Upadacitinib Is a Better Choice than Abrocitinib for Patients with Moderate-to-Severe Atopic Dermatitis: An Updated Meta-Analysis

Zhang, Ying; Hong, Pan; Rai, Saroj; Liu, Ruikang; Liu, Bo

doi:https://doi.org/10.1155/2023/9067797

Journal of Clinical Pharmacy and Therapeutics

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Abstract Introduction Methods Discussion Conclusion Abbreviations Data Availability Ethical Approval Disclosure Conflicts of Interest Authors’ Contributions Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 9067797 | https://doi.org/10.1155/2023/9067797

Upadacitinib Is a Better Choice than Abrocitinib for Patients with Moderate-to-Severe Atopic Dermatitis: An Updated Meta-Analysis

Ying Zhang,¹Pan Hong,²Saroj Rai,³Ruikang Liu,⁴and Bo Liu⁵

Academic Editor: Ali Imran

Received02 Nov 2022

Revised11 Apr 2023

Accepted18 Apr 2023

Published08 May 2023

Abstract

Background. Blocking agent for immune cytokine pathways is a novel treatment for atopic dermatitis (AD). Janus kinase (JAK) family is one of the cytoplasmic tyrosine kinases that mediate a variety of cytokines. Eight randomized controlled trials (RCTs) of JAK1 inhibitors (upadacitinib and abrocitinib) in AD have been published in the past three years. Objective. To evaluate the efficacy and safety of JAK1 inhibitors and compare upadacitinib with abrocitinib for the treatment of moderate-to-severe AD. Methods. Two independent reviewers searched Medline, Embase, Web of Science, and Cochrane databases updated on Apr 11th, 2023. We included data from phase two and three RCTs. Primary outcomes included the proportion of Investigator’s Global Assessment (IGA) responders and Eczema Area and Severity Index-75 (EASI-75) responders. Results. In all, eight RCTs were included in our study with 4634 moderate-to-severe AD patients. Both JAK1 inhibitors showed apparent therapeutic effects, but the 200 mg abrocitinib group demonstrated less efficacy than the 30 mg upadacitinib group in IGA responders (end of treatment) and EASI-75 responders (after 2 weeks of treatment). However, both JAK1 inhibitor groups demonstrated significantly higher risks of acne (9.0%) and headache (6.3%). Besides, upadacitinib showed significantly higher risks of upper respiratory tract infection (7.6%) and nasopharyngitis (9.7%), and abrocitinib showed significantly higher risks of nausea (9.6%). Conclusion. JAK1 inhibitors demonstrate promising efficacy in AD with rapid response and dose-dependent response and significantly higher risks of acne and headache. Based on existing data, oral 30 mg upadacitinib QD has better outcome than oral 200 mg abrocitinib QD and is a recommended dosage regimen for moderate-to-severe AD patients. Oral 15 mg upadacitinib QD might be an alternative dosage regimen in case of treatment-emergent adverse events.

1. Introduction

Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease characterized by severe pruritus and affects up to 10% of adults and 25% of children and adolescents [1, 2]. AD has complex pathophysiology involving environmental factors, impaired skin barrier function, genetic susceptibility, and immune imbalance [1]. These pathophysiological changes result in the loss of transepidermal water, xerosis, and eczema, leading to the destruction of skin barriers in about 80% of AD patients [3–5]. Individuals with AD are also at high risk of asthma, allergic rhinitis, and food allergy, which could also increase the hazards of relevant health and psychosocial outcomes [6].

Although topical anti-inflammatory agents and emollients are the primary treatment for AD, they are not effective enough for patients with moderate-to-severe AD [7]. Topical corticosteroids (TCS) are widely regarded as the first-line choice for moderate-to-severe AD, but side effects of TCS could be hardly ignored, including skin atrophy, hypothalamic-pituitary-adrenal axis suppression, and acneiform or rosacea-like eruptions [7]. Charman et al. had reported a phenomenon called TCS phobia: they included 200 patients with atopic eczema for the questionnaire, and the outcome demonstrated that 145 patients (72.5%) worried about TCS treatment, while 48 patients (24%) admitted noncompliance because of safety concerns [8]. As for other options, systemic corticosteroids are not recommended due to side effects and rebound [6, 9]. Phototherapy is also constrained by adverse events like actinic damage, local erythema, burning, and stinging [9]. Therefore, a new efficient therapeutic agent for AD that avoids most of the side effects mentioned above is needed.

Recently, biological blocking agents for immune cytokine pathways were reported as an optional treatment for moderate-to-severe AD [6]. In recent years, the US Food and Drug Administration approval had been given to two oral JAK inhibitors (abrocitinib and upadacitinib) [10]. Eight randomized clinical trials (RCTs) of JAK1 inhibitors in AD have been published in the past three years [11–17]. JAK1 inhibitors regulate signal transduction and relieve pruritus through IL-4, IL-13, and other cytokines such as IL-31, IL-22, and thymic stromal lymphopoietin [18]. Meanwhile, JAK1 inhibitors could avoid potential risks of neutropenia and anemia caused by JAK2 inhibition [19]. Therefore, we conducted this meta-analysis to evaluate the efficacy and safety of JAK1 inhibitors, especially upadacitinib versus abrocitinib, for the treatment of moderate-to-severe AD. Both upadacitinib and abrocitinib are oral selective JAK inhibitors with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 (TYK2).

2. Methods

2.1. Search Strategy

Our review was registered in PROSPERO (registration number CRD42021244435) before the literature search. We followed the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Table S1). Two independent reviewers (RL and PH) searched Web of Science, PubMed, Embase, and Cochrane databases updated on Mar 21st, 2021 for RCTs (we processed another search at the end of the study on Apr 11th, 2023). The search strategy used for the PubMed database is available as supplementary material (Table S2). To expand the search range, the keywords were “atopic dermatitis,” “Janus kinase inhibitor,” or “JAK inhibitor.” The link https://clinicaltrials.gov was searched for completed but unpublished RCTs. Two researchers (YZ and SR) independently screened the titles and abstracts. They only reviewed full-text articles which met the inclusion criteria. Reference lists of eligible reviews and trials were searched for additional citations.

2.2. Selection Criteria

There was no restriction on sex, age, nationality, and race. Oral placebo treatment with an identical appearance was regarded as a comparison. There was no restriction on the dosage of JAK1 inhibitors. We only discussed data from the phase two and three RCTs. We only included data from patients with moderate-to-severe AD in the meta-analysis. Patients were permitted to use oral antihistamines and nonmedicated emollient. Patients with acute or chronic medical or psychiatric conditions, laboratory abnormalities, infectious diseases, coagulation disorders, receiving other therapies (individual explanation in different trials) before randomization, or having prior exposure to any JAK1 inhibitor were excluded. Concomitant use of topical (corticosteroids, calcineurin inhibitors, phosphodiesterase inhibitors, tars, antibiotic creams, or topical antihistamines) or other systemic therapies for AD or rescue medication were also prohibited.

2.3. Data Extraction

Two researchers (YZ and PH) independently extracted data from eligible articles. The extracted data included characteristics of the study, characteristics of the patient, baseline, and outcome data. Decisions were made by consulting another reviewer SR when YZ and PH met disagreements and failed consensus. They would also contact the corresponding author by email to send additional information when data were incomplete. Outcomes were classified as primary outcomes and secondary outcomes. Primary outcomes included the proportion of IGA responders (IGA ≤ 1 or achieving a ≥2-point improvement from baseline) and the proportion of EASI-75 responders (improvement ≥75% in EASI from baseline). All assessment tools, in included RCTs, are shown in Table S3.

2.4. Quality Assessment

Two researchers (YZ and RL) used Cochrane risk of bias assessment tool (CROBAT) to assess the quality of included studies independently. CROBAT included “allocation concealment,” “random sequence generation,” “blinding of participants and personnel,” “blinding of outcome assessment,” “incomplete outcome data,” “selective reporting,” and “other bias” (Table S4). Each question had 3 answers: “low risk,” “moderate risk,” and “high risk.” According to the published information, researchers would assess the risk level of RCTs. Another reviewer BL would make decision when YZ and RL met disagreements and failed consensus. Small-study effects that led to potential reporting or publication bias could be calculated by Egger’s test [20]. Publication bias was evaluated by funnel plots and was considered a statistically significant risk of bias. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool to evaluate the quality of evidence for each outcome. The GRADE tool classified evidence of outcomes into “high,” “moderate,” “low,” and “very low.” Each assessment could reduce or promote the level of quality. Specific rules are explained in Table S4.

2.5. Statistical Analysis

STATA 16.0 and Review Manager 5.3 were used in our study. All forest plots were produced by Review Manager 5.3 with inverse variance as the statistical method. Continuous data using different scales would be measured by standard mean difference (SMD) with 95% confidence intervals (CI), while using the same scale would be summarized by weighted mean difference (WMD) with 95% CI. Dichotomous data would be calculated by odds ratio (OR) with 95% CIs [21]. Heterogeneity in the result of the meta-analysis was assessed using Cochrane Q and I² statistics with appropriate analysis models. All statistical tests were two-tailed, and was regarded as a statistically significant difference. Egger’s tests were performed by STATA 16.0.

Subgroup analysis would be carried out when detailed data were available. It would be based on the type, dosage, and treatment time of JAK1 inhibitors. Different doses of the same drug were compared directly by the forest plot, where value of the test for overall effect would demonstrate the significance. Besides, value of the test for subgroup difference demonstrated the difference between different drugs because we regarded two drugs as two subgroups. Sensitivity analysis was performed in the meta-analysis by excluding each study once at a time to check whether the effectiveness of the outcome was determined by individual studies.

3. Result

3.1. Search Results

Figure 1 shows detailed steps of the literature search, in which 404 studies were reviewed: 314 studies were excluded after screening titles and abstracts, remaining 90 studies were reviewed in full text. After excluding 82 studies according to selection criteria, eight RCTs with 4634 moderate-to-severe AD patients were included in our meta-analysis [11–17].

3.2. Study Characteristics

As shown in Table 1, all RCTs were multicentre trials: 6 (75%) were phase III clinical trials, and 2 (25%) were phase II clinical trials. The sample size of included studies ranged from 167 to 901. There was no significant difference between the JAK1 inhibitor group and placebo group in general information (age, sex, disease duration, IGA point, and EASI). Figure S1 demonstrates the risk of bias summary. All included RCTs met compliance with the selection criteria. All RCTs were blind and followed the rules of randomization and allocation concealment. Three RCTs without results posted on https://clinicaltrials.gov had risks of incomplete outcome data. Detailed assessment outcomes of CROBAT are shown in Table S5.

3.3. Primary Outcome

All the results of primary outcomes are listed in Table 2. Outcomes of JAK1 inhibitors measured at the end of treatment (EOT) demonstrated therapeutic effects on IGA responder (OR = 7.65 95% CI 5.52–10.61) in Figure 2 and EASI-75 responder (OR = 8.73 95% CI 6.52–11.68) in Figure 3. Therapeutic effects of JAK1 inhibitors also appeared in the EASI-75 responder (OR = 8.36 95% CI 5.75–12.15) after 2 weeks of treatment. Besides, Table 2 confirmed the dose-dependent response (significant different effect between different dose of the same drug) of abrocitinib and upadacitinib, and 30 mg of upadacitinib was the most efficacious dosage (IGA: OR = 16.20 95% CI 12.26–21.42; EASI-75: OR = 15.22 95% CI 9.96–23.25). In addition, Table 2 also demonstrates both abrocitinib and upadacitinib had positive significant differences compared with placebo.

3.4. Adverse Events

We had analysed the frequently treatment-emergent adverse events (incidence rate >5.0%) in RCTs, including nasopharyngitis (9.7%), nausea (9.6%), acne (9.0%), upper respiratory tract infection (7.6%), and headache (6.3%). In Table 3, JAK1 inhibitors showed significant increase in all of these adverse events compared with placebo. Among these adverse events, the proportions of acne in the JAK1 inhibitor group (OR = 6.59 95% CI 4.72–9.18) and nausea in the abrocitinib group (OR = 5.18 95% CI 3.05–8.81) were significantly higher. Furthermore, compared with the 30 mg upadacitinib group, the 15 mg upadacitinib group had significantly lower risk of any treatment-emergent adverse events (OR 0.76 95% CI 0.63–0.93, ). Abrocitinib also had a similar dose-dependent risk but without a significant difference. There was no significant difference in serious adverse events in both abrocitinib and upadacitinib groups (Table 3).

3.5. Secondary Outcome

For the EASI-related secondary outcomes, Table S6.1 shows positive effects of JAK1 inhibitors in EASI-50, 90, and 100 with high GRADE quality, and the percentage change of EASI displayed a significant reduction but with high heterogeneity (I² = 100%). Besides, the upadacitinib group demonstrated a significant advantage over the abrocitinib group on EASI-100 (OR = 18.97 95% CI 11.92–30.18; subgroup difference: ).

Moreover, the JAK1 inhibitor group resulted in more pruritus numerical rating scale (NRS) responders (defined as a 4-point or greater improvement from baseline in NRS score) than the placebo group (OR = 5.74 95% CI 4.18–7.88), and upadacitinib group displayed significant differences compared with the abrocitinib group in Table S6.2 (OR = 9.21 95% CI 7.74–10.95; subgroup difference: ). JAK1 inhibitors also showed significant differences in scoring atopic dermatitis (SCORAD) and decreased lesion area, but the levels of GRADE assessment were not high due to high heterogeneity and risk of publication bias.

In our supplemental tables, we have presented various outcomes: PRISMA checklist (Table S1), detailed search strategy (Table S2), different assessment tools in included RCTs (Table S3) and our meta-analysis (Table S4), and outcome of CROBAT (Table S5). Table S6 shows the secondary outcomes including EASI-50/90/100 responders and other outcomes such as Pruritus NRS responder, SCORAD responder, and BSA change. We also provide a recommendation of inflammatory diseases with JAK inhibitors treatment in Table S7.

4. Discussion

Our meta-analysis included eight high-quality multicentre RCTs with 4634 patients. We confirmed the effects of JAK1 inhibitors on moderate-to-severe AD both at EOT and after 2 weeks of treatment (Table 2). However, both upadacitinib and abrocitinib groups demonstrated significant differences in acne and headache. Besides, upadacitinib had significantly higher risks of upper respiratory tract infection and nasopharyngitis, and abrocitinib had significantly higher risks of nausea (Table 3). As for subgroup analysis, we observed that both upadacitinib and abrocitinib demonstrated significant therapeutic effects and dose-dependent relationships (30 mg upadacitinib group and 200 mg abrocitinib group showed better outcomes than lower dose groups). Rapid response was displayed on JAK1 inhibitors after 2 weeks of treatment, both upadacitinib and abrocitinib demonstrated significant differences in EASI-75 responder compared with the placebo (Table 2). Furthermore, upadacitinib demonstrated better rapid response (curative effect after 2 weeks of treatment) than abrocitinib (EASI-75 responder: OR = 13.45 95% CI 8.72–20.75; subgroup difference: ; IGA responder: not available, lack of data). Upadacitinib also showed better outcome on IGA responder (OR = 12.18 95% CI 8.40–17.66; subgroup difference: ), EASI-90 responder (OR 13.04 95% CI 8.39–20.27; subgroup difference: ), and EASI-100 responder (OR = 18.97 95% CI 11.92–30.18; subgroup difference: ) at EOT (Table S6.1). Further advantages of upadacitinib versus abrocitinib were shown on pruritus NRS responder (OR 9.21 95% CI 7.74–10.95; subgroup difference: ) and SCORAD responder (OR 10.13 95% CI 4.73–21.72; subgroup difference: ) (Table S6.2). In all, 30 mg upadacitinib QD is the recommended regimen for moderate-to-severe AD, while 15 mg upadacitinib QD is an alternative with lower risks of treatment-emergent adverse events (OR = 0.76 95% CI 0.63–0.93).

Based on the current understanding of immunological mechanisms, various inhibitors targeting cytokines and interfering with signaling pathways have been developed. JAK1, 2, 3, and TYK2 signal pathways modulate the inflammatory processes by activating intracytoplasmic transcription factors, namely signal transducer and activator of transcription (STAT) [22]. Activated proteins form dimers and translocate into the nucleus to modulate the expression of genes and finally regulate type-2 differentiation, T-cell activation, innate immunity, and epidermal differentiation complexes [6, 23]. JAK1 inhibitor regulates signal transduction and relieves pruritus through IL-4, IL-13, and other cytokines such as IL-31, IL-22, and thymic stromal lymphopoietin [18]. Furthermore, Oetjen et al. confirmed that chronic itch depended on neuronal JAK1 signaling by activating IL-31 and other itching factors in sensory neurons [24]. Moreover, JAK2 participates in signal transduction by erythropoietin and other colony-stimulating factors, which results in frequent neutropenia and anemia events in JAK2 inhibitors [25]. Therefore, compared with other JAK inhibitors, JAK1 inhibitors had the potential advantage of improving pruritus and avoiding hematologic adverse events [19]. Apart from the general mechanism of the JAK1 inhibitor mentioned before, upadacitinib also decreases the production of proinflammatory mediators induced by IL-6, IL-15, IFN-α, and IFN-γ [26]. As for pharmacology, upadacitinib demonstrated an oral bioavailability of 76% with rapid absorption (plasma concentrations peak at around 1 to 2 hours after administration) and a 4-hour half-life, while abrocitinib also had rapidly absorbed after oral administration (reaching plasma concentrations peak within 1 h) and a 5-hour half-life [27, 28].

A new recommendation for immune-mediated inflammatory diseases with JAK inhibitors treatment was formulated by an expert committee comprising 29 multinational and experienced clinicians [29]. High levels of agreement were voted on for every point (10-point scale). It recommended that severe infections, severe organ dysfunction, pregnancy, and lactation were contraindications of JAK inhibitors (vote 100%, 9.9 points) and consider dosage should be adjusted in patients with higher age (>70 years) and significantly impaired renal or hepatic function (vote 100%, 9.9 points). As for the adverse events, serious infections, particularly opportunistic infections, including herpes zoster, received general consent. The risk of infection could be lowered by reducing or eliminating concomitant glucocorticoid use (vote 100%, 9.9 points). Lymphopenia, thrombocytopenia, neutropenia, and anemia may also occur (vote 100%, 9.8 points). More detailed recommendations are displayed in Table S7.

Various adverse events were reported, in included RCTs. Both abrocitinib and upadacitinib demonstrated risks of acne and headache in our study. Although most of these symptoms were not serious, they might exacerbate the manifestation of AD, resulting in lower quality of life. Besides, 28 (1.5%) patients in the upadacitinib group and 13 (1.0%) patients in the abrocitinib group had reported herpes zoster, but the difference in incidence rate was insignificant, and all cases of herpes zoster infection were nonserious, and none led to discontinuation of RCTs. Furthermore, JAK1 inhibitors might suppress platelet production by inhibiting Ashwell–Morrell receptors and downstream inhibition of thrombopoietin production [30]. Dose-related decreases in median platelet count were reported in all RCTs of abrocitinib, but the minimum level of platelet occurred in the 4th week and gradually returned to the baseline value with the ongoing administration of the drug. Besides, no platelet-related event was reported in RCTs of upadacitinib. Therefore, it seems platelet count is reversible in most patients, and no clinically important event was observed (such as hemorrhage associated with the decreased platelet counts. A recent meta-analysis included 42 studies that discussed the venous thromboembolism (VTE) risk with JAK inhibitors; no evidence could support the current warnings of VTE risk for JAK inhibitors [31]. Another meta-analysis included 82 studies had also concluded that JAK inhibitors demonstrated no increased risk of malignancy or serious infections on multiple immune-mediated diseases [32]. Other side effects, including acne, nasopharyngitis, headache, and nausea, were frequently reported in included RCTs, but most side effects were not severe and relieved after drug withdrawal.

Several previous meta-analyses discussed the JAK inhibitors treatment on AD. Among these studies, only one network meta-analysis showed a similar design and conclusion to our study [33]. However, it only included one RCT of abrocitinib and one RCT of upadacitinib, and adverse events were not included in the data analysis. Our study focused on evaluating JAK1 inhibitors and comparing the efficacy and safety of upadacitinib and abrocitinib for moderate-to-severe AD. In summary, our study demonstrated rapid response and dose-dependent response on both JAK1 inhibitors and corroborated the advantages of upadacitinib.

Still, our study has certain limitations. Firstly, three RCTs of upadacitinib had no 12-week data, and three RCTs of abrocitinib had no 16-week data. Therefore, we chose to analyse the results at EOT time rather than a specific same time period. Because both 12-week and 16-week RCTs showed significant effects in their endpoint outcomes, and the differences in our analysis were also significant, thus the heterogeneity led by different timing was acceptable without compromising our conclusion. Besides, adverse events with complicated causes demonstrated negative significant differences in JAK1 inhibitors, but it was difficult to explain the mechanism and provide recommendations. Close monitoring is required for high dose JAK1 inhibitors treatment, and low dosage regimen might be an alternative in case of adverse events. Moreover, different sample sizes between phase two and three RCTs might affect the veracity potentially.

5. Conclusion

JAK1 inhibitors demonstrate promising efficacy in AD with rapid response and dose-dependent response and significantly higher risks of acne and headache. Based on existing data, oral 30 mg upadacitinib QD has better outcome than oral 200 mg abrocitinib QD and is a recommended dosage regimen for moderate-to-severe AD patients. Oral 15 mg upadacitinib QD might be an alternative dosage regimen in case of treatment-emergent adverse events.

Abbreviations

JAK:	Janus kinase
AD:	Atopic dermatitis
TCS:	Topical corticosteroids
TYK:	Tyrosine kinase
PRISMA:	Preferred Reporting Items for Systematic Reviews and Meta-Analyses
IGA:	Investigator’s Global Assessment
EASI:	Eczema Area and Severity Index
BSA:	Body surface area
SCORAD:	Scoring atopic dermatitis
NRS:	Numerical rating scale
DLQI:	Dermatology life quality index
POEM:	Patient-oriented eczema measure
CROBAT:	Cochrane risk of bias assessment tool
GRADE:	Grading of Recommendations, Assessment, Development, and Evaluation
RCTs:	Randomized controlled trials
WMD:	Weighted mean difference
SMD:	Standard mean difference
CIs:	Confidence intervals
OR:	Odds ratio
EOT:	End of treatment.

Data Availability

All data generated or analysed during this study are extracted from RCTs searched from online databases (Medline, Embase, Web of Science, Cochrane database, and https://clinicaltrial.gov).

Ethical Approval

Ethical approval was not required, given that analyses were conducted on deidentified, secondary data derived from published studies. Our review followed the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the protocol was registered in PROSPERO (registration number CRD42021244435). Included studies must be in accordance with the Declaration of Helsinki and International Council for Harmonization Good Clinical Practice Guidelines and approved by respective ethics committees. Written informed consent of patients was also required.

Disclosure

Ying Zhang is the first author of the manuscript.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

BL was in charge of the main idea and was the guarantor of integrity of the entire clinical study; RL and YZ were in charge of the study concepts, design, manuscript preparation, and editing; RL and PH searched databases independently. YZ and SR screened the titles and abstracts, articles meeting inclusion criteria; YZ and PH independently extracted data from eligible articles and conducted data analysis. YZ and RL independently assessed the quality of included studies; PH and SR were in charge of language polishing and grammar revision.

Supplementary Materials

Figure S1: risk of bias summary. Table S1: PRISMA checklist. Table S2: search strategy in Pubmed. Table S3: assessment standards in RCTs. Table S4: assessment tools in meta-analysis. Table S5: assessment result of CROBAT. Table S6: result of secondary outcomes. Table S7: recommendation of inflammatory diseases with JAK inhibitors treatment. (Supplementary Materials)

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Copyright © 2023 Ying Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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