Efficacy and safety of tralokinumab in the treatment of atopic dermatitis: A systematic review and meta-analysis of randomized controlled trials

Background:

To assess the efficacy and safety of Tralokinumab in the treatment of moderate-to-severe atopic dermatitis (AD).

Methods:

PubMed, Embase, Clinical Trials Website, and Cochrane Library were systematically searched for eligible randomized controlled trials which assessed the effects of Tralokinumab on AD. Primary outcomes included Scoring Atopic Dermatitis score, EASI-75%, and Investigator’s Global Assessment score of 0 or 1 in 12 to 16 weeks. Secondary outcomes included the Eczema area and severity index score, the Numeric Rating Scales score, the dermatology life quality index score, and the overall incidence of adverse events. The quality of included studies was evaluated using the Cochrane System and the modified Jadad scale. Analysis was performed using Stata 16 software.

Results:

Eight randomized controlled trials involving 2878 patients were included in this meta-analysis. Compared to placebo, Tralokinumab treatment exhibited a significantly higher Scoring Atopic Dermatitis score [SMD = −0.53, 95% confidence intervals [CI]: −0.62 to −0.44, P < .00001], an increased number of patients with EASI-75% [odds ratio (OR) = 2.44, 95% CI: 2.00–2.97, P < .00001] and Investigator’s Global Assessment score of 0 or 1 in 12 to 16 weeks [OR = 2.12, 95% CI: 1.71–2.63, P < .00001]. No significant difference was observed in the incidence of overall adverse events [OR = 1.00, 95% CI: 0.85–1.18, P = 1.00] between the 2 groups.

Conclusion:

Tralokinumab is effective and safe in treatment of moderate-to-severe AD.

1. Introduction

Atopic dermatitis (AD), a chronic inflammatory skin disorder,^[1] affects up to 20% of the global population.^[2] AD showed a diverse range of clinical symptoms and manifestations, including persistent pruritus, pain, xerosis, fissuring or hyperpigmentation of the skin, crusting and exudation.^[3] The symptoms of AD generally appear before the age of 5 in 85% to 90% of patients, and may persist, recur, or worsen over time, which significantly affect their mental health and the quality of life.^[4,5] Systemic therapeutic agents for this condition primarily consist of second-generation nonsedating antihistamines, glucocorticoids, and immunosuppressive agents such as cyclosporine, methotrexate, and azathioprine.^[6] Although cyclosporine is the most effective systemic treatment for AD, its narrow therapeutic index increases the risk of nephrotoxicity and infection with long-term use. Thus, the development of novel therapeutic agents for AD with higher efficacy and safety is imperative.^[7–10] In recent years, the biological therapy has emerged as a promising avenue for AD treatment, such as anti-IL-4Ra (dupilumab),^[11] Janus kinase inhibitors (upadacitinib and abrocitinib),^[12,13] topical phosphodiesterase-4 inhibitors (difamilast),^[14] and interleukin 13 (IL-13) blockers like Lebrikizumab and tralokinumab.^[15]

Tralokinumab, a fully humanized IgG4 monoclonal antibody that specifically targets IL-13, has been approved by both the U.S. Food and Drug Administration and the European Union for treating moderate-to-severe atopic dermatitis since 2021. One meta-analysis has evaluated the efficacy and safety of IL-13 inhibitors in the treatment of moderate-to severe AD.^[16] However, the therapeutic effect of tralokinumab might be partially veiled by pooling different doses of lebrikizumab and tralokinumab together, which may result in heterogeneity and biased effect estimates as these medications can have substantial dose-response effects. Currently, emerging studies have investigated the effects of Tralokinumab on AD.^[17–19] Based on the latest research findings, this study systematically evaluated the efficacy and safety of Tralokinumab for the treatment of moderate-to severe AD.

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.

2.2. Literature search

PubMed, Embase, Clinical Trials Website, and Cochrane Library databases were searched from the first record to April 20, 2023 using the following terms: “Atopic dermatitis” and “anti-IL-13 or Tralokinumab or CAT-354.” Additional studies were retrieved by checking the reference lists of relevant studies.

2.3. Inclusion and exclusion criteria

Inclusion criteria: Design: randomized controlled trials (RCTs); Population: Moderate-to-severe AD ≥ 1 year; Atopic dermatitis involving ≥ 10% of the body surface area, overall Investigator’s Global Assessment score ≥ 3; Eczema area and severity index (EASI) score ≥ 12; Not suitable for local treatment or local treatment cannot adequately control the disease; Age ≥ 12 years; Intervention: Tralokinumab (600 mg loading dose, 300 mg Q2W); Control: Placebo; and Primary outcomes: The baseline change in the Scoring Atopic Dermatitis score in 12 to 16 weeks Scoring Atopic Dermatitis score (SCORAD score); The percentage of cases showing at least 75% reduction of EASI in 12 to 16 weeks (EASI-75%); The percentage of cases showing an Investigator’s Global Assessment score of 0 or 1 in 12 to 16 weeks (IGA 0/1). Secondary outcome: The baseline alterations of the Eczema area and severity index score (EASI score) in 12 to 16 weeks (EASI score); The Numeric Rating Scales score: the number of patients with a reduction in the score by at least 4 The Numeric Rating Scales score (NRS score); the baseline changes in the Dermatology Life Quality Index score (DLQI score); The total adverse effect rate: During the course of the trial, the subjects had all physical abnormalities unrelated to the purpose of the treatment (AE); The serious adverse effect rate: During the course of the trial, subjects were hospitalized for adverse reactions or reactions that were life threatening or resulted in permanent or significant damage to the body or organs serious adverse effects.

Patients that previously received Tralokinumab, or systemic immunosuppressive drugs, or phototherapy in the last 2 to 6 weeks were excluded. Reviews, conference abstracts, letters, retrospective or case series were excluded.

2.4. Study selection

Two authors independently reviewed the identified studies. The full text of the relevant articles was reviewed after screening their titles and abstracts. Disagreements were resolved by discussion with another author.

2.5. Data extraction

The following information was extracted: authors, publication year, characteristics of patients, interventions, background treatment, number of cases, duration of treatment, outcome indicators, and the items for evaluating the quality of included studies.

2.6. Risk of bias assessment

The quality of the included studies was assessed following the risk of bias assessment form provided by the Cochrane systematic evaluation manual, and was scored using a modified Jadad scale. Studies with randomization, allocation concealment and double-blind methods were scored as 2, those with unclear methods were scored as 1, and those with inappropriate methods were scored as 0. Studies with withdrawal or missing visit description were scored as 1, and studies that did not provide any description were scored as 0. The total score was 7. A total score of 4 or less indicated a poor quality of the study.

2.7. Data analysis

Data analysis was performed using Review Manager 5.3 (The Cochrane Collaboration, UK) and Stata 16 (Stata Corporation, CollegeStation, USA). Dichotomous variable information (e.g., IGA 0/1) and continuous variable information (e.g., EASI score) were present using odds ratio (OR) and weighted mean difference with 95% confidence intervals (CI), respectively. The χ² test was performed to test the heterogeneity among included studies. Fixed-effects model was used when statistical heterogeneity was low (P > .1 and I² ≤ 50%); otherwise, random-effects model was used. The source of heterogeneity was examined through subgroup analysis and sensitivity analysis. The risk of publication bias was analyzed using Egger test.

3. Results

3.1. Study characteristics

According to the search strategy, 585 relevant studies were initially retrieved. Seven studies containing 8 RCTs^[17–23] (one of which included clinical trial data) were finally included through screening and reading of the full text. The flowchart of study selection was shown in Figure 1. Among these included studies, 5 were conducted in different regions and races,^[17,20–23] 6 were large-scale population studies^{[17,19,21–23]} that were published between 2019 and 2023. One study involved 2 randomized, placebo-controlled trials.^[21] The duration of studies ranged from 12 weeks to 16 weeks. The dosage of Tralokinumab supplementation used in all included studies were 300 mg biweekly and the first dose of double. Based on the criteria of Jadad score, all included studies were rated as high quality. The basic features of included studies were shown in Table 1.

Figure 1.

The flow diagram of study selection.

Table 1.

Study characteristics.

Study (yr)	Intervening measure	N	Age/Year	Gender/n		Treatment/Week	Outcome	Jaded score
				Male	Female
Wollenberg A (2021a)[11]	Tralokinumab 300 mg q2w	603	38.6 ± 13.7	351	252	16	①②③④⑤⑥⑦⑧	7
	Placebo	199	39.4 ± 15.2	123	76	16
Wollenberg A (2021b)[11]	Tralokinumab 300 mg q2w	593	37.2 ± 14.7	359	234	16	①②③④⑤⑥⑦⑧	7
	Placebo	201	35.1 ± 14.0	114	87	16
Silverberg JI (2021)[12]	Tralokinumab 300 mg q2w	253	39.8 ± 15.3	125	128	16	①②③④⑤⑥⑦⑧	7
	Placebo	127	37.7 ± 14.8	84	43	16
Gutermuth J (2022)[13]	Tralokinumab 300 mg q2w	140	33.0 ± 12.3	82	58	16	①②③⑤⑥⑦⑧	7
	Placebo	137	34.0 ± 9.5	83	54	16
Wollenberg A (2019)[14]	Tralokinumab 300 mg q2w	52	35.7 ± 14.6	33	19	12	①③④⑥⑦⑧	7
	Placebo	51	39.4 ± 14.5	22	29	12
NCT03526861 (2021)[15]	Tralokinumab 300 mg q2w	101	14.6 ± 1.8	49	52	16	①②③④⑤⑥⑦⑧	7
	Placebo	100	14.4 ± 1.6	54	46	16
Wollenberg A (2022)[16]	Tralokinumab 300 mg q2w	107	34.0 ± 11.2	54	53	16	②③⑦⑧	7
	Placebo	108	34.4 ± 10.8	35	73	16
NCT04587453 (2022)[17]	Tralokinumab 300 mg q2w	53	39.0 ± 13.7	36	17	16	①②③⑤⑥⑦⑧	7
	Placebo	53	38.9 ± 12.1	31	22	16

① The baseline change in the SCORAD score in 12–16 weeks (SCORAD score); ② The percentage of cases showing at least 75% reduction of EASI in 12–16 weeks (EASI-75); ③ The percentage of cases showing an IGA score of 0 or 1 in 12–16 weeks (IGA 0/1); ④ The baseline alterations of the EASI score in 12–16 weeks (EASI score); ⑤ The NRS score: the number of patients with a reduction in the score by at least 4 (NRS score); ⑥ the baseline changes in the DLQI score (DLQI score); ⑦ The total adverse effect rate; ⑧ The serious adverse effect rate.

3.2. Quality evaluation

All included studies were randomized, double-blind clinical trials that described specific protocols for allocation concealment and random sequence generation. Moreover, all studies mentioned dropouts and lost visits, and all had Jadad scores of 7. The detailed information for the risk of bias of the included studies were shown in Table 2.

Table 2.

The quality assessment of each included study.

Study (yr)	Random			Blinding			Lost/Exit		Total
	Without/Unclear/False	Mentioned but No specific method	“Random” and describe the correct method	Without/False	Mentioned but No specific method	“Double-blind”and describe the correct method	Not mentioned	Description of cases and reasons	Score
Wollenberg A (2021a)[11]	2		1	2		1		1	7
Wollenberg A (2021b)[11]	2		1	2		1		1	7
Silverberg JI (2021)[12]	2		1	2		1		1	7
Gutermuth J (2022)[13]	2		1	2		1		1	7
Wollenberg A (2019)[14]	2		1	2		1		1	7
NCT03526861(2021)[15]	2		1	2		1		1	7
Wollenberg A (2022)[16]	2		1	2		1		1	7
NCT04587453(2022)[17]	2		1	2		1		1	7

Studies with randomization, allocation concealment and double-blind methods were scored as 2, those with unclear methods were scored as 1, and those with inappropriate methods were scored as 0; Studies including withdrawal or missing visit description were scored as 1, and studies that did not provide any description were scored as 0. The total score was 7. A total score of 4 or less indicated that the quality of the study was poor.

3.3. Results of meta-analyses

3.3.1. SCORAD score.

Six studies^[17–21,23] reported changes in the SCORAD score in patients receiving Tralokinumab. As the heterogeneity across the articles was low (P = .27 and I² = 21%), we selected the fixed-effects model. The patients receiving Tralokinumab showed significant relief SCORAD scores compared to those with placebo [SMD = −0.53, 95% CI: −0.62 to−0.44] (P < .00001) (Fig. 2).

Figure 2.

A Forest plot showing that Tralokinumab reduced SCORAD scores compared to placebo.

3.3.2. EASI-75%.

Six studies^{[17–19,21–23]} reported changes in the EASI-75% population after treatment with Tralokinumab. Fixed-effects model was selected according to the heterogeneity across studies (P = .14 and I² = 38%). The results showed that the number of patients with the desired EASI-75% was significantly higher in the Tralokinumab group than that in the placebo group [OR = 2.44, 95% CI: 2.00 to 2.97] (P < .00001) (Fig. 3).

Figure 3.

A Forest plot showing that the number of patients with the desired EASI-75% was significantly higher in the Tralokinumab group than that in the placebo group.

3.3.3. IGA 0/1.

Seven studies^[17–23] reported IGA 0/1. As the heterogeneity among the articles was low (P = .71 and I² = 0%), we selected a fixed-effects model. The number of patients with the desired IGA 0/1 scores was significantly higher in the Tralokinumab group [OR = 2.12, 95% CI: 1.71–2.63] (P < .00001) (Fig. 4).

Figure 4.

A Forest plot showing that the number of patients with the desired IGA 0/1 scores was significantly higher in the Tralokinumab group than that in the placebo group. IGA 0/1 = Investigator’s Global Assessment score of 0 or 1 in 12 to 16 weeks.

3.3.4. The incidence of overall side effects.

Seven studies^[17–23] reported the incidence of the overall side reaction. Using a fixed-effects model (P = .05, I² = 49%), no significant difference was found between the Tralokinumab group and the placebo group [OR = 1.00, 95% CI: 0.85–1.18] (P = 1.00) (Fig. 5).

Figure 5.

A Forest plot showing that no significant difference was found between the Tralokinumab group and the placebo group.

3.3.5. Other efficacy outcomes.

More effective indicators were also found in the patients from the Tralokinumab group, including the EASI score [SMD = −0.58, 95% CI: (−0.68,−0.49)] (P < .00001); the NRS score [SMD = 1.88, 95% CI: (1.52, 2.34)] (P < .00001); and the DLQI score [SMD = –0.40, 95% CI: (−0.48,−0.31)] (P < .00001). (Table 3).

Table 3.

Meta-analysis of other efficacy and safety measures.

Outcome	N	Intervening measure	Study	I 2	Analysis mode	SMD/OR	95% CI	P value
EASI Score*	2214	Tralokinumab vs Placebo	5 [11–12,14–15]	19%	Fixed-effect	−0.58	(−0.68, −0.49)	<.00001
NRS Score†	2499	Tralokinumab vs Placebo	6 [11–13,15,17]	42%	Fixed-effect	1.88	(1.52, 2.34)	<.00001
DLQI Score‡	2634	Tralokinumab vs Placebo	7 [11–15,17]	5%	Fixed-effect	−0.40	(−0.48, −0.31)	<.00001
Serious adverse events	2857	Tralokinumab vs Placebo	8 [11–17]	0	Fixed-effect	0.58	(0.35, 0.95)	.03
Injection site reactions	1748	Tralokinumab vs Placebo	5 [11–13,15,17]	0	Fixed-effect	10.90	(3.24, 36.61)	.0001
Upper respiratory tract infection	1953	Tralokinumab vs Placebo	6 [11–15]	0	Fixed-effect	1.22	(0.85, 1.76)	.29
Headache	1959	Tralokinumab vs Placebo	6 [11–15]	0	Fixed-effect	1.48	(0.98, 2.23)	.06
Conjunctivitis	2434	Tralokinumab vs Placebo	5 [11–13,15]	0	Fixed-effect	2.45	(1.36, 4.41)	.003

CI = confidence intervals, OR = odds ratio.

^*EASI Score: The baseline alterations of the EASI score in 12–16 weeks.

^†NRS Score: The NRS score: the number of patients with a reduction in the score by at least 4.

^‡DLQI Score: the baseline changes in the DLQI score.

3.3.6. Other security outcomes.

Tralokinumab group showed a significantly lower incidence of severe side reaction compared to the placebo group [OR = 0.58, 95% CI: (0.35, 0.95)] (P = .03). However, the incidences of pain reactions at the injection site [OR = 10.90, 95% CI: (3.24, 36.61)] (P = .0001) and conjunctivitis [OR = 2.45, 95% CI: (1.36, 4.41)] (P = .003) were significantly higher in the Tralokinumab group than those in placebo group. Other safety outcomes, such as headache, did not exhibit any significant difference between these 2 groups [OR = 1.48, 95% CI: (0.98, 2.23)] (P = .06) (Table 3).

3.3.7. Publication bias.

The funnel plot was not performed to assess possible publication bias because the number of included studies was <10.

4. Discussion

Atopic dermatitis is the primary contributor to the global burden of skin diseases, and affect an estimated 230 million individuals worldwide.^[24] The incidence of atopic dermatitis continues to rise annually.^[25] In recent years, significant advancements have been made in comprehending this disease’s pathogenesis. Along with previously recognized Th1 and Th2 immune responses, numerous critical immune cells and cytokines such as Th17, Th22, and IL-13 are identified in AD pathogenesis.^[7–10,21] However, the therapeutic outcomes for AD patients remain unsatisfactory, prompting the development of novel biological agents with higher efficacy and fewer side effects.^[26] It is worth noting that several studies have shown that IL-4 and IL-13 affect the microenvironment of skin tumors as well as disease progression.^[27] Additionally, some patients with severe and rapidly developing AD are eventually diagnosed with skin cancer.^[28] Therefore, it is necessary to perform a biopsy on the skin lesion to make a precise diagnosis, especially for AD patients aged 40 years or older. Subsequently, a close pathological examination should be conducted to rule out the possibility of misdiagnosis or progression into skin cancers.

IL-13 is a type 2 immune cytokine that has been underutilized in the treatment of atopic dermatitis.^[15] Recent studies^[15,29] have demonstrated the role of IL-13 in AD, including recruitment of inflammatory cells, alterations to the skin microbiome, impaired epidermal barrier function, and stimulation of peripheral sensory neurons that induce pruritus.^[1] Considering the strong effects of IL-13 on the occurrence and progression of AD, it is necessary to develop strategies to inhibit its activity. Tralokinumab, as the first agent that can specifically bind and inhibit IL-13 cytokine, can prevent IL-13 from binding to IL-13Rα1/IL-13Rα2 by combining with the epitope of IL-13 and overlapping with the binding site of the IL-13Rα receptor.^[30] Firstly, Tralokinumab can promote and enhance the regeneration of skin cells by inhibiting STAT6 activation and increasing AMP production by keratinocytes.^[15,31] Secondly, Tralokinumab can alleviate Th2-mediated inflammation by suppressing eosinophil recruitment, IgE production, and Th2 cell differentiation.^[32] Thirdly, Tralokinumab exhibits clinically significant efficacy in reducing AD severity through downregulating YKL-40 levels.^[33] Finally, Tralokinumab can mitigate pruritus by inhibiting the stimulation of peripheral itch-sensory neurons,^[34] thereby ameliorating AD symptoms.

Compared to the placebo, we showed that treatment with Tralokinumab significantly reduced SCORAD scores, increased EASI scores and DLQI scores, and increased the number of patients with EASI-75%, IGA 0/1, and NRS scores. This suggests that Tralokinumab can significantly reduce the area of eczema, the degree of pruritus, and overall symptoms, as well as improve the quality of life for patients. In terms of safety, there was no statistical difference in the incidence of overall adverse reactions between patients receiving Tralokinumab and those receiving placebo. However, injection site reactions and conjunctivitis were significantly increased among patients who received Tralokinumab as compared to placebo. Therefore, patients should take care of the injection site and those with a history of eye diseases should be treated with caution.

For serious adverse reactions, the placebo group showed higher incidence than the Tralokinumab group. However, the incidence of serious adverse reactions showed no difference when excluded 1 study that included patients who were 12 to 17 years old.^[17] We thus speculated that Tralokinumab might have a higher safety profile for adolescents, suggesting that Tralokinumab could be the next dupilumab, which is a biological agent approved to treat children with moderate-to-severe AD. More clinical studies are required to evaluate the effects of Tralokinumab in the treatment of AD in children.

Although Tralokinumab’s efficacy in treating AD has been evaluated in 1 meta-analysis^[16] consisting of 5 RCTs,^[20–23] our study further incorporated 3 recently published RCTs and showed several novel findings.^[17–19] Firstly, we observed that Tralokinumab treatment caused a significant increase in the risk of pain at the injection site. Secondly, heterogeneity across all outcomes was significantly reduced, making our results more convincing. Finally, we included 1 study which enrolled patients with AD aged between 12 and 17 years old,^[17] providing the first evidence for Tralokinumab treatment of AD in adolescents.

Eight RCTs,^[17–23] all of which were randomized, double-blind, multicenter studies with high quality (Jadad scores of 7), were included in this study. The overall quality of the studies was high. Additionally, 2 large multinational phase III studies^[21] demonstrated that Tralokinumab was well-tolerated over 52 weeks and had an overall frequency and severity of adverse events comparable to placebo, consistent with those observed in the phase II trial.^[20] Furthermore, long-term administration of Tralokinumab not only enhances skin colonization by Staphylococcus aureus, but also reduces the incidence of eczema.^[21] These findings suggest that Tralokinumab is effective and safe for prolonged treatment in AD.

This meta-analysis has several limitations. Firstly, more well-designed RCTs, particularly those with positive drug-controlled outcomes, are still necessary to evaluate the efficacy and safety of Tralokinumab for treating AD. Secondly, the sample size was relatively small. Finally, since moderate-to-severe AD often requires long-term treatment, the efficacy and safety of longer duration of Tralokinumab treatment for AD need to be determined in future studies.

5. Conclusion

This meta-analysis demonstrates that Tralokinumab is effective and safe in treating moderate-to-severe AD. Tralokinumab may be recommended as an option to treat moderate-to-severe AD in patients that do not respond well to other therapeutic agents.

Author contributions

Conceptualization: Xia Li, Hai-Xia Lin.

Data curation: Dan-Jie Zhao.

Formal analysis: Ling-Mei Huang, Long Chen.

Methodology: Dan-Jie Zhao, Jie Xiao.

Validation: Dan-Jie Zhao, Ling-Mei Huang.

Writing – original draft: Dan-Jie Zhao, Hai-Xia Lin.

Writing – review & editing: Xia Li, Hai-Xia Lin.