bias VISualization tool to create “traffic light” plots of domain-level judgments [48]. Most of the enrolled RCTs were judged to have a “low” risk of bias (Figure S2).

3.4. Efficacy Outcomes

3.4.1. EASI-75 Response

Twelve studies (involving 3498 patients) reported EASI-75 response as the indicator of efficacy outcome. A random-effects meta-analysis showed that patients treated with JAK inhibitors (both oral and topical) were associated with higher rates of achieving EASI-75 response (RR = 2.84; 95% CI = 2.20–3.67) than those treated with placebo (Figure 1); no significant heterogeneity was observed (I2 = 38.9%; P = 0.08).

3.4.2. IGA Response

Eleven studies (involving 2417 patients) reported IGA responses. Figure 2 shows that patients treated with JAK inhibitors (both oral and topical) were associated with higher rates of achieving IGA responses (RR = 2.99; 95% CI = 2.26–3.95) than those treated with placebo; no significant heterogeneity was observed (I2 = 0%; P = 0.60).

3.4.3. Pruritus-NRS Response

Eight studies (involving 3036 patients) reported pruritus-NRS responses. The meta-analysis revealed that patients treated with JAK inhibitors were associated with higher rates of achieving pruritus-NRS responses (RR = 2.52; 95% CI = 1.90–3.35) compared with those treated with placebo (Figure 3). No significant heterogeneity was observed (I2 = 39.4%; P = 0.12).

3.4.4. Subgroup Analyses and Meta-Regression of Efficacy Outcomes

The subgroup analyses indicated that JAK inhibitors improved AD. From the meta-regression analyses, we identified age as a potential effect modifier of EASI-75 responses. Studies involving children and adolescents showed a higher RR of achieving an EASI-75 response than those exclusively involving adults (Table S2). According to the subgroup analyses of different JAK inhibitors at different time points, gusacitinib was unlikely to achieve EASI-75 and IGA responses (Table S3).

3.5. Safety Outcomes

3.5.1. TEAEs

Twelve studies (involving 3402 patients) were included in the analysis of TEAEs. AD patients treated with JAK inhibitors had relatively higher risks of developing TEAEs (RR = 1.14; 95% CI = 1.02–1.28) than those treated with placebo (Table 2). Most TEAEs were tolerable; nasopharyngitis was the most reported event (Table 3), followed by upper respiratory tract infection, headache, nausea, diarrhea, elevated blood creatine phosphokinase levels, and acne. Herpesvirus infection was reported in patients treated with abrocitinib or baricitinib. However, substantial heterogeneity was observed among studies (I2 = 52%; P = 0.023). Table 2 shows several potential effect modifiers accounting for the considerable heterogeneity among the TEAEs, including administration route, AD severity, and treatment duration. Patients who were administered oral JAK inhibitors experienced moderate to severe AD at baseline. Those treated with JAK inhibitors for >12 weeks were more likely to develop TEAEs.

3.5.2. AEs Leading to Drug Discontinuation

Fourteen studies (involving 3926 patients) were included in the analysis of AEs that led to drug discontinuation. Table 2 shows that patients who were administered with JAK inhibitors were unlikely to have higher risks of developing AEs (RR = 0.89; 95% CI = 0.57–1.38) than those treated with placebo. No significant heterogeneity was detected (I2 = 0%; P = 0.62).

3.5.3. Sensitivity Analyses

As shown in Table S4, a sensitivity analysis of the overall effects on each outcome before and after the application of modified HKSJ adjustment yielded similar results, demonstrating the robustness of the findings.

3.6. Publication Bias

No publication bias was detected after the visual inspection of the funnel plot or Egger’s regression test except for the pruritus-NRS response outcome (Figure S3).

3.7. GRADE Approach for CoE

We presented the CoE using a modified GRADE evidence profile (Table 4) on the GRADEpro website (https://gdt.gradepro.org/ accessed on 23 February 2021). The GRADE guidelines [49] indicated that publication bias levels were downgraded for studies that identified conflicts of interest. The overall CoE of the efficacy outcomes was deemed “moderate.” Owing to the “high” bias risk of BREEZE-AD4 2020, the overall CoE of the safety outcomes was considered “low.” The NNTs for patients achieving IGA, EASI-75, and pruritus-NRS response were 3.97, 5.72, and 4.91, respectively. The NNH for patients experiencing TEAEs was 14.80.

4. Discussion

Our study provides evidence that JAK inhibitors are more effective in achieving EASI-75, IGA, and pruritus-NRS responses than placebo in patients with AD. AD patients treated with JAK inhibitors had relatively higher risks of developing TEAEs, but no higher risks were observed regarding AEs leading to drug discontinuation. From the viewpoint of evidence-based medicine based on the GRADE approach, the overall CoE of the efficacy outcomes was “moderate,” while that of the safety outcomes was considered “low”.
A previous meta-analysis of five RCTs demonstrated that JAK inhibitors lowered EASI and pruritus scores [20], which is consistent with the findings of this study. However, in contrast to the former study with a small sample size that represented only four countries, we included 15 multi-center RCTs in more than 10 countries and performed subgroup analyses and meta-regressions to identify potential effect modifiers of the efficacy and safety outcomes. Additionally, sensitivity analyses confirmed the robustness of our results. We also applied a GRADE assessment and furnished the NNT and NNH results to facilitate evidence-based decisions in the treatment of AD in clinical practice. Hence, our updated meta-analysis is robust and provides more evidence than a previously published meta-analysis [20].
Given that different kinds of JAK inhibitors seemed to have different effects in AD patients, there were no head-to-head comparisons between JAK inhibitors. According to our subgroup analyses of different JAK inhibitors at different time points, gusacitinib was unlikely to achieve EASI-75 and IGA responses. In the original article, gusacitinib showed benefits in achieving EASI-50 but not EASI-75 [47]. This may also be subject to the lack of statistical power due to an insufficient number of participants. Additionally, topical delgocitinib had higher rates of achieving EASI-75 response than placebo but not IGA response. Other topical agents such as tofacitinib or ruxolitinib demonstrated better response than placebos regarding IGA and pruritus-NRS responses. As seen in Table 3, ruxolitinib and delgocitinib seemed to have fewer TEAEs than other JAK inhibitors. This discovery is important to clinicians because these topical agents may serve as better options than oral forms for their effectiveness and fewer side effects.
We selected EASI as an efficacy outcome because it is adequately validated and recommended for the evaluation of the clinical signs of AD in RCTs [50,51]. However, an EASI assessment is not always feasible in routine practice as it is complex and time-consuming [50,51]. IGA is a rapid and easily interpreted alternative to EASI, and it should be included in the measurement outcomes for clinical trial approval under US drug regulations [52]. Despite the lack of standardization and validation, our meta-analysis of the IGA responses indicated less heterogeneity. Moreover, because EASI and IGA were evaluated by medical professionals, a patient-oriented scale is also critical for the assessment of drug efficacy. Consequently, considering chronic and intense pruritus is the major symptom observed in AD patients, we analyzed the previously validated pruritus-NRS as an efficacy outcome [53].
We performed several subgroup analyses and observed that children and adolescents had a higher RR of attaining an EASI-75 response. Only one RCT exclusively assessed pediatric patients. Therefore, no conclusions could be drawn regarding the efficacy of JAK inhibitors in this population.
The administration of JAK inhibitors was associated with an elevated risk of TEAEs. Nevertheless, most TEAEs were mild and tolerable. Nasopharyngitis, headache, and upper respiratory tract infection were the most common TEAEs observed in the enrolled RCTs, consistent with the findings of other systemic immunomodulators in AD management [54,55]. Recently, the warning black box issued by the Food and Drug Administration (FDA) reported an increased risk of serious cardiovascular problems with an oral form of tofacitinib, a JAK inhibitor in treating rheumatoid arthritis (RA) and ulcerative colitis [56]. Among the management of RA patients, JAK inhibitors (baricitinib, filgotinib, and tofacitinib) have also received warnings from the FDA about the increased risk of thromboembolic events and the higher rates of all-cause mortality. Even though the pharmacological features of the topical tofacitinib in AD may differ from that of oral usage in the above circumstances, these safety issues should not be ignored.
Recent studies have reported that AD exhibits complex dysregulations and multiple clinical phenotypes [57,58,59]. By contrast, between-study heterogeneity with seven distinct JAK inhibitors was observed to be unremarkable in most analyses. We hypothesized that the intracellular blockade by JAK inhibitors results in relatively less interference with the extracellular environment [60,61] and is indicated by the marked homogeneity among various types of JAK inhibitors in clinical settings. Furthermore, we identified administration route, severity, and treatment duration as potential effect modifiers for TEAE outcomes (Table 2). Systemic drug absorption via oral administration, severe inflammatory reactions in patients with moderate to severe AD, and longer treatment durations over 12 weeks could explain the results we obtained from the meta-regression analyses.
NNT/NNH is the average number of patients undergoing treatment with a particular therapy to achieve one additional positive/negative outcome compared with the placebo [62]. NNT < 10 and NNH ≥ 10 indicate “clinically desirable” benefit or harm of a particular therapeutic intervention [63]. In this study, the NNT was <10 for all efficacy outcomes, representing desirable effects compared with placebos. Despite the NNH for TEAEs being 14.80, the AEs were relatively innocuous. We believe that our findings could be helpful for clinical dermatologists in treating patients with AD.
A key strength of our study is the updated literature review and meta-analysis via an evidence-based approach. We provide CoE based on the GRADE system and calculate the NNTs/NNHs, which could guide clinicians in decision-making for AD treatment. However, the findings of this study must be considered with certain limitations in mind. First, we only compared the effects of JAK inhibitors against placebos. Comparisons of different types of JAK inhibitors were not performed in this study. Accordingly, we assume rigorous head-to-head RCTs to be beneficial in the comparison of the efficacy and safety outcomes of various JAK inhibitors. Second, we could not draw a firm conclusion concerning the efficacy of JAK inhibitors for the treatment of pediatric patients with AD because only one RCT that assessed patients aged less than 18 years was enrolled in this study. Given that pediatric AD is common, additional trials to clarify the effectiveness and safe dosage of JAK inhibitors in children and adolescents with AD are required. Third, it has only been five years since JAK inhibitors were approved for the treatment of AD; consequently, only a few RCTs with long-term follow-ups are available at present. Because we could only elucidate the short-term effects of JAK inhibitors, the results of this meta-analysis do not guarantee the long-term safety of JAK inhibitors. Hence, the evidence-based results presented herein must be interpreted with caution.

5. Conclusions

This systematic review and meta-analysis provide updated evidence for current AD guidelines. The findings demonstrate that JAK inhibitors have favorable efficacy (overall CoE: “moderate”) in the treatment of AD with tolerable safety issues (overall CoE: “low”). However, planned prospective studies involving long-term follow-up of AEs and cost-effective analyses could aid clinical decisions in the application of JAK inhibitors for the treatment of AD.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/jpm11040279/s1, Figure S1: Flowchart of the Material and Methods: PRISMA flow diagram of the study. RCT, randomized controlled trial, Figure S2: Summary of Risk of Bias Assessment, Figure S3: Funnel Plot of Pruritus-NRS Response. Table S1: Search strategies modified in MEDLINE (a), Embase (b), Cochrane CENTRAL (c), and Web of Science (d), Table S2: Subgroup analyses and meta-regressions of efficacy outcomes, Table S3: Subgroup analyses of efficacy outcomes for various Janus kinase inhibitors at different time points, Table S4: Sensitivity analysis of overall effects of each outcome before and after modified Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment.

Author Contributions

H.-R.T., J.-W.L., L.-Y.C., and T.-L.C. had access to all the study data and take responsibility for the integrity of the data and the accuracy of data analysis. T.-L.C. conceptualized, designed, and supervised the study. H.-R.T., J.-W.L., and T.-L.C. performed data acquisition, analysis, or interpretation. All the authors contributed in drafting the manuscript and provided administrative, technical, or material support. T.-L.C. performed critical revision of the manuscript for important intellectual content. H.-R.T., J.-W.L., and T.-L.C. performed the statistical analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval were waived for this study because the data were retrieved from published clinical trials in the public databases.

Informed Consent Statement

Patient consent was waived due to because the data were retrieved from published clinical trials, in which informed consent was obtained by the primary investigators.

Data Availability Statement

The data in this study were collated from published clinical trials, which could be accessed by the public.

Acknowledgments

We thank Ching-Ju Fang (Medical Library, National Cheng Kung University, Tainan, Taiwan) for her assistance and helpful comments that substantially improved the quality of our literature search. We also thank the Department of Medical Research of Hualien Tzu Chi Hospital and the Buddhist Tzu Chi Medical Foundation for their invaluable contributions to the methodology used in this systematic review and meta-analysis.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Silverberg, J.I.; Hanifin, J.M. Adult eczema prevalence and associations with asthma and other health and demographic factors: A US population-based study. J. Allergy Clin. Immunol. 2013, 132, 1132–1138. [Google Scholar] [CrossRef]
  2. Bylund, S.; von Kobyletzki, L.B.; Svalstedt, M.; Svensson, Å. Prevalence and incidence of atopic dermatitis: A systematic review. Acta Derm. Venereol. 2020, 100, adv00160. [Google Scholar] [CrossRef] [PubMed]
  3. Langan, S.M.; Irvine, A.D.; Weidinger, S. Atopic dermatitis. Lancet 2020, 396, 345–360. [Google Scholar] [CrossRef]
  4. Kaufman, B.P.; Guttman-Yassky, E.; Alexis, A.F. Atopic dermatitis in diverse racial and ethnic groups-Variations in epidemiology, genetics, clinical presentation and treatment. Exp. Dermatol. 2018, 27, 340–357. [Google Scholar] [CrossRef] [Green Version]
  5. Nettis, E.; Ortoncelli, M.; Pellacani, G.; Foti, C.; Di Leo, E.; Patruno, C.; Rongioletti, F.; Argenziano, G.; Ferrucci, S.M.; Macchia, L.; et al. A multicenter study on the prevalence of clinical patterns and clinical phenotypes in adult atopic dermatitis. J. Investig. Allergol. Clin. Immunol. 2020, 30, 448–450. [Google Scholar] [CrossRef] [PubMed]
  6. Laughter, M.R.; Maymone, M.B.; Mashayekhi, S.; Arents, B.W.; Karimkhani, C.; Langan, S.M.; Dellavalle, R.P.; Flohr, C. The global burden of atopic dermatitis: Lessons from the global burden of disease study 1990–2017. Br. J. Dermatol. 2021, 184, 304–309. [Google Scholar] [CrossRef] [PubMed]
  7. Eichenfield, L.F.; Tom, W.L.; Berger, T.G.; Krol, A.; Paller, A.S.; Schwarzenberger, K.; Bergman, J.N.; Chamlin, S.L.; Cohen, D.E.; Cooper, K.D.; et al. Guidelines of care for the management of atopic dermatitis, Section 2: Management and treatment of atopic dermatitis with topical therapies. J. Am. Acad. Dermatol. 2014, 71, 116–132. [Google Scholar] [CrossRef] [Green Version]
  8. Ring, J.; Alomar, A.; Bieber, T.; Deleuran, M.; Fink-Wagner, A.; Gelmetti, C.; Gieler, U.; Lipozencic, J.; Luger, T.; Oranje, A.P.; et al. Guidelines for treatment of atopic eczema (atopic dermatitis) part I. J. Eur. Acad. Dermatol. Venereol. 2012, 26, 1045–1060. [Google Scholar] [CrossRef] [PubMed]
  9. Katayama, I.; Aihara, M.; Ohya, Y.; Saeki, H.; Shimojo, N.; Shoji, S.; Taniguchi, M.; Yamada, H. Japanese guidelines for atopic dermatitis 2017. Allergol. Int. 2017, 66, 230–247. [Google Scholar] [CrossRef]
  10. Worm, M.; Francuzik, W.; Kraft, M.; Alexiou, A. Modern therapies in atopic dermatitis: Biologics and small molecule drugs. J. Dtsch. Dermatol. Ges. 2020, 18, 1085–1092. [Google Scholar] [CrossRef]
  11. Dattola, A.; Bennardo, L.; Silvestri, M.; Nisticò, S.P. What′s new in the treatment of atopic dermatitis? Dermatol. Ther. 2019, 32, e12787. [Google Scholar] [CrossRef] [PubMed]
  12. Yasuda, T.; Fukada, T.; Nishida, K.; Nakayama, M.; Matsuda, M.; Miura, I.; Dainichi, T.; Fukuda, S.; Kabashima, K.; Nakaoka, S.; et al. Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis. J. Clin. Invest. 2016, 126, 2064–2076. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Amano, W.; Nakajima, S.; Kunugi, H.; Numata, Y.; Kitoh, A.; Egawa, G.; Dainichi, T.; Honda, T.; Otsuka, A.; Kimoto, Y.; et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J. Allergy Clin. Immunol. 2015, 136, 667–677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Fridman, J.S.; Scherle, P.A.; Collins, R.; Burn, T.; Neilan, C.L.; Hertel, D.; Contel, N.; Haley, P.; Thomas, B.; Shi, J.; et al. Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J. Invest. Dermatol. 2011, 131, 1838–1844. [Google Scholar] [CrossRef] [Green Version]
  15. Jin, W.; Huang, W.; Chen, L.; Jin, M.; Wang, Q.; Gao, Z.; Jin, Z. Topical application of JAK1/JAK2 inhibitor momelotinib exhibits significant anti-inflammatory responses in DNCB-induced atopic dermatitis model mice. Int. J. Mol. Sci. 2018, 19, 3973. [Google Scholar] [CrossRef] [Green Version]
  16. Schwartz, D.M.; Kanno, Y.; Villarino, A.; Ward, M.; Gadina, M.; O’Shea, J.J. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017, 17, 78. [Google Scholar] [CrossRef] [Green Version]
  17. Honstein, T.; Werfel, T. The show must go on: An update on clinical experiences and clinical studies on novel pharmaceutical developments for the treatment of atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 2020, 20, 386–394. [Google Scholar] [CrossRef]
  18. Gadina, M.; Le, M.T.; Schwartz, D.M.; Silvennoinen, O.; Nakayamada, S.; Yamaoka, K.; O’Shea, J.J. Janus kinases to jakinibs: From basic insights to clinical practice. Rheumatology 2019, 58, i4–i16. [Google Scholar] [CrossRef]
  19. Bieber, T.; Thyssen, J.P.; Reich, K.; Simpson, E.L.; Katoh, N.; Torrelo, A.; De Bruin-Weller, M.; Thaci, D.; Bissonnette, R.; Gooderham, M.; et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J. Eur. Acad. Dermatol. Venereol. 2020, 35, 476–485. [Google Scholar] [CrossRef]
  20. Arora, C.J.; Khattak, F.A.; Yousafzai, M.T.; Ibitoye, B.M.; Shumack, S. The effectiveness of Janus kinase inhibitors in treating atopic dermatitis: A systematic review and meta-analysis. Dermatol. Ther. 2020, 33, e13685. [Google Scholar] [CrossRef]
  21. Higgins, J.P.T.; Thomas, J.; Chandler, J.; Cumpston, M.; Li, T.; Page, M.J.; Welch, V.A. Cochrane Handbook for Systematic Reviews of Interventions Version 6.2. Available online: www.training.cochrane.org/handbook (accessed on 25 January 2021).
  22. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; the PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann. Intern. Med. 2009, 151, 264–269. [Google Scholar] [CrossRef] [Green Version]
  23. Sarri, G.; Patorno, E.; Yuan, H.; Guo, J.J.; Bennett, D.; Wen, X.; Zullo, A.R.; Largent, J.; Panaccio, M.; Gokhale, M.; et al. Framework for the synthesis of non-randomised studies and randomised controlled trials: A guidance on conducting a systematic review and meta-analysis for healthcare decision making. BMJ Evid. Based Med. 2020, 9. [Google Scholar] [CrossRef]
  24. Sterne, J.A.; Savović, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.Y.; Corbett, M.S.; Eldridge, S.M.; et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019, 366, l4898. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Page, M.J.; McKenzie, J.E.; Chau, M.; Green, S.E.; Forbes, A. Methods to select results to include in meta-analyses deserve more consideration in systematic reviews. J. Clin. Epidemiol. 2015, 68, 1282–1291. [Google Scholar] [CrossRef] [PubMed]
  26. Cadham, C.J.; Jayasekera, J.C.; Advani, S.M.; Fallon, S.J.; Stephens, J.L.; Braithwaite, D.; Jeon, J.; Cao, P.; Levy, D.T.; Meza, R.; et al. Smoking cessation interventions for potential use in the lung cancer screening setting: A systematic review and meta-analysis. Lung Cancer 2019, 135, 205–216. [Google Scholar] [CrossRef]
  27. Ueta, T.; Noda, Y.; Toyama, T.; Yamaguchi, T.; Amano, S. Systemic vascular safety of ranibizumab for age-related macular degeneration: Systematic review and meta-analysis of randomized trials. Ophthalmology 2014, 121, 2193–2203. [Google Scholar] [CrossRef]
  28. Higgins, J.P.; Thompson, S.G.; Deeks, J.J.; Altman, D.G. Measuring inconsistency in meta-analyses. BMJ 2003, 327, 557–560. [Google Scholar] [CrossRef] [Green Version]
  29. IntHout, J.; Ioannidis, J.P.; Borm, G.F. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med. Res. Methodol. 2014, 18, 25. [Google Scholar] [CrossRef] [Green Version]
  30. Hartung, J.; Knapp, G. On tests of the overall treatment effect in meta-analysis with normally distributed responses. Stat. Med. 2001, 20, 1771–1782. [Google Scholar] [CrossRef]
  31. Saueressig, T.; Owen, P.J.; Zebisch, J.; Herbst, M.; Belavy, D.L. Evaluation of exercise interventions and outcomes after hip arthroplasty: A systematic review and meta-analysis. JAMA Netw. Open 2021, 4, e210254. [Google Scholar] [CrossRef]
  32. Mc Cord, K.A.; Ewald, H.; Agarwal, A.; Glinz, D.; Aghlmandi, S.; Ioannidis, J.P.; Hemkens, L.G. Treatment effects in randomised trials using routinely collected data for outcome assessment versus traditional trials: Meta-research study. BMJ 2021, 372, n450. [Google Scholar] [CrossRef]
  33. Janiaud, P.; Axfors, C.; Schmitt, A.M.; Gloy, V.; Ebrahimi, F.; Hepprich, M.; Smith, E.R.; Haber, N.A.; Khanna, N.; Moher, D.; et al. Association of convalescent plasma treatment with clinical outcomes in patients with COVID-19: A systematic review and meta-analysis. JAMA 2021, 325, 1185–1195. [Google Scholar] [CrossRef]
  34. Guyatt, G.H.; Oxman, A.D.; Vist, G.E.; Kunz, R.; Falck-Ytter, Y.; Alonso-Coello, P.; Schünemann, H.J. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008, 336, 924–926. [Google Scholar] [CrossRef] [Green Version]
  35. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Kaino, H.; Nagata, T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J. Am. Acad. Dermatol. 2020, 82, 823–831. [Google Scholar] [CrossRef] [Green Version]
  36. Reich, K.; Kabashima, K.; Peris, K.; Silverberg, J.I.; Eichenfield, L.F.; Bieber, T.; Kaszuba, A.; Kolodsick, J.; Yang, F.E.; Gamalo, M.; et al. Efficacy and safety of baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2020, 156, 1333–1343. [Google Scholar] [CrossRef]
  37. Silverberg, J.I.; Simpson, E.L.; Thyssen, J.P.; Gooderham, M.; Chan, G.; Feeney, C.; Biswas, P.; Valdez, H.; DiBonaventura, M.; Nduaka, C.; et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2020, 156, 863–873. [Google Scholar] [CrossRef] [PubMed]
  38. Simpson, E.L.; Lacour, J.P.; Spelman, L.; Galimberti, R.; Eichenfield, L.; Bissonnette, R.; King, B.; Thyssen, J.; Silverberg, J.; Bieber, T.; et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: Results from two randomized monotherapy phase III trials. Br. J. Dermatol. 2020, 183, 242–255. [Google Scholar] [CrossRef] [PubMed]
  39. Simpson, E.L.; Sinclair, R.; Forman, S.; Wollenberg, A.; Aschoff, R.; Cork, M.; Bieber, T.; Thyssen, J.P.; Yosipovitch, G.; Flohr, C.; et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 2020, 396, 255–266. [Google Scholar] [CrossRef]
  40. Bissonnette, R.; Papp, K.A.; Poulin, Y.; Gooderham, M.; Gooderham, M.; Raman, M.; Mallbris, L.; Wang, C.; Purohit, V.; Mamolo, C.; et al. Topical tofacitinib for atopic dermatitis: A phase IIa randomized trial. Br. J. Dermatol. 2016, 175, 902–911. [Google Scholar] [CrossRef] [PubMed]
  41. Gooderham, M.J.; Forman, S.B.; Bissonnette, R.; Beebe, J.S.; Zhang, W.; Banfield, C.; Zhu, L.; Papacharalambous, J.; Vincent, M.S.; Peeva, E. Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: A phase 2 randomized clinical trial. JAMA Dermatol. 2019, 155, 1371–1379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Guttman-Yassky, E.; Silverberg, J.I.; Nemoto, O.; Forman, S.B.; Wilke, A.; Prescilla, R.; de la Peña, A.; Nunes, F.P.; Janes, J.; Gamalo, M.; et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J. Am. Acad. Dermatol. 2019, 80, 913–921.e9. [Google Scholar] [CrossRef]
  43. Guttman-Yassky, E.; Thaçi, D.; Pangan, A.L.; Hong, H.C.; Papp, K.A.; Reich, K.; Beck, L.A.; Mohamed, M.F.; Othman, A.A.; Anderson, J.K.; et al. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 2020, 145, 877–884. [Google Scholar] [CrossRef] [Green Version]
  44. Kim, B.S.; Howell, M.D.; Sun, K.; Papp, K.; Papp, K.; Nasir, A.; Kuligowski, M.E.; INCB 18424-206 Study Investigators. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J. Allergy Clin. Immunol. 2020, 145, 572–582. [Google Scholar] [CrossRef] [Green Version]
  45. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Nagata, T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: A phase II, multicentre, randomized, vehicle-controlled clinical study. Br. J. Dermatol. 2018, 178, 424–432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Oda, M.; Kabashima, K.; Nagata, T. Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis. J. Allergy Clin. Immunol 2019, 144, 1575–1583. [Google Scholar] [CrossRef]
  47. Bissonnette, R.; Maari, C.; Forman, S.; Bhatia, N.; Lee, M.; Fowler, J.; Tyring, S.; Pariser, D.; Sofen, H.; Dhawan, S.; et al. The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: Results from a randomized double-blind placebo-controlled study. Br. J. Dermatol. 2019, 181, 733–742. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. McGuinness, L.A.; Higgins, J.P.T. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res. Syn. Methods 2021, 12, 55–61. [Google Scholar] [CrossRef] [PubMed]
  49. Guyatt, G.H.; Oxman, A.D.; Montori, V.; Vist, G.; Kunz, R.; Brozek, J.; Alonso-Coello, P.; Djulbegovic, B.; Atkins, D.; Falck-Ytter, Y.; et al. GRADE guidelines: 5. Rating the quality of evidence--publication bias. J. Clin. Epidemiol. 2011, 64, 1277–1282. [Google Scholar] [CrossRef]
  50. Schmitt, J.; Langan, S.; Deckert, S.; Svensson, A.; von Kobyletzki, L.; Thomas, K.; Spuls, P. Assessment of clinical signs of atopic dermatitis: A systematic review and recommendation. J. Allergy Clin. Immunol. 2013, 132, 1337–1347. [Google Scholar] [CrossRef]
  51. Fishbein, A.B.; Silverberg, J.I.; Wilson, E.J.; Ong, P.Y. Update on atopic dermatitis: Diagnosis, severity assessment, and treatment selection. J. Allergy Clin. Immunol. Pract. 2020, 8, 91–101. [Google Scholar] [CrossRef] [PubMed]
  52. Futamura, M.; Leshem, Y.A.; Thomas, K.S.; Nankervis, H.; Williams, H.C.; Simpson, E.; Information, P.E.K.F.C. A systematic review of Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: Many options, no standards. J. Am. Acad. Dermatol. 2016, 74, 288–294. [Google Scholar] [CrossRef]
  53. Silverberg, J.I.; Margolis, D.J.; Boguniewicz, M.; Fonacier, L.; Grayson, M.H.; Ong, P.Y.; Fuxench, Z.C.; Simpson, E.L. Validation of five patient-reported outcomes for atopic dermatitis severity in adults. Br. J. Dermatol. 2020, 182, 104–111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Silverberg, J.I.; Pinter, A.; Pulka, G.; Poulin, Y.; Bouaziz, J.D.; Wollenberg, A.; Murrell, D.F.; Alexis, A.; Lindsey, L.; Ahmad, F.; et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J. Allergy Clin. Immunol. 2020, 145, 173–182. [Google Scholar] [CrossRef] [Green Version]
  55. Guttman-Yassky, E.; Blauvelt, A.; Eichenfield, L.F.; Paller, A.S.; Armstrong, A.W.; Drew, J.; Gopalan, R.; Simpson, E.L. Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: A phase 2b randomized clinical trial. JAMA Dermatol. 2020, 156, 411–420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA Approves Boxed Warning about Increased Risk of Blood Clots and Death with Higher Dose of Arthritis and Ulcerative Colitis Medicine Tofacitinib (Xeljanz, Xeljanz XR). 2019. Available online: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and (accessed on 2 April 2021).
  57. Brunner, P.M.; Guttman-Yassky, E. Racial differences in atopic dermatitis. Ann. Allergy Asthma Immunol. 2019, 122, 449–455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Zhou, L.; Leonard, A.; Pavel, A.B.; Malik, K.; Raja, A.; Glickman, J.; Estrada, Y.D.; Peng, X.; Del Duca, E.; Sanz-Cabanillas, J.; et al. Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis. J. Allergy Clin. Immunol. 2019, 144, 144–156. [Google Scholar] [CrossRef] [Green Version]
  59. Løset, M.; Brown, S.J.; Saunes, M.; Hveem, K. Genetics of atopic dermatitis: From DNA sequence to clinical relevance. Dermatology 2019, 235, 355–364. [Google Scholar] [CrossRef]
  60. Renert-Yuval, Y.; Guttman-Yassky, E. New treatments for atopic dermatitis targeting beyond IL-4/IL-13 cytokines. Ann. Allergy Asthma Immunol. 2020, 124, 28–35. [Google Scholar] [CrossRef] [Green Version]
  61. Bieber, T. Interleukin-13: Targeting an underestimated cytokine in atopic dermatitis. Allergy 2020, 75, 54–62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Mendes, D.; Alves, C.; Batel-Marques, F. Number needed to treat (NNT) in clinical literature: An appraisal. BMC Med. 2017, 15, 112. [Google Scholar] [CrossRef] [Green Version]
  63. Citrome, L. Quantifying clinical relevance. Innov. Clin. Neurosci. 2014, 11, 26–30. [Google Scholar] [PubMed]
Jpm 11 00279 g001 550
Figure 1. Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a 75% improvement in Eczema Area and Severity Index (EASI) score from the baseline (EASI-75 response). CI, confidence interval.
Figure 1. Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a 75% improvement in Eczema Area and Severity Index (EASI) score from the baseline (EASI-75 response). CI, confidence interval.
Jpm 11 00279 g001
Jpm 11 00279 g002 550
Figure 2. Association of Janus kinase (JAK) inhibitors versus placebo achieving of an Investigator Global Assessment (IGA) of 0 (clear) or 1 (almost clear) with at least a two-point reduction from the baseline (IGA response). CI, confidence interval.
Figure 2. Association of Janus kinase (JAK) inhibitors versus placebo achieving of an Investigator Global Assessment (IGA) of 0 (clear) or 1 (almost clear) with at least a two-point reduction from the baseline (IGA response). CI, confidence interval.
Jpm 11 00279 g002
Jpm 11 00279 g003 550
Figure 3. Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a four-point improvement in pruritus Numerical Rating Scale (NRS) score from the baseline (pruritus-NRS response). CI, confidence interval.
Figure 3. Association of Janus kinase (JAK) inhibitors versus placebo achieving at least a four-point improvement in pruritus Numerical Rating Scale (NRS) score from the baseline (pruritus-NRS response). CI, confidence interval.
Jpm 11 00279 g003
Table
Table 1. Characteristics of studies included in the meta-analysis.
Table 1. Characteristics of studies included in the meta-analysis.
SourceClinical Trial IdentifierStudy DesignStudy PeriodNo. of
Participants (Age)		Definition
of AD		Severity
of AD		InterventionsMechanism of InhibitionEndpointEfficacy OutcomesSafety OutcomesCOI
Bissonnette 2016 NCT02001181Phase II RCTDecember 2013–September 201469 (18–60 y)Hanifin and Rajka criteriaMild to moderateTreatment: topical tofacitinib, 2% twice daily
Placebo: topical control vehicle twice daily		JAK1 and JAK3Week 4IGA, EASI, and BSATEAEs and SAEsYes
Bissonnette 2019 NCT03139981Phase I RCTApril 2017–
November 2017		36 (18–75 y)AAD guidelineModerate to severeTreatment: oral gusacitinib, 20 mg, 40 mg, 80 mg once daily
Placebo: oral vehicle once daily 		JAK1, JAK2, JAK3, TYK2, and SYKWeek 4IGA, EASI, pruritus NRS, and BSATEAEs, SAEs, and AEDCYes
Gooderham 2019 NCT02780167Phase II RCTApril 2016–
April 2017		267 (18–75 y)AAD guidelineModerate to severeTreatment: oral abrocitinib, 10 mg, 30 mg, 100 mg, 200 mg once daily
Placebo: oral control vehicle once daily		JAK1 Week 12IGA, EASI, pruritus NRS, BSA, SCORAD, DLQI, HADS, and POEMTEAEs and SAEsYes
Guttman-Yassky 2018 NCT02576938Phase II RCTFebruary 2016–
March 2017		124 (≥18 y)Hanifin and Rajka criteriaModerate to severeTreatment: oral baricitinib, 2 mg and 4 mg once daily plus TCSPlacebo: oral control vehicle once dailyJAK1 and JAK2 Week 16IGA, EASI, pruritus NRS, SCORAD, DLQI, and POEMTEAEs, SAEs, and AEDC Yes
Guttman-Yassky 2019NCT02925117Phase II RCTNovember 2016–
April 2017		167 (18–75 y)Hanifin and Rajka criteriaModerate to severeTreatment: oral upadacitinib, 7.5 mg, 15 mg, 30 mg once daily
Placebo: oral control vehicle once daily		JAK1Week 16IGA, EASI, pruritus NRS, BSA, SCORAD, and POEMTEAEs, SAEs, and AEDC Yes
Kim 2020 NCT03011892Phase II RCTJanuary 2017–
November 2017		307 (18–70 y)NAMild to moderateTreatment: topical ruxolitinib, 0.15%, 0.5%, 1.5% once daily, and 1.5% twice daily; Placebo: topical control vehicle twice dailyJAK1 and JAK2Week 8pruritus NRS, and Skindex-16TEAEs, SAEs, and AEDCYes
Nakagawa 2017 JapicCTI-152887Phase II RCTApril 2015–
May 2016		327 (16–65 y)JDA guidelineModerate to severeTreatment: topical delgocitinib, 0.25%, 0.5%, 1%, 3% twice daily
Placebo: topical control vehicle twice daily		JAK1, JAK2, JAK3, and TYK2Week 4IGA, mEASI, pruritus NRS, and BSASAEs and AEDCYes
Nakagawa 2019 JapicCTI-173553Phase II RCTMarch 2017–
February 2018		103 (2–15 y)JDA guidelineMild to moderateTreatment: topical delgocitinib, 0.25%, 0.5% twice daily
Placebo: topical control vehicle twice daily		JAK1, JAK2, JAK3, and TYK2Week 4IGA, mEASI, pruritus NRS, and BSASAEs and AEDCYes
Nakagawa 2020 JapicCTI-173554Phase III RCTMarch 2017–
September 2018		158 (≥16 y)JDA guidelineModerate to severeTreatment: topical delgocitinib, 0.5% twice daily
Placebo: topical control vehicle twice daily		JAK1, JAK2, JAK3, and TYK2Week 4IGA, mEASI, pruritus NRS, BSA,
and Skindex-16		TEAEs, SAEs, and AEDCYes
Reich 2020 NCT03733301
(BREEZE-AD7)		Phase III RCTNovember 2018–August 2019329 (≥18 y)AAD guidelineModerate to severeTreatment: oral baricitinib, 2 mg, 4 mg once daily plus TCS
Placebo: oral control vehicle once daily		JAK1 and JAK2Week 16IGA, EASI-50, EASI-75, EASI-90, pruritus NRS, pain NRS, SCORAD, ADSS, POEM, HADS, DLQI, and WPAITEAEs, SAEs, and AEDCYes
Silverberg 2020NCT03575871
(JADE MONO-2)		Phase III RCTJune 2018–
August 2019		391 (≥12 y)Hanifin and Rajka criteriaModerate to severeTreatment: oral abrocitinib, 100 mg and 200 mg once daily
Placebo: oral control vehicle once daily		JAK1Week 12IGA, EASI, pruritus NRS, PSAAD, DLQI, CDLQI, POEM, and HADSSAEs and AEDCYes
Simpson 2020a NCT03334396
(BREEZE-AD1)		Phase III RCTNovember 2017–January 2019624 (≥18 y)AAD guidelineModerate to severeTreatment: oral baricitinib, 1 mg, 2 mg, 4 mg once daily
Placebo: oral control vehicle once daily		JAK1 and JAK2Week 16IGA, EASI, pruritus NRS, pain NRS, SCORAD, and ADSSTEAEs, SAEs, and AEDCYes
Simpson 2020b NCT03334422
(BREEZE-AD2)		Phase III RCTNovember 2017–December 2018615 (≥18 y)AAD guidelineModerate to severeTreatment: oral baricitinib, 1 mg, 2 mg, 4 mg once daily
Placebo: oral control vehicle once daily		JAK1 and JAK2Week 16IGA, EASI, pruritus NRS, pain NRS, SCORAD, and ADSSTEAEs, SAEs, and AEDCYes
Simpson 2020c NCT03349060
(JADE MONO-1)		Phase III RCTDecember 2017–March 2019387 (≥12 y)Hanifin and Rajka criteriaModerate to severeTreatment: oral abrocitinib, 100 mg and 200 mg once daily
Placebo: oral control vehicle once daily		JAK1Week 12IGA, EASI, pruritus NRS, PSAAD, DLQI, CDLQI, and POEMTEAEs, SAEs, and AEDCYes
BREEZE-AD4 2020 *NCT03428100
(BREEZE-AD4)		Phase III RCTMay 2018463 (≥18 y)AAD guidelineModerate to severeTreatment: oral baricitinib, 1 mg, 2 mg, 4 mg once daily
Placebo: oral control vehicle once daily		JAK1 and JAK2Week 16NATEAEs, SAEs, and AEDCYes
AAD, American Academy of Dermatology; AD, atopic dermatitis; ADSS, atopic dermatitis sleep scale; AE, adverse event; AEDC, adverse events leading to drug discontinuation; BSA, body surface area; CDLQI, children’s dermatology life quality index; COI, conflict of interest; DLQI, dermatology life quality index; EASI, eczema area and severity index; HADS, hospital anxiety and depression scale; IGA, investigator global assessment; JAK, Janus kinase; JDA, Japanese Dermatological Association; mEASI, modified eczema area and severity index; NA, not applicable; NRS, numerical rating scale; POEM, patient-oriented eczema measure; PSAAD, pruritus and symptoms assessment for atopic dermatitis; RCT, randomized controlled trial; SAE, serious adverse event; SCORAD, scoring atopic dermatitis; SYK, spleen tyrosine kinase; TEAE, treatment-emergent adverse event; TYK: tyrosine kinase; WPAI, work productivity and activity impairment questionnaire * BREEZE-AD4 is an ongoing RCT. Its safety outcomes were presented in Bieber et al. (2020).
Table
Table 2. Safety outcomes of Janus kinase inhibitors.
Table 2. Safety outcomes of Janus kinase inhibitors.
Treatment-Emergent Adverse EventsMeta-RegressionAdverse Events Leading to Drug Discontinuation Meta-Regression
SubgroupsNo. of Studies Pooled RR (95% CI)p-ValueI2 (%)τ2p-ValueNo. of StudiesPooled RR (95% CI)p-ValueI2 (%)τ2p-Value
Overall121.14 (1.02 to 1.28) *0.02352.0 140.89 (0.57 to 1.38)0.6210.0
Route of administration 0.0130.033 00.064
Oral91.18 (1.06 to 1.32) **0.00348.3 91.03 (0.64 to 1.64)0.9170.0
Topical30.77 (0.49 to 1.20)0.25525.2 50.26 (0.07 to 1.02)0.0540.0
Severity of atopic dermatitis 0.0120.021 00.036
Mild to moderate20.73 (0.47 to 1.13)0.16333.1 30.16 (0.03 to 0.84) *0.0310.0
Moderate to severe101.18 (1.06 to 1.31) **0.00243.7 111.01 (0.64 to 1.60)0.9290.0
Age of participants 0.0190.483 00.200
Adults only101.12 (0.99 to 1.26)0.06855.3 91.10 (0.63 to 1.93)0.7280.0
Contain children or adolescents21.41 (1.06 to 1.88) *0.0190.0 50.60 (0.29 to 1.26)0.1930.0
Mechanism of action 0.0120.062 00.750
Selective for JAK1 inhibition31.29 (1.11 to 1.50) *0.0010.0 30.77 (0.39 to 1.52)0.4560.0
Selective for JAK1/JAK2 inhibition61.14 (0.98 to 1.31)0.08259.4 61.22 (0.60 to 2.51)0.58213.3
Selective for JAK1/JAK3 inhibition10.56 (0.32 to 1.00) *0.049NA 10.14 (0.01 to 2.59)0.186NA
Pan-JAK inhibition20.99 (0.66 to 1.48)0.9170.0 40.55 (0.11 to 2.63)0.5040.0
Treatment duration 0.0130.026 00.134
<12 weeks40.84 (0.63 to 1.11)0.2238.2 60.37 (0.11 to 1.26)0.1200.0
≥12 weeks81.20 (1.07 to 1.34) **0.00252.5 81.01 (0.63 to 1.63)0.9650.0
* p < 0.05; ** p < 0.01; CI, confidence interval; RR, risk ratio.
Table
Table 3. Treatment-emergent adverse events reported in the studies included in the meta-analysis.
Table 3. Treatment-emergent adverse events reported in the studies included in the meta-analysis.
JAK Inhibitors by MechanismNo. of PatientsNo. (%) of Patients with Common TEAEs
NasopharyngitisURTIHeadacheNauseaDiarrheaBlood CPK IncreaseAcneHerpes Viral Infection
Selective for JAK1 inhibition
Abrocitinib834 73 (8.8)85 (10.2)64 (7.7)94 (11.3)10 (1.2)8 (1.0)11 (1.3)10 (1.2)
Upadacitinib1269 (7.1)17 (13.5)10 (7.9)7 (5.6)4 (3.2)7 (5.6)12 (9.5)0
Selective for JAK1/JAK2 inhibition
Baricitinib1318118 (9.0)36 (2.7)64 (4.9)2 (0.2)25 (1.9)27 (2.0)5 (0.4)74 (5.6)
Ruxolitinib20410 (4.9)5 (2.5)4 (2.0)00000
Selective for JAK1/JAK3 inhibition
Tofacitinib352 (5.7)1 (2.9)1 (2.9)1 (2.9)0000
Pan-JAK inhibition
Gusacitinib273 (11.1)07 (25.9)5 (18.5)3 (11.1)000
Delgocitinib43928 (6.4)000004 (0.9)0
AD, atopic dermatitis; AE, adverse event; NA, not applicable; RR, relative risk; SAE, serious adverse event; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.
Table
Table 4. Certainty of evidence based on GRADE (Janus kinase inhibitors vs. placebo in atopic dermatitis).
Table 4. Certainty of evidence based on GRADE (Janus kinase inhibitors vs. placebo in atopic dermatitis).
Certainty AssessmentSummary of Findings
Participants (Studies)
Follow Up		Risk of BiasInconsistencyIndirectnessImprecisionPublication BiasOverall Certainty of EvidenceRelative Effect (95% CI)NNTs or NNHs
EASI-75 response
3498
(12 RCTs)		Not seriousNot seriousNot seriousNot seriousLikely a⨁⨁⨁◯
MODERATE		2.84 (2.20 to 3.67)3.97
IGA response
2417
(11 RCTs)		Not seriousNot seriousNot seriousNot seriousLikely a⨁⨁⨁◯
MODERATE		2.99 (2.26 to 3.95)5.72
Pruritus-NRS response
3036
(8 RCTs)		Not seriousNot seriousNot seriousNot seriousLikely a⨁⨁⨁◯
MODERATE		2.52 (1.90 to 3.35)4.91
TEAEs
3402
(12 RCTs)		Serious bNot seriousNot seriousNot seriousLikely a⨁⨁◯◯
LOW		1.14 (1.02 to 1.28)14.80
AEs leading to drug discontinuation
3926
(14 RCTs)		Serious bNot seriousNot seriousNot seriousLikely a⨁⨁◯◯
LOW		0.89 (0.57 to 1.38)NR
AEs, Adverse Events; CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; IGA, Investigator’s Global Assessment; NNTs/NNHs, number-needed-to-treats/number-needed-to-harms; NR: not reasonable (no statistical significance in meta-analysis; therefore, calculation of this value is not reasonable); NRS, Numerical Rating Scale; RCT, randomized controlled trial; TEAEs, treatment emergent AEs. a Potential conflict of interest was indicated. b One study was judged as “high” bias risk.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Tsai, H.-R.; Lu, J.-W.; Chen, L.-Y.; Chen, T.-L. Application of Janus Kinase Inhibitors in Atopic Dermatitis: An Updated Systematic Review and Meta-Analysis of Clinical Trials. J. Pers. Med. 2021, 11, 279. https://doi.org/10.3390/jpm11040279

AMA Style

Tsai H-R, Lu J-W, Chen L-Y, Chen T-L. Application of Janus Kinase Inhibitors in Atopic Dermatitis: An Updated Systematic Review and Meta-Analysis of Clinical Trials. Journal of Personalized Medicine. 2021; 11(4):279. https://doi.org/10.3390/jpm11040279

Chicago/Turabian Style

Tsai, Hou-Ren, Jing-Wun Lu, Li-Yu Chen, and Tai-Li Chen. 2021. "Application of Janus Kinase Inhibitors in Atopic Dermatitis: An Updated Systematic Review and Meta-Analysis of Clinical Trials" Journal of Personalized Medicine 11, no. 4: 279. https://doi.org/10.3390/jpm11040279

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop