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Abstract

Objective: To evaluate the association between IL-25, IL-33 and AD more generally. Methods: Databases, including PubMed, Web of Science, EMBASE, Scopus, CNKI and Sinomed were searched. Based on the criteria, publications were collected. The evaluation of study quality was through Newcastle-Ottawa Scale (NOS). Fixed or random effect model was selected according to the between-study heterogeneity to evaluate the association. The analysis procedure and the construction plots were using Review Manager 5.3 software. Results: Six studies were included. A total of 282 subjects were included from four studies to analyze the association between IL-25 and AD. The level of IL-25 was significantly elevated in AD patients, comparing with the control subjects (SMD = 0.89, 95% CI: 0.64, 1.14, p < 0.05). For IL-33, a total of 247 subjects were included from two studies, and the level of IL-33 was also significantly elevated in AD patients comparing to the control subjects (SMD = 0.49, 95% CI: 0.19, 0.80, p < 0.05). Conclusions: The serum levels of IL-25, IL-33 are elevated in AD patients of this study. The IL-25 and IL-33 are significantly associated with the risk of AD. Further studies with larger samples, in multiple countries and focused on different age groups are need.

Keywords

IL-25 IL-33 cytokine atopic dermatitis meta-analysis

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease, with a recurrent course and persistent pruritus.¹ AD affects about 20% of the pediatric population and 10% adults.^2,3 The prevalence of AD is increasing rapidly, especially in developing counties, and now, AD has been a global health issue, for the severity of disease burden to patients.⁴ Atopic dermatitis may be the first sign of other manifestations of allergic diseases, such as asthma, allergic rhinitis and food allergy, which called “atopic march”.⁵

The pathophysiology of AD is rather complex. Multiple factors contribute to the genesis of AD, including genetic factors, epidermal barrier, immunological factors, microbiome and so on.¹ These factors play key roles in the mechanism of AD. Also, those factors may interact with each other.⁶ Immunological factor is a key role in the pathophysiology of AD. Innate lymphoid cells (ILCs) and Th2 lymphocytes can stimulate the production of multiple cytokines, such as IL-4, IL-5, IL-13, IL-25 and IL-33.^1,7 On the surface of ILCs, various receptors were expressed, such as IL-25 receptor, IL-33 ST2 receptor, Thymic stromal lymphopoietin (TSLP) receptor. Those receptors are found to be over-expressed in the skin lesions of AD patients.^8,9

IL-25 is a member of IL-17 cytokine family, which contributes to the defend of extracellular pathogens and induces the inflammatory response.¹⁰ IL-25 is produced by Th2 cells and promotes the production of other type 2 cytokines.¹¹ In allergic diseases, studies found that IL-25 generated by memory Th2 cells can induce the inflammation in asthma and blockade of IL-25 can reduced the infiltration T cells in the airway.¹⁰ As a type 2 cytokine, IL-25 also takes part in the process of AD. Studies in mouse and patients found the elevated serum IL-25 levels in AD.^12,13 IL-33 belongs to IL-1 cytokine family. The receptors of IL-33 (ST2) are expressed on many cells, including Th2 cells, basophils, mast cells, and ILC2s. After the stimulation of IL-33, more cytokines and chemokines can be released.¹⁴ In keratinocytes, IL-33 is expressed constitutively. IL-33 acts as an alarmin in immune response.¹⁵ In AD, Nygaard et, al.¹⁶ found that IL-33 could be a critical biomarker.

Studies have investigated associations between IL-25, IL-33 and AD. However, drawbacks are existed for a single study. For example, the sample sizes and statistical power may be limited. Besides, among different studies, divergent results may be shown. We performed this meta-analysis, aiming to evaluate the association between IL-25, IL-33 and AD more generally.

Methods

Search for publications

Six databases, including PubMed, Web of Science, EMBASE, Scopus, CNKI and Sinomed, were searched to collect publications. The search strategies were shown in Supplementary material.

Criteria for publication selection

The inclusion criteria were as followed: (1) published studies on IL-25 or IL-33 and atopic dermatitis (AD); (2) the type was case–control study; (3) the diagnose of AD was under certain criteria; (4) control were healthy or disease-free individuals; (5) the level of IL-25 or IL-33 was shown or could be extracted; (6) publications in Chinese and English.

The exclusion criteria were as followed: (1) conference reports, case reports, reviews, commentary or animal studies; (2) overlapping data or duplicate published studies; (3) the data could not be obtained or calculated from the data shown in the publications.

Two researchers (Boyang Zhou and Surong Liang) completed the selection of the publications independently. When there met disagreements, another researcher (Xueping Yue) would check the publications and make the decisions.

Extraction of data

After the study was included, the following information was extracted: (1) author’s name and year of publication, as study ID; (2) country/region where the study conducted; (3) diagnostic criteria of AD; (4) case numbers of AD and control subjects; (5) age of AD and control subjects; (6) method and unit of the detection; (7) level of IL-25 or IL-33. Two researchers (Boyang Zhou and Shuai Shang) conducted the extraction of the information. Another researcher (Xueping Yue) would check the input results and make corrections if possible.

Quality assessment

Case–control studies were included. The evaluation of study quality was based on Newcastle-Ottawa Scale (NOS).¹⁷ The NOS possesses a total score of 9, which consists of scoring for selection, comparability and exposure. For each study, the total score ≥6 can be considered as high-quality. Two researchers (Boyang Zhou and Shuai Shang) conducted the assessment. When there met inconsistency, another researcher (Xueping Yue) would re-assess the quality, and the final score was made after discussion.

Statistical analysis

In the data combination procedure, fixed or random effect model was selected according to the between-study heterogeneity. I² test were used to evaluate the heterogeneity. When I²>50% and p-value <0.10, the heterogeneity was significant, and the random effect model was selected. Otherwise, the fixed effects model was used. Sensitivity analysis was then performed through omitting each study one by one in each comparison, aiming to test the impact of a single study. If there were five or more studies included in a comparison, publication bias was assessed by funnel plot. The analysis procedure and the construction plots were using Review Manager 5.3 software.

Results

Selection for inclusion of the publications

For IL-25, a total of 1212 publications were obtained. Then, after duplicated ones were removed, there were 732 publications for screening the tittle and abstract. In this procedure, 10 publications were first included. After checking the whole content, four studies were included for meta-analysis based on the criteria.

For IL-33, a total of 3298 publications were obtained. Then, after duplicated ones were removed, there were 1812 publications for screening the tittle and abstract. In this procedure, 22 publications were first included. After checking the whole content, two studies were included for meta-analysis based on the criteria. The flowchart of the selection procedure was in Figure 1.

Figure 1.

Flowchart of selection 653x688 mm (168 x 168 DPI).

Main characteristics of studies

Six studies were included in our meta-analysis.^{13,16,18–21} Four studies reported association between IL-25 and AD.^13,18–20 A total of 162 AD patients and 120 control subjects were included. Among those studies, two were conducted in China^18,19 and two in Poland.^13,20 The diagnostic criteria were Wiiliams in two^18,19 and Hanifin and Rajka in two.^13,20 Two studies reported association between IL-33 and AD.^16,21 A total of 194 AD patients and 53 control subjects were included. In both studies, one was conducted in Japan²¹ and one in Denmark.¹⁶ The diagnostic criteria were both Hanifin and Rajka. The detailed characteristics were in Table 1 and the results of study quality assessment were in Table 2.

Table 1.

Information of included studies.

Study ID	Country	Diagnostic criteria	Number		Age (years)		Detection
Study ID	Country	Diagnostic criteria	AD	Control	AD	Control	Method	Unit	AD	Control
IL-25	—	—	—	—	—	—	—	—	—	—
Li 2015	China	Wiiliams	40	30	25.8 ± 10.57	23.8 ± 9.70	ELISA	ng/L	160.54 ± 34.89	120.41 ± 43.07
Jaworek 2020	Poland	Hanifin and rajka	31	20	Median 34	Median 27	ELISA	pg/mL	17.2 ± 3.0	15.2 ± 3
Basałygo 2021	Poland	Hanifin and rajka	43	22	26	29	ELISA	pg/mL	145 ± 98	74 ± 23
Yu 2022	China	Wiiliams	48	48	28.14 ± 9.42	27.94 ± 9.81	ELISA	ng/L	159.80 ± 33.46	123.34 ± 42.38
IL-33	—	—	—	—	—	—	—	—	—	—
Tamagawa-mineoka 2014	Japan	Hanifin and rajka	62	22	Meidan 31	Meidan 28	ELISA	pg/mL	391.98 ± 916.62	14.83 ± 19.64
Nygaard 2016	Denmark	Hanifin and rajka	132	31	21.4 ± 11.8	38.7 ± 14.9	ELISA	pg/mL	174.7 ± 210.0	76.3 ± 76.2

Table 2.

Study quality assessment through Newcastle-Ottawa Scale.

	Tamagawa-mineoka 2014	Li 2015	Nygaard 2016	Jaworek 2020	Basałygo 2021	Yu 2022
Selection	—	—	—	—	—	—
Adequate definition of cases	★	★	★	★	★	★
Representativeness of cases	★	★	★	★	★	★
Selection of control subjects	\	★	\	★	★	★
Definition of control subjects	★	★	★	★	★	★
Comparability	—	—	—	—	—	—
Control for important factors	★	★★	★	★	★	★★
Exposure	—	—	—	—	—	—
Exposure assessment	★	★	★	★	★	★
Same method of ascertainment for all subjects	★	★	★	★	★	★
Non-response rate	★	★	★	★	★	★
Total score	7	9	7	8	8	9

Results of the relationship

For IL-25, a total of 282 subjects were included from four studies.^13,18,19,20 The pooled data suggested that the level of IL-25 was significantly elevated in AD patients comparing to the control subjects, with SMD = 0.89 (95% CI: 0.64, 1.14), p < 0.05. The result was in Figure 2.

Figure 2.

Forest plot of association between IL-25 and AD 309x61 mm (168 x 168 DPI).

For IL-33, a total of 247 subjects were included from two studies.^16,21 The pooled data suggested that the level of IL-33 was significantly elevated in AD patients comparing to the control subjects, with SMD = 0.49 (95% CI: 0.19, 0.80), p < 0.05. The result was in Figure 3.

Figure 3.

Forest plot of association between IL-33 and AD 438x68 mm (168 x 168 DPI).

Evaluation of publication bias and sensitivity analysis

There were four and two studies included for both comparisons, and publication bias was not evaluated.

In sensitivity analysis, under the analysis comparison between IL-33 and AD, when the study Nygaard 2016¹⁶ was ignored, the significance vanished, with SMD = 0.47 (95% CI: −0.02, 0.96), p = 0.06. Sensitivity analysis indicated that the result of IL-33 and AD was not robust ideally (Figure 4).

Figure 4.

Forest plots of sensitivity analysis of IL-33 and AD: without Nygaard 2016 367x57 mm (168 x 168 DPI).

Discussion

The mechanism of AD is complex. Multiple factors contribute to the occurrence of disease synergistically. Immunological factor plays a key role.²² In this study, we analyzed the association between IL-25, IL-33 and AD through meta-analysis. Traditionally, the treatments of AD include skin care, topical corticosteroids and other anti-inflammatory drugs, oral corticosteroids, and oral cyclosporin.²³ These methods are slow on effects. Also, the efficacy is not perfect ideally. AD patients are in urgent need for the treatment method with better efficacy, for the psychopsychological impact and the huge burden of the disease.^24,25

With increasing researches on etiology and pathogenesis, more methods have been developed, one of which is monoclonal antibodies. Clinically, Dupilumab, a fully human monoclonal antibody that blocks the IL-4 and IL-13 pathway, has been proved with optimistic efficacy.^26,27 Dupilumab is the first monoclonal antibody that approved for the treatment of AD, and now the use of Dupilumab is expanding.²⁸ Recently, Tralokinumab, an anti-IL-13 monoclonal antibody was reported with optimistic effectiveness, and now was approved to AD in Europe and America.^29,30,31 Besides, there are many other antibodies which are under clinical trials, such as Lebrikizumab (anti-IL-13)³², Tezepelumab (anti-TSLP).³³ Apart from monoclonal antibodies, Janus kinase (JAK) inhibitors hold great potential to become a promising AD therapy.³⁴ Etokimab is an anti-IL-33 monoclonal antibody, and it is now under trials of AD.³⁵ Clinical trial performed by Chen et, al. Found that clinical benefit was observed in patients under Etokimab treatment.³⁶ Currently, there is no anti-IL-25 antibody approved for use clinically. Surprisingly, certain anti-IL-25 antibodies are under clinical trials of asthma in America and China. However, the use of anti-IL-25 antibodies on AD patients is lacking. We evaluated the association between IL-25, IL-33 and AD through meta-analysis, and our results can lay a basis for further investigation of related monoclonal antibodies.

In this meta-analysis, a total of 282 subjects, comprising 162 AD cases and 120 control subjects, were included from four studies for IL-25. The result demonstrated that the serum level of IL-25 was elevated in AD patients significantly comparing with the control subjects. From the sensitivity analysis, when each study was excluded from the comparison one by one, the significance did not alter, so the result of this comparison was robust. Therefore, from our analysis, the IL-25 is significantly associated with the risk of AD. IL-25 can promote the production of other Th2 cytokines. In an asthma model, the blockage of IL-25 could decrease the levels of these cytokines.³⁷ Through the inducing of Th2 cytokines in serum and skin, IL-25 participants in the genesis of AD.^13,38 Currently, clinical trials of IL-25 inhibitors are ongoing. However, these trails are mainly to asthma patients, while no ongoing trail targeting AD patients is reported up to now. From our results, the IL-25 inhibitors have the potential to be applied to AD patients. However, there is still a need to investigate the difference of IL-25 in patients with different ages, regions and gene backgrounds. Furthermore, investigations on polymorphisms of IL-25 gene are need. For example, the C424 C/A polymorphism, at exon two of the IL-25 gene, have been reported to be associated with multiple sclerosis.³⁹ The gene polymorphisms may alter the structure and function of IL-25. For AD patients, investigations of gene polymorphisms can provide more specific appliance of biological inhibitors.

For IL-33, a total of 247 subjects, comprising 194 AD cases and 53 control subjects, were included from two studies. The pooled data suggested that the level of IL-33 was significantly elevated in AD patients comparing to the control subjects. The sensitivity analysis showed that the result of IL-33 may not robust ideally, because when the study the study Nygaard 2016¹⁶ was ignored, the significance vanished, however, it was still near significance, with p = 0.06. From these results, it still can be concluded that IL-33 is associated with AD. IL-33 is a cytokine from the IL-1 family, and expressed in epithelial cells, endothelial cells and fibroblast-like cells. In homeostasis and inflammation, IL-33 both play important roles. In tissue damage or immune respond, IL-33 functions as an alarmin, to alert cells to express ST2 receptor and cytokines.⁴⁰ The main targets of IL-33 include ILC2s, regulatory T cells (Tregs) and so on.⁴¹ These cells are also vital in AD. IL-33 can reduce skin barrier function, and mediate pruritus. IL-33 activates ILC2 and Th2 cells to produce type2 cytokines to form skin lesions.¹⁵ IL-33 is involved in the pathogenesis of AD through multiple pathways. Clinical trial showed optimistic efficacy of etokimab. With increasing trails of the anti-IL-33 monoclonal antibody on AD, in the future, it has the potential to be approved for AD patients. To use the treatment methods to patients from different regions, with different genetic background more specifically, more studies on the polymorphisms of IL-33 to AD are need.

To our knowledge, this is the first meta-analysis study focusing on the IL-25, IL-33 and atopic dermatitis. IL-25 and IL-33 are both type 2 cytokines. Along with thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 act as alarmins in type 2 immunity. When cells and tissues are damaged or triggered by allergens or pathogens, those alarmins were produced, which can promote the production of other cytokines.⁴² In AD, Salimi et, al. Found that genes encoding of the IL-25 receptor, and IL-33 receptor demonstrated up-regulation clearly in skin samples of the lesions.⁴³ In the skin, IL-25 can inhibit expression filaggrin and act with other cytokines; besides, overexpression of IL-33 of skin can lead to skin inflammation. As a result, the skin barrier defects were caused.⁴⁴ AD is associated with other diseases or conditions, such as asthma, rhinitis, food or inhalant allergy, which defined as “atopic march”.^45,46 Besides skin, IL-25 and IL-33 were also associated with other inflammation diseases through the interaction with other cells, cytokines and chemokines.⁴⁴ For patients with AD or other type 2 inflammation diseases, more benefits may be obtained with treatment methods with both targets. Like Dupilumab which blocks IL-4 and IL-13, current studies provide a basis to investigate further biologicals blocking both IL-25 and IL-33.

There were some limitations that showed in our study. Firstly, the location of the included studies was limited in Asia and Europe, so more studies in other regions are still need. Secondly, the number of included studies in both comparisons were less than five, therefore the publication bias was not evaluated. Also due to the included studies, further analysis by different subgroups was not performed.

Conclusions

This meta-analysis study revealed that the serum levels of IL-25, IL-33 are elevated in AD patients. The IL-25 and IL-33 are associated with the risk of AD. Further studies with larger samples, in multiple countries and focused on different age groups are need.

Supplemental Material

Supplemental Material - Association between IL-25, IL-33 and atopic dermatitis: A systematic review and meta-analysis

Supplemental Material for Association between IL-25, IL-33 and atopic dermatitis: A systematic review and meta-analysis by, Boyang Zhou, Xueping Yue, urong Liang, Shuai Shang, Lujing Xiang, Kefei Zhou, and Linfeng Li in European Journal of Inflammation.

Footnotes

Declaration of conflict interest

The authors declare no potential conflicts of interest with respect to research, authorship and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Beijing Municipal Natural Science Foundation (7222037).

ORCID iDs

Boyang Zhou

Linfeng Li

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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Association between IL-25,IL-33 and atopic dermatitis: A systematic review and meta-analysis

Abstract

Keywords

Introduction

Methods

Search for publications

Criteria for publication selection

Extraction of data

Quality assessment

Statistical analysis

Results

Selection for inclusion of the publications

Main characteristics of studies

Results of the relationship

Evaluation of publication bias and sensitivity analysis

Discussion

Conclusions

Supplemental Material

Supplemental Material - Association between IL-25, IL-33 and atopic dermatitis: A systematic review and meta-analysis

Footnotes

Declaration of conflict interest

Funding

ORCID iDs

Supplemental Material

References

Supplementary Material