
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

39312340
MD-D-24-01961
00041
10.1097/MD.0000000000039826
3
4000
Research Article
Systematic Review and Meta-Analysis
Efficacy and safety of upadacitinib in the treatment of moderate-to-severe atopic dermatitis in adolescents: A systematic review and meta-analysis of randomized controlled trials
Huang Lingmei MM 598778879@qq.com
a
Zhao Danjie MM 384207432@qq.com
a
Lin Haixia MM 349586078@qq.com
a
Zheng Hong MM 1484480866@qq.com
a
Li Xia MM 282813558@qq.com
a
Chen Long MM clsszy@qq.com
a
https://orcid.org/0009-0000-1631-8388
Tang Peng MM b*
a Department of Pharmacology, The First People’s Hospital of Shuangliu District, West China (Airport) Hospital of Sichuan University, Chengdu, China
b Department of TCM Pharmacy, Chengdu Integrated TCM and Western Medicine Hospital, Chengdu, China.
* Correspondence: Peng Tang, Department of TCM Pharmacy, Chengdu Integrated TCM and Western Medicine Hospital, Chengdu 610000, China (e-mail: tangpeng19940308@163.com).
20 9 2024
20 9 2024
103 38 e3982623 2 2024
01 9 2024
02 9 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Background:

To assess the efficacy and safety of upadacitinib in adolescents with moderate-to-severe atopic dermatitis (AD).

Methods:

A comprehensive search was conducted using PubMed, Medline, Embase, Web of Science, Clinical Trials Website, and Cochrane Library databases, spanning from their inception until February 18, 2024. The review incorporated all randomized controlled trials examining upadacitinib’s efficacy in managing moderate to severe AD among adolescent patients. The methodological quality of the selected studies underwent thorough assessment utilizing the Cochrane systematic review methodology. Statistical analyses of the outcome measures were executed employing the Review Manager 5.3 software.

Results:

The meta-analysis encompassed 4 studies in total. Compared to placebo, upadacitinib at doses of both 15 and 30 mg was associated with a significant enhancement in the eczema area and severity index-75% ([odds ratio, OR = 11.06, 95% confidence interval, CI (6.78–18.04), P < .00001]; [OR = 21.73, 95% CI (12.73–37.11), P < .00001]), a reduction in the numerical rating scale of ≥4 ([OR = 6.16, 95% CI (3.56–10.64), P < .00001]; [OR = 10.58, 95% CI (6.12–18.29), P < .00001]), and improvement in the investigator’s global assessment to 0/1 ([OR = 8.85, 95% CI (4.86–16.10), P < .00001]; [OR = 21.43, 95% CI (11.64–39.46), P < .00001]). Regarding safety, upadacitinib at both 15 and 30 mg doses was linked to a statistically significant rise in the overall incidence of adverse events when juxtaposed with placebo ([OR = 1.57, 95% CI (1.01–2.44), P = .04]; [OR = 2.21, 95% CI (1.44–3.41), P = .0003]). Nevertheless, no statistically significant disparity was discovered in the occurrence of serious adverse events between upadacitinib and placebo ([OR = 1.02, 95% CI (0.27–3.84), P = .98]; [OR = 0.42, 95% CI (0.09–1.93), P = .26]).

Conclusion:

The findings from this meta-analysis indicate that upadacitinib demonstrates substantial effectiveness and tolerability in treating moderate to severe AD in adolescents. Moreover, upadacitinib provides a rapid reduction in pruritus and markedly ameliorates symptoms and signs, with the 30 mg dosage showing a more pronounced therapeutic effect relative to the 15 mg dosage.

adolescent
atopic dermatitis
JAK1 inhibitors
meta-analysis
RCTs
upadacitinib
OPEN-ACCESSTRUE
SDCT
==== Body
pmc1. Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease,[1] with about 80% of patients developing symptoms within the first few years of life.[2] The prevalence of AD in adolescents can be as high as 24.6%.[3] Acute symptoms include open sores, ulcers on the skin surface, which cause skin damage, intense and persistent itching, and progress to dry, cracked, painful, red or darkened skin, scabbing, and oozing.[4] Subacute symptoms manifest as scales and dry cracks, with the skin becoming mossy over time.[5] While some patients may experience a gradual improvement in symptoms with age, approximately 30% of adolescents continue to suffer symptoms during their teenage years.[6] These adolescent patients are more susceptible to bullying and have higher rates of truancy, depression, insomnia, or suicidal tendencies compared to their peers.[7–9] Therefore, AD not only diminishes the quality of life for adolescents but also significantly impacts their mental health.

Recommendations propose that adolescents with mild symptoms may only require local skin moisturization and, if needed, the use of topical anti-inflammatory and immunomodulatory treatments such as topical corticosteroids, calcineurin inhibitors, and the more recent phosphodiesterase-4 inhibitors.[10] However, localized treatment methods mentioned above may not provide significant relief for adolescents with moderate-to-severe AD, leading them to turn to systemic immunotherapy drugs. Due to the complexity of the disease, its tendency to relapse, and drug resistance,[11] along with adolescents being in a developmental stage that places emphasis on self-image during puberty, the need for treatment drugs that are more safe, tasteless, invisible, and do not interfere with daily activities is urgent. This limitation restricts the use of certain medications, such as methotrexate and mycophenolate mofetil.[12,13] Janus kinase (JAK) inhibitors, as a novel type of small molecule targeted drug preparation with rapid onset and multi-target advantages, offer a new option for adolescents with moderate-to-severe AD.[14]

Upadacitinib is a selective, reversible JAK1 inhibitor, an oral small molecule drug approved for treating adolescents aged 12 to 17 with moderate-to-severe AD by both the European Medicines Agency and the U.S. Food and Drug Administration.[15] In comparison to the latest biologic approved for adolescent AD patients, Dupilumab,[16] upadacitinib’s oral dosing not only provides convenience in administration but also eliminates the discomfort and fear associated with injections, addressing the tasteless and invisible medication preferences of adolescent AD patients. While several clinical trials have reported the efficacy of upadacitinib in treating moderate-to-severe AD in adolescents,[17–20] there is a lack of comprehensive systematic evaluation. This study aims to offer evidence-based information on the efficacy and safety of upadacitinib in treating adolescents with moderate-to-severe AD through a systematic meta-analysis for its clinical application.

2. Methods

2.1. Ethical statements

No ethical approval is required because this is a literature-based study. This systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines.[21]

2.2. Search strategy

PubMed, Medline, Embase, Web of Science, Clinical Trials Website and Cochrane Library databases were searched from the first record to February 18, 2024 using the following terms: “atopic dermatitis” and “adolescent” and “upadacitinib or ABT-494.” Additional studies were retrieved by checking the reference lists of relevant studies. Only trials published in English were included.

2.3. Inclusion and exclusion criteria

Inclusion criteria. Design: randomized controlled trials (RCTs); population: moderate-to-severe AD ≥ 1 year; age: between ≥ 12 and < 18 years; eczema area and severity index (EASI) score ≥ 16; investigator’s global assessment (IGA) score ≥ 3; atopic dermatitis involving ≥ 10% of the body surface area; baseline weekly average of daily worst pruritus numerical rating scale (NRS) ≥ 4.

Exclusion criteria. Patients that previously received JAK inhibitor drugs and other drugs to improve symptoms of adolescent AD patients were excluded. Reviews, conference abstracts, letters, retrospective or case series were excluded.

2.4. Interventions measures

According to the randomized controlled double-blind method, adolescent patients were divided into: ① Experimental group: oral administration of upadacitinib 15 or 30 mg; ② Control group: oral administration of placebo with the same course and method as experimental group. Other intervention measures were consistent between the experimental group and the control group.

2.5. Outcome measures

Primary outcome. Percentage of participants achieving at least a 75% reduction in EASI from baseline at week 16 (EASI-75%); percentage of participants achieving a reduction of ≥4 points from baseline in worst pruritus NRS at week 16 (NRS ≥ 4); percentage of participants achieving IGA for AD of 0 or 1 with a reduction from baseline of ≥2 points at week 16 (IGA 0/1).

Secondary outcome. Percentage of participants achieving a 90% reduction from baseline in EASI score at week 16 (EASI-90%); percentage of participants achieving a 100% reduction from baseline in EASI score at week 16 (EASI-100%); percent change from baseline in EASI score at week 16 (EASI baseline score); percent change from baseline in worst pruritus NRS at week 16 (NRS baseline score); percent change from baseline in scoring atopic dermatitis (SCORAD) score at week 16 (SCORAD baseline score). The overall adverse events rate: during the course of the trial, the subjects had all physical abnormalities unrelated to the purpose of the treatment (AE); the serious adverse events rate: during the course of the trial, subjects were hospitalized for adverse events or events that were life threatening or resulted in permanent or significant damage to the body or organs serious adverse events (SAE).

2.6. Data extraction and quality assessment

Two authors independently reviewed relevant studies to assess the accuracy of the retrieval process. Then they screened the titles and abstracts of the literature and, if necessary, reviewed the entire work. Any discrepancies were resolved through discussion with a third author. Authors, publication year, patient characteristics, interventions, number of cases, treatment duration, and outcome measures were among the extracted data. The quality of the literature included in this study was evaluated using the risk of bias assessment table provided by the Cochrane Handbook for Systematic Reviews.

2.7. Data analysis

Data analysis was conducted using Review Manager 5.3 (The Cochrane Collaboration, UK). Dichotomous variables (such as EASI-75%) and continuous variables (such as EASI baseline score) were expressed as odds ratios (ORs) and weighted mean differences with their respective 95% confidence intervals (CIs). The χ2 test was employed to assess the heterogeneity among the included studies. A fixed-effect model was applied when statistical heterogeneity was determined to be low (P > .1 and I2 ≤ 50%). Conversely, if significant heterogeneity was present, a random-effects model was employed. Subgroup analysis and sensitivity analysis were conducted to investigate the sources of heterogeneity.

3. Results

3.1. Literature search results

According to the search criteria, an initial pool of 529 pertinent publications was identified, from which 305 duplicate entries were removed, yielding 224 unique articles. After examining the titles and abstracts, 196 studies were eliminated for various reasons, encompassing animal trials, retrospective analyses, or lack of relevance to the subject matter. Subsequently, the other 28 articles were examined in full. Additional exclusions were made, consisting of 14 review articles, 2 studies lacking a control cohort, 3 studies that did not report relevant data, and 5 observational studies. Ultimately, 4 randomized controlled trials were included, encompassing 581 patients diagnosed with moderate-to-severe AD. Of these, 193 were assigned to the placebo cohort, 192 to the 15 mg upadacitinib cohort, and 196 to the 30 mg upadacitinib cohort, involving diverse populations across different regions and ethnicities, with a treatment period of 16 weeks. Figure 1 depicts the literature search and selection procedure. Table 1 provides a comprehensive overview of the key features of the incorporated studies.

Table 1 Study characteristics.

Study (year)	Phase	Intervening measure	N	Age/years	Gender/n	Treatment/week	Outcome	
Female	Male	
Guttman et al (2021)[17]	Phase III	Upadacitinib 15 mg QD	58	15.2 ± 1.79	38	20	16	①②③④⑤⑥⑦⑧⑨⑩	
	Upadacitinib 30 mg QD	62	15.8 ± 1.70	26	36	16	
	PBO	60	15.5 ± 1.67	35	25	16	
Katoh et al (2023)[18]	Phase III	Upadacitinib 15 mg QD	10	15.4 ± 1.9	3	7	16	①②③④⑨⑩	
	Upadacitinib 30 mg QD	10	16.3 ± 1.5	2	8	16	
	PBO	9	14.9 ± 1.6	2	7	16	
Paller et al (2023)[19]	Phase III	Upadacitinib 15 mg QD	64	15.5 ± 1.99	34	30	16	①②③④⑤⑥⑦⑧⑨⑩	
	Upadacitinib 30 mg QD	64	15.7 ± 1.63	36	28	16	
	PBO	61	15.1 ± 1.70	33	28	16	
Reich et al (2021)[20]	Phase III	Upadacitinib 15 mg QD	60	15.4 ± 1.65	27	33	16	①②③④⑤⑥⑦⑨⑩	
	Upadacitinib 30 mg QD	60	15.3 ± 1.86	25	35	16	
	PBO	63	15.1 ± 1.85	36	27	16	
① EASI-75%; ② NRS ≥ 4; ③ IGA 0/1; ④ EASI-90%; ⑤ EASI-100%; ⑥ EASI baseline score; ⑦ NRS baseline score; ⑧ SCORAD baseline score; ⑨ AE; ⑩ SAE.

AE = serious adverse events, EASI = eczema area and severity index, NRS = numerical rating scale, IGA = investigator’s global assessment, PBO = placebo, QD = quaque die, SAE = serious adverse events, SCORAD = scoring atopic dermatitis.

Figure 1. The flow diagram of study selection.

3.2. Quality assessment of included studies

This investigation encompassed 4 randomized,[17–20] double-blind, controlled clinical trials. Each trial meticulously described the methods used for random sequence generation and allocation concealment, provided details on withdrawals and attrition rates, and exhibited no indication of bias related to selection, execution, measurement, attrition, or reporting processes. Overall, the caliber of these clinical investigations was considered comparatively elevated (Fig. 2).

Figure 2. Bias risk assessment chart.

3.3. Efficacy indicators

3.3.1. Eczema area and severity index-75%

All 4 trials[17–20] documented the shifts in the quantity of adolescents who attained EASI-75% following treatment with either 15 or 30 mg upadacitinib. Considering the low heterogeneity noted among the trials (15 mg: P = .21, I2 = 34%; 30 mg: P = .94, I2 = 0%), a fixed-effects (FE) model was applied. The findings indicated that the proportion of adolescent subjects attaining EASI-75% was markedly greater in both the 15 and 30 mg upadacitinib cohorts relative to the placebo cohort. Specifically, the 15 mg cohort had an OR of 11.06 with a 95% CI of 6.78 to 18.04, whereas the 30 mg cohort presented an OR of 21.73 with a 95% CI of 12.73 to 37.11. These differences were highly statistically significant for both dosage cohorts (P < .00001) (Fig. 3).

Figure 3. Meta-analysis forest plot of EASI-75%. EASI = eczema area and severity index.

3.3.2. Investigator’s global assessment 0/1

All 4 trials[17–20] documented shifts in the quantity of adolescents who achieved IGA 0/1 following administration of either 15 or 30 mg upadacitinib. Considering the low heterogeneity noted among the trials (15 mg: P = .48, I2 = 0%; 30 mg: P = .88, I2 = 0%), a FE model was utilized. The findings demonstrated that the number of adolescent patients attaining IGA 0/1 was considerably greater in both upadacitinib dosage cohorts relative to the placebo cohort. Specifically, the 15 mg cohort exhibited an OR of 8.85 with a 95% CI of 4.86 to 16.10, whereas the 30 mg cohort demonstrated an OR of 21.43 with a 95% CI of 11.64 to 39.46. These differences were found to be statistically significant (P < .00001) for both dosage cohorts (Fig. 4).

Figure 4. Meta-analysis forest plot of IGA 0/1. IGA = investigator's global assessment.

3.3.3. Numerical rating scale ≥ 4

All 4 trials[17–20] documented alterations in the quantity of adolescent subjects attaining a reduction of ≥ 4 in NRS after being treated with 15 or 30 mg upadacitinib. Considering the low heterogeneity detected among the investigations (15 mg: P = .17, I2 = 41%; 30 mg: P = .14, I2 = 46%), a FE model was employed. The findings demonstrated that the proportion of adolescent participants achieving an NRS reduction of 4 or more was notably superior in both upadacitinib dosage cohorts relative to the placebo cohort. Specifically, the 15 mg cohort exhibited an OR of 6.16 with a 95% CI of 3.56 to 10.64, while the 30 mg cohort presented an OR of 10.58 with a 95% CI of 6.12 to 18.29. These differences were statistically significant (P < .00001) for both dosage cohorts (Fig. 5).

Figure 5. Meta-analysis forest plot of NRS ≥ 4. NRS = numerical rating scale.

3.3.4. Adverse event

All 4 trials[17–20] reported the incidence of total AE after administering upadacitinib at 15 and 30 mg doses. Considering the low heterogeneity detected among the investigations (15 mg: P = .82, I2 = 0%; 30 mg: P = .99, I2 = 0%), a FE model was applied. The findings indicated that the frequency of total AE for both dosages of upadacitinib was greater than that for the placebo cohort. Specifically, the 15 mg cohort had an OR of 1.57 with a 95% CI of 1.01 to 2.44 (P = .04), while the 30 mg cohort presented an OR of 2.21 with a 95% CI of 1.44 to 3.41 (P = .0003). These differences were statistically significant for both dosage cohorts (Fig. 6).

Figure 6. Meta-analysis forest plot of AE. AE = adverse events.

3.3.5. Serious adverse event

All 4 trials[17–20] also examined the incidence of SAE after administering 15 and 30 mg of upadacitinib. Considering the low heterogeneity detected among the investigations (15 mg: P = .71, I2 = 0%; 30 mg: P = .38, I2 = 0%), a FE model was utilized. The observations suggested no notable disparities in the incidence of SAE between either dose of upadacitinib and the placebo cohort. Specifically, the 15 mg cohort exhibited an OR of 1.02 with a 95% CI of 0.27 to 3.84 (P = .98), while the 30 mg cohort exhibited an OR of 0.42 with a 95% CI of 0.09 to 1.93 (P = .26) (Fig. 7).

Figure 7. Meta-analysis forest plot of SAE. SAE = serious adverse events.

3.3.6. Other efficacy outcomes

A meta-analysis was also performed to assess additional efficacy indicators for adolescent AD patients. The findings revealed that, in comparison to the placebo, both dosages of upadacitinib not only significantly elevated the proportion of individuals reaching EASI-90%, EASI-100%, and a reduction of ≥4 in NRS within 24 hours of administration but also substantially lowered the baseline levels of EASI, NRS, and SCORAD. This resulted in marked improvements in the overall eczema area, pruritus severity, and overall symptoms, demonstrating a dose-dependent relationship. Further details are provided in Table 2 and Figure S1, Supplemental Digital Content, http://links.lww.com/MD/N624.

Table 2 Meta-analysis of other efficacy and other safety measures.

Outcome	Intervening measure	Dosage	Study	I 2	Analysis mode	WMD/OR	95% CI	P value	
EASI-90%	Upadacitinib vs PBO	15 mg	4[17–20]	72%	Random-effect	11.55	(2.65, 50.46)	.001	
30 mg	59%	26.09	(7.61, 89.46)	<.00001	
EASI-100%	Upadacitinib vs PBO	15 mg	3[17,19,20]	11%	Fixed-effect	7.11	(2.56, 19.75)	.0002	
30 mg	7%	13.70	(5.07, 36.99)	<.00001	
24 hours NRS reduction ≥ 4	Upadacitinib vs PBO	15 mg	4[17–20]	30%	Fixed-effect	4.13	(1.57, 10.86)	.004	
30 mg	28%	7.49	(2.95, 19.01)	<.0001	
EASI baseline scores	Upadacitinib vs PBO	15 mg	3[17,19,20]	95%	Random-effect	−32.58	(−41.47, −23.69)	<.00001	
30 mg	82%	−39.92	(−44.45, −35.38)	<.00001	
NRS baseline scores	Upadacitinib vs PBO	15 mg	3[17,19,20]	64%	Random-effect	−32.81	(−37.91, −27.71)	<.00001	
30 mg	98%	−38.15	(−59.98, −16.33)	.0006	
SCORAD baseline scores	Upadacitinib vs PBO	15 mg	2[17,19]	0%	Random-effect	−31.62	(−34.23, −29.02)	<.00001	
30 mg	79%	−41.75	(−47.61, −35.90)	<.00001	
Blood creatine phosphokinase increased acne	Upadacitinib vs PBO	15 mg	4[17–20]	0%	Fixed-effect	2.38	(0.77, 7.36)	.13	
30 mg	0%	3.63	(1.17, 11.24)	.03	
	Upadacitinib vs PBO	15 mg	4[17–20]	0%	Fixed-effect	5.70	(2.11, 15.36)	.0006	
30 mg	0%	7.14	(2.69, 18.93)	<.0001	
Headache	Upadacitinib vs PBO	15 mg	3[17,19,20]	0%	Fixed-effect	1.70	(0.69, 4.22)	.25	
30 mg	0%	1.66	(0.67, 4.12)	.27	
Serious infection	Upadacitinib vs PBO	15 mg	3[17,19,20]	3%	Fixed-effect	1.49	(0.71, 3.16)	.29	
30 mg	0%	1.30	(0.60, 2.83)	.50	
Allergic dermatitis	Upadacitinib vs PBO	15 mg	3[17,19,20]	8%	Fixed-effect	0.35	(0.12, 0.99)	.05	
30 mg	0%	0.16	(0.04, 0.61)	.008	
Upper respiratory tract infection	Upadacitinib vs PBO	15 mg	4[17–20]	18%	Fixed-effect	2.12	(0.86, 5.19)	.10	
30 mg	0%	2.27	(0.93, 5.56)	.07	
Nasopharyngitis	Upadacitinib vs PBO	15 mg	4[17–20]	0%	Fixed-effect	1.36	(0.55, 3.32)	.50	
30 mg	36%	0.97	(0.38, 2.45)	.95	
Bold values indicate P > 0.05.

CI = confidence intervals, EASI = eczema area and severity index, NRS = numerical rating scale, OR = odds ratio, PBO = placebo, SCORAD = scoring atopic dermatitis.

3.3.7. Other security outcomes

A meta-analysis examining the rates of adverse reactions in adolescent AD patients showed that both doses of upadacitinib, relative to placebo, were linked to a markedly higher incidence of acne. Nevertheless, no significant differences were detected in the rates of headaches, serious infections, upper respiratory tract infections, and nasopharyngitis. Furthermore, the incidence of elevated blood creatine phosphokinase was found to be positively correlated with the dosage. Specifically, 30 mg upadacitinib notably raised the incidence of elevated blood creatine phosphokinase, whereas 15 mg upadacitinib did not exhibit a substantial variance compared to the placebo. Detailed findings are available in Table 2 and Figure S2, Supplemental Digital Content, http://links.lww.com/MD/N625.

3.4. Publication bias

According to the Cochrane Library Handbook, Chapter 5, it is advised that tests for funnel plot asymmetry or more advanced regression-based evaluations should incorporate a minimum of 10 studies. The rationale behind this recommendation is that conducting a meta-analysis with fewer studies diminishes the power of the test to identify any underlying asymmetry. Therefore, funnel plots were not constructed in this systematic review to evaluate potential publication bias.

4. Discussion

Research indicates that children with a familial history of AD exhibit a higher prevalence of the condition compared to other adolescents.[22,23] This heightened susceptibility is attributed to compromised epidermal barrier function resulting from mutations in epidermal structural proteins. Upadacitinib has been shown to enhance the differentiation of corneal-forming cells and the expression of epidermal-related proteins, leading to increased generation of filaggrin, loricin, and natural moisturizing factor, thereby mitigating skin surface damage and ulcers.[24,25] Given the differential expression of key cellular factors involved in inflammation and immunity across age groups, the targets and medications for managing AD vary accordingly.[26] Itchiness stands out as the predominant symptom in AD patients, often resulting in vigorous scratching that inflicts damage to the skin barrier, exacerbating the itching sensation and perpetuating a cycle of itch-scratch.[27] This poses a significant challenge for adolescents undergoing puberty. Studies suggest that the sensation of itch relies on neuron JAK1 signaling,[28] and upadacitinib can regulate autoimmune and inflammatory factors by inhibiting the JAK-STAT pathway, alleviating inflammation and immune responses universally, while also blocking JAK1 receptors to alleviate itching symptoms.[29]

The findings of this study reveal significant improvement in EASI scores, NRS scores, and SCORAD scores after 16 weeks of upadacitinib treatment compared to baseline. The percentage of adolescent patients achieving EASI-75%, EASI-90%, EASI-100%, IGA 0/1, and NRS reduction ≥ 4 saw significant increases, with statistically significant differences (P < .05). Systematic analysis indicated a marked reduction in itching symptoms in adolescent patients with NRS reduction ≥ 4 after a 24-hour upadacitinib treatment, regardless of the 15 or 30 mg dosage groups. Subgroup analysis outcomes indicated that both doses of upadacitinib had a significant effect on improving abnormal indicators in adolescents with moderate-to-severe AD, with the 30 mg dosage group exhibited greater improvement compared to the 15 mg group, displaying dose-dependent characteristic. Consequently, upadacitinib can improve overall symptoms, dermatitis area, and rapidly relieve itching in adolescents with moderate-to-severe AD.

In terms of safety, the incidence of adverse reactions in both upadacitinib dosage groups was significantly higher than in the placebo group (P < .05). A detailed analysis of specific adverse reactions in adolescents with AD was conducted cautiously due to the black box warning.[30] Notably, no instances of cancer, thrombosis, severe cardiac events, or mortality specified in the black box warning were observed among adolescent patients. Common adverse reactions recorded included elevated creatine phosphokinase, acne, headache, rhinopharyngitis, and infections. Acne occurrence notably increased in both upadacitinib dosage groups (P < .05), with the 15 mg group showing no significant difference in elevated occurrence rates of blood creatine phosphokinase elevation compared to the placebo, while a significant difference was evident in the 30 mg group. This suggests a dose-dependent relationship in adverse reactions. To be specific, if creatine phosphokinase ≥ 4 × upper limit of normal accompanied by symptoms suggestive of myositis or rhabdomyolysis, according to the clinical study protocol, the subjects were asked to interrupt upadacitinib. Fortunately, there were no adverse reactions such as myositis and rhabdomyolysis in both upadacitinib dosage groups-in other words, none has discontinued use because of elevated creatine phosphokinase in upadacitinib dosage groups. Therefore, based on the existing research, it is acceptable to maintain treatment was continued even if creatine phosphokinase elevations. There were no significant differences in severe adverse reactions compared to the placebo group. A 3-year clinical study on continuous upadacitinib treatment in adolescents with AD demonstrated sustained symptom improvement, particularly in rash area and itching severity.[31] Safety profiles remained consistent with the aforementioned results, with no severe adverse reactions reported in the black box warning. Overall, it indicates that most adverse reactions resulting from upadacitinib are mild and manageable.

This study encompassed 4 RCTs,[17–20] all of which were high-quality, randomized, double-blind, and multicenter trials. Nevertheless, there are limitations given that upadacitinib is a novel treatment approach necessitating further RCTs, particularly positive drug-controlled trials, for a comprehensive assessment of its efficacy and safety. Furthermore, long-term clinical research data remain limited, with only 1 trial conducted and a relatively small overall sample size. Consequently, there is a need for additional data for verification in the future.

5. Conclusion

The meta-analysis underscores that upadacitinib outperforms placebo in treating adolescents with moderate-to-severe AD, yielding prompt relief of skin itching, effective symptom improvement, and enhanced quality of life. The 30-mg dosage exhibits superior efficacy to the 15-mg dosage, with mild, tolerable adverse reactions, acceptable long-term safety, and a reduced risk of severe adverse reactions mentioned in the black box warning. Consequently, upadacitinib may be a convenient, effective and safe choice for adolescents with moderate-to-severe AD.

Author contributions

Conceptualization: Peng Tang.

Data curation: Lingmei Huang, Danjie Zhao.

Formal analysis: Lingmei Huang, Haixia Lin.

Methodology: Danjie Zhao, Hong Zheng, Xia Li, Long Chen.

Validation: Lingmei Huang, Danjie Zhao.

Writing – original draft: Danjie Zhao, Peng Tang.

Writing – review & editing: Lingmei Huang, Danjie Zhao, Peng Tang.

Supplementary Material

Abbreviations:

AD atopic dermatitis

AE serious adverse events

CI confidence intervals

EASI eczema area and severity index

FE fixed-effects

IGA investigator’s global assessment

JAK Janus kinase

NRS numerical rating scale

OR odds ratio

RCTs randomized controlled trials

SCORAD scoring atopic dermatitis

SAE serious adverse events

The authors have no funding and conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Supplemental Digital Content is available for this article.

How to cite this article: Huang L, Zhao D, Lin H, Zheng H, Li X, Chen L, Tang P. Efficacy and safety of upadacitinib in the treatment of moderate-to-severe atopic dermatitis in adolescents: A systematic review and meta-analysis of randomized controlled trials. Medicine 2024;103:38(e39826).

LH and DZ contributed equally to this work.
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