Effect of systemic immunomodulatory therapies on mental health in atopic dermatitis: a systematic review and network meta-analysis

doi:10.21203/rs.3.rs-5244528/v1

Background: Atopic dermatitis (AD) is a prevalent chronic skin condition that may cause significant mental health challenges, including anxiety and depression. This study aimed to evaluate the effects of different systemic immunomodulatory therapies on the anxiety and depression in patients with AD.

Methods: We searched the MEDLINE (via Ovid, from 1946), EMBASE (via Ovid, from 1974), the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov from the date of their inception to June 1, 2024. We included randomized controlled trials (RCT) involving both children and adults with moderate-to-severe atopic AD receiving systemic immunomodulatory therapies. Network meta-analysis were performed using mean changes from baseline and their standard deviations (SDs) by Bayesian random effects model. All analyses were conduct using R version 3.6.3.

Results: Eighteen RCTs reported in 15 studies involving 7,784 patients were eligible. The risk of bias of two outcomes reported in each trial were low or probably low. Measured by Hospital Anxiety and Depression Scale, high-certainty evidence demonstrated that “Abrocitinib (200 mg, oral, qd)” (anxiety: MD -1.2, 95%CI: -1.7 to -0.69; depression: MD -1.1, 95%CI: -1.8 to -0.29), “Dupilumab (300 mg, subcutaneously, q1w)” (anxiety: MD -1.9, 95%CI: -2.4 to -1.4, depression: MD -1.8, 95%CI: -2.7 to -0.85), “Dupilumab (300 mg, subcutaneously, q2w)” (anxiety: MD -1.7, 95%CI: -2.2 to -1.2; depression: MD -1.6, 95%CI: -2.3 to -0.76), and “Lebrikizumab (250 mg, subcutaneously, q2w)” (anxiety: MD -1.6, 95%CI: -2.3 to -0.97, depression: MD -1.6, 95%CI: -2.5 to -0.58), were the most effective drugs for both anxiety and depression in both adults and children patients, respectively; “Baricitinib (4 mg, oral, qd)” (MD -1.1, 95%CI: -1.9 to -0.34) was only efficient with depression.

Conclusions: Systemic immunomodulatory therapy could significantly alleviate anxiety and depression in patients with AD, particularly with the subcutaneous administration of Dupilumab at a 300 mg dose.

Atopic dermatitis

Immunomodulatory therapies

Anxiety

Depression

Network meta-analysis

Question

What is the impact of systemic immunomodulatory therapies on anxiety and depression in patients with atopic dermatitis (AD)?

Findings

In this systematic review and meta-analysis of 18 randomized controlled trials involving 7,784 patients, therapies such as Dupilumab and Abrocitinib significantly reduced anxiety and depression scores in both children and adults with moderate-to-severe AD, highlighting their dual benefit in treating skin symptoms and mental health concerns.

Meaning

This study provides valuable insights for clinicians by emphasizing the importance of addressing mental health in the management of AD.

Atopic dermatitis (AD) is a prevalent chronic skin condition characterised by recurrent episodes of inflammation, intense itching, and skin damage^1,2. Beyond its physical manifestations, individuals with AD frequently encounter significant mental health challenges, including anxiety and depression. A significantly association between adult AD and depression (OR 2.19, 95%CI 1.87–2.57) and anxiety (OR 2.19, 95% CI 1.75–2.73) has been reported, respectively; while AD has also been suggested to be associated with depression in children (OR 1.27, 95% CI 1.12–1.45)³. These mental health issues not only diminish the quality of life for patients but may also interfere with the effectiveness of treatments^3,4. Therefore, the comprehensive management of AD requires the involving of mental health promotion. In recent years, immunomodulatory therapies have become increasingly utilized in the treatment of AD, encompassing agents such as abrocitinib, baricitinib, dupilumab, and lebrikizumab^5–8. However, the impact of these agents on anxious and depressive symptoms remains uncertain, with some studies indicating that specific immunotherapies are associated with a significant reduction in anxiety and depressive symptoms, but others observe only marginal effects^7–10. This variability highlighting the need for a more systematic investigation.

This study aims to conduct a systematic review and network meta-analysis to evaluate the effects of different systemic immunomodulatory therapies on the anxiety and depression, with a view to provide reliable evidence for the selection of immunotherapy for the treatment of patients with AD.

This study was registered in PROSPERO (CRD42023426363), and conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) extension to NMA¹¹, as well as the methods outline in the Cochrane Handbook for Systematic Reviews of Interventions¹².

Search strategy

We searched the MEDLINE (via Ovid, from 1946), EMBASE (via Ovid, from 1974), the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov from the date of their inception to June 1, 2024, with no language restrictions. The full search strategy is detailed in the supplement material (appendix Text S1). Additionally, we searched grey literature and examined the reference lists of the included studies and relevant systematic reviews.

Eligibility criteria

We included trials involving both children and adults with moderate-to-severe atopic AD treated with systemic immunomodulatory therapies (e.g., oral, intravenous, or subcutaneous), with no restrictions on age or sex. There were no restrictions on the use of adjunctive topical anti-inflammatory therapies (e.g., corticosteroids, calcineurin inhibitors, phosphodiesterase inhibitors) and on comparator, including placebo. Outcomes related to anxiety and depression were included, with no restrictions on the measurement scale employed (e.g., Hospital Anxiety and Depression Scale, The Patient Reported Outcome Measurement Information System-anxiety/depression). Randomized controlled trials (RCTs) were included without restricting of the type, and for crossover RCTs, only data from before the crossover were used.

Two independent investigators screened titles and abstracts according to the above eligibility criteria, and the potentially relevant studies were further screened the full text. Any discrepancies were resolved by discussion between the two screeners and, when necessary, with a third review author. We completed the screening process using Covidence software (www.covidence.org).

Data collection

The following information were independently extracted using a standardized and pre-piloted spreadsheet: first author, publication year, study location, trial name and registration number, duration of AD, sample size, age, percentage of males, baseline scores of Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scales (PP-NRS), intervention details (eg, name, dose, frequency, formulation, duration), concurrent treatments during the study, and outcomes. When data were not reported, the authors of the original studies were contacted to provide the missing information. Data presented only in figures and/or graphs were converted to numerical values using Plot Digitizer software (http://plotdigitizer.sourceforge.net). If multiple records reported on a single trial, all available information was consolidated and treated as a single clinical trial. Conversely, if a single publication reported on two or more trials, each study was treated separately. Any discrepancies were resolved through discussion.

Quality assessment

The quality of included trials were independently assessed by two reviewers using the revised Cochrane risk-of-bias tool for randomised trials (RoB 2)¹³, and any discrepancies were resolved through discussion. RoB 2 is structured to provide judgements about the risk of eight different sources of bias: bias arising from the randomization process, bias arising from the randomization process, bias due to blinding of participants, bias due to blinding of intervention implementer, bias in measurement of the outcome, bias due to missing outcome data, bias in selection of the reported results, and other biases (eg, competing risks). Each domain can be judged as “low risk of bias”, “probably low risk of bias”, “probably high risk of bias” and “high risk of bias”. We judged missing data to be at low risk of bias if less than 20% was missing. We rated outcomes to be at high risk of bias if any domain was rated as “high risk of bias” or “probably high risk of bias”.

Data analysis

We conducted analyses following the intent-to-treat principle. Both outcomes (anxiety and depression) reported in this study are continuous outcomes. So, meta-analyses were performed using mean changes from baseline and their standard deviations (SDs)¹⁴. According to the Cochrane Handbook, we calculated mean changes and SDs from pre- and post-intervention data¹⁴. When SDs were not directly available and could not be confirmed via correspondence, we estimated them using provided data (standard errors, P values, confidence intervals, interquartile ranges, or graphs) per Cochrane guidelines¹⁴. In cases with no calculable SDs, we applied established imputation methods¹⁵. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were followed to convert all measures of the same outcome to the most familiar instrument for clinicians before conducting the meta-analysis^16,17.

Pairwise meta-analyses were performed for each direct comparison, summarizing continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). Network meta-analyses integrated both direct and indirect evidence within a Bayesian framework using a multivariate consistency model with random effects. Sensitivity analysis was performed using fixed effects meta-analysis for both outcomes¹⁶. Prespecified subgroup analyses were carried out for patient age (adults vs. children), with the credibility of subgroup effects assessed using the ICEMAN tool¹⁸.

We performed this network meta-analyses using the “gemtc” package in R version 4.6.3 (RStudio, Boston, MA)¹⁹.

Certainty of evidence

To assess the certainty of evidence for both outcomes, we used the GRADE approach in our network meta-analysis^20,21. We evaluated risk of bias, imprecision, inconsistency, indirectness, and publication bias, rating the certainty of evidence as high, moderate, low, or very low²¹. To address the transitivity assumption, we compared the distribution of potential effect modifiers (eg, risk of bias, mean age, proportion of males, distribution of race, duration of AD, treatment duration, baseline scores of Eczema Area and Severity Index, and baseline scores of Peak Pruritus Numeric Rating Scales) across treatments²². Imprecision at the network level was assessed using the minimally important difference (MID) as the threshold. In the absence of authoritative standards, we set the non-zero target of certainty (eg, any benefit or any harm relative to placebo, and interventions relative to one another) as the MID. We evaluated inconsistency (heterogeneity) in direct comparisons using visual inspection of forest plots and the I² statistic²³. Clinical experts assessed whether clinical heterogeneity was present. Publication bias was evaluated using funnel plots and the Egger test, as well as by reviewing trial registries for completed trials lacking corresponding publications or reports²⁴. We evaluated local incoherence using the node-splitting method and compared direct and indirect evidence within each closed loop of the network²⁵.

We ranked interventions based on the certainty of the evidence and Surface Under the Cumulative Ranking Curve (SUCRA) scores²⁶, classifying them into three categories of effectiveness. Interventions were categorized as “least effective (Category 0)” if their outcomes did not significantly differ from placebo; “inferior to the most effective but superior to the least effective (Category 1)” if they outperformed placebo but were not superior to other interventions; and “most effective (Category 2)” if they surpassed at least one category 1 intervention. For evidence rated as low or very low certainty, these categories were qualified with “may be” to reflect the uncertainty.

Our systematic search identified 13037 records from databases, as well as 3 studies identified from other ways, from which we included 18 eligible trials reported in 15 studies involving 7784 patients with sample sizes ranged from 211 to 708 (Fig. 1). Appendix Text S2 lists the eligible trials.

Characteristics of trials

The participants included in the 18 trials were all with a confirmed diagnosis of choric AD. Detailed inclusion and exclusion criteria are provided in appendix Table S1. The trials, conducted from 2016 through 2023, with ten trials including adult patients only ^27–34, three trials including only children^35–37, five trials including both children and adults^38–41. The median of mean age was 35.6 years. The median proportion of men was 57.2%, and the median proportions of White, Black, and Asian individuals were 67.6%, 8.2%, and 19.4%, respectively. The median of mean duration of AD was 23.61 years, with a baseline median of mean EASI scores of 30.2, and the baseline median of mean PP-NRS scores of 7.1. Eleven trials reported that participants received other treatments other than the systemic immunomodulatory drugs during the trial, and all trials reported funding support from pharmaceutical companies.

Four unique systemic immunomodulatory drugs were investigated among the included studies, namely Abrocitinib, Baricitinib, Dupilumab and Lebrikizumab, compared with the common comparator placebo (Table 1). Abrocitinib is an oral medication available in doses of 10 mg, 30 mg, 100 mg, and 200 mg, taken once daily, with treatment duration of either 12 weeks or 16 weeks. Baricitinib in doses of 1 mg, 2 mg, and 4 mg, oral, taken once daily, with a treatment course of 16 weeks. Dupilumab and Lebrikizumab are both subcutaneous injection drugs with a treatment duration of 16 weeks, and they have various administration methods (see detail in appendix Table S2).

Table 1

The Characteristics of included trials
Study	Duration of AD (Mean, SD; years)	Age group	Sample sizes	Age (Mean, SD; years)	Male, %	White, %	Black, %	Asian, %	EASI (Mean, SD)	PP-NRS (Mean, SD)	Treatments received during study	Funding
Bieber 2021	22.68, 15.59	Adults	595	37.89, 14.74	50.59%	72.27%	3.53%	22.18%	31.14, 13.12	7.3, 1.7	therapy with topical or systemic medication when required	Pfizer
Eichenfield 2021	10, 5.2	Children	287	14.9, 1.7	50.52%	55.75%	5.92%	32.75%	29.9, 12.5	7, 1.8	therapy with topical or systemic medication when required	Pfizer
Silverberg 2020	21, 14.7	Both	391	35.1, 15.1	58.57%	59.34%	5.37%	32.99%	28.5, 11.5	7, 1.7	Not report	Pfizer
Simpson 2020	23.55, 15.09	Both	387	32.54, 15.98	56.85%	72.09%	8.27%	14.99%	30.5, 13.54	7, 1.91	Not report	Pfizer
Gooderham 2019	23.9, 16.06	Adults	269	40.8, 15.92	45.72%	72.49%	14.50%	10.04%	25.4, 12.33	7.4, 2.09	Not report	Pfizer
Reich 2020	24.04, 13.38	Adults	329	33.8, 12.43	65.65%	45.59%	NR	51.06%	29.57, 12.22	7.13, 1.93	Corticosteroids	Incyte Corporation
Simpson 2021	23.67, 16.62	Adults	440	39.67, 16.31	50.91%	57.05%	18.18%	18.41%	27.1, 11.31	7.17, 2.17	Not report	Incyte Corporation
Bieber 2022	26.08, 14.99	Adults	463	38.2, 13.6	64.15%	77.75%	2.38%	19.22%	31.82, 12.69	6.78, 2.06	Not report	Eli Lilly and Company
Simpson 2020(BREEZE-AD1)	25.81, 15.04	Adults	624	35.6, 12.8	62.66%	58.65%	NR	30.29%	31.19, 12.41	6.48, 2.05	Not report	Incyte Corporation
Simpson 2020(BREEZE-AD2)	24.2, 13.79	Adults	615	34.59, 12.69	61.95%	68.46%	NR	29.76%	33.4, 13.42	6.64, 2.19	Not report	Incyte Corporation
de Bruin-Weller 2018	29.85, 16.34	Adults	325	38.4, 13.13	61.23%	96.31%	0.62%	1.85%	31.46, 19.32	6.76, 4.81	corticosteroids	Sanofi and Regeneron Pharmaceuticals Inc
Paller 2020	7.27, 2.29	Children	367	8.43, 1.73	49.86%	69.21%	16.89%	7.63%	37.9, 11.77	7.77, 1.53	corticosteroids	Sanofi and Regeneron Pharmaceuticals Inc
Simpson 2016(SOLO1)	26.67, 17.31	Adults	671	38.67, 16.79	58.12%	67.06%	6.86%	23.99%	30.76, 14.83	7.67, 1.95	Moisturizers BID; rescue therapy with topical or systemic medication at invetigators' discretion	Sanofi and Regeneron Pharmaceuticals Inc
Simpson 2016(SOLO2)	24.83, 14.57	Adults	708	34.67, 15.78	57.63%	69.07%	6.78%	19.63%	29.37, 14.62	7.77, 1.81	Moisturizers BID; rescue therapy with topical or systemic medication at invetigators' discretion	Sanofi and Regeneron Pharmaceuticals Inc
Simpson 2020	12.2, 3.2	Children	251	14.5, 1.7	58.96%	62.55%	11.95%	15.14%	35.5, 14.2	7.6, 1.7	Moisturizers	Sanofi and Regeneron Pharmaceuticals Inc
Silverberg 2023(ADvocate1)	22.6, 15.07	Both	424	35.5, 17.35	50.24%	68.16%	11.56%	16.51%	29.5, 11.89	7.2, 1.83	Emollients	Dermira
Silverberg 2023(ADvocate2)	20.6, 14.82	Both	427	36.2, 16.93	50.59%	59.25%	8.20%	28.57%	29.7, 11.59	7.1, 1.9	Emollients	Dermira
Simpson 2023	21.1, 16.35	Both	211	37.2, 19.3	51.18%	61.61%	13.27%	14.69%	27.3, 10.94	7.1, 1.87	Low-mid potency TCS or TCI as needed	Dermira

Quality of trials

The risk of bias of two outcomes reported in each trial were low or probably low, see detail in the appendix Table S3.

Summaries of primary outcomes

All 18 trials reported both anxiety and depression outcomes, therefore, the network plot for both are identical (see Fig. 2). Table 2 is the league table of anxiety and depression outcome for different interventions The results of GRADE assessment for all comparisons of two outcomes are shown in appendix Table S4-5., and was summarized in Table 3.

Anxiety

This outcome is presented as measured using the anxiety subscale of Hospital Anxiety and Depression Scale (HADS-A) (range: 0 to 21, higher score indicates greater severity). High-certainty evidence demonstrated that “Abrocitinib (200 mg, oral, qd)” (MD -1.2, 95%CI: -1.7 to -0.69), “Dupilumab (300 mg, subcutaneously, q1w)” (MD -1.9, 95%CI: -2.4 to -1.4), “Dupilumab (300 mg, subcutaneously, q2w)” (MD -1.7, 95%CI: -2.2 to -1.2), and “Lebrikizumab (250 mg, subcutaneously, q2w)” (MD -1.6, 95%CI: -2.3 to -0.97), were the most effective drugs. According to the SUCRA analysis results, “Dupilumab (300 mg, subcutaneously, q1w)” is ranked first, followed by “Abrocitinib (100 mg, oral, qd)” (MD -0.76, 95%CI: -1.3 to -0.23; high-certainty evidence), “Baricitinib (1 mg, oral, qd)” (MD -0.58, 95%CI: -1 to -0.12; high-certainty evidence), “Baricitinib (2 mg, oral, qd)” (MD -0.91, 95%CI: -1.3 to -0.51; high-certainty evidence), “Baricitinib (4 mg, oral, qd)” (MD -1.1, 95%CI: -1.6 to -0.68; high-certainty evidence), and “Dupilumab (300 mg, subcutaneously, q4w)” (MD -0.92, 95%CI: -1.9 to -0.07; moderate-certainty evidence) inferior to the most effective, but superior to placebo. Low-certainty evidence demonstrated that “Abrocitinib (10 mg, oral, qd)” (MD 0.52, 95%CI: -1.3 to 2.3), “Abrocitinib (30 mg, oral, qd)” (MD -1.3, 95%CI: -3.4 to 0.66), “Dupilumab (100/200 mg, subcutaneously, q2w)” (MD -0.6, 95%CI: -1.8 to 0.64), and “Dupilumab (200/300 mg, subcutaneously, q2w) (MD -0.63, 95%CI: -1.9 to 0.72), were maybe not convincingly different compared to placebo.

Depression

This outcome is presented as measured using depression subscale of Hospital Anxiety and Depression Scale (HADS-D) (range: 0 to 21, higher score indicates greater severity). High-certainty evidence demonstrated that “Abrocitinib (200 mg, oral, qd)” (MD -1.1, 95%CI: -1.8 to -0.29), “Baricitinib (4 mg, oral, qd)” (MD -1.1, 95%CI: -1.9 to -0.34), “Dupilumab (300 mg, subcutaneously, q1w)” (MD -1.8, 95%CI: -2.7 to -0.85), “Dupilumab (300 mg, subcutaneously, q2w)” (MD -1.6, 95%CI: -2.3 to -0.76), and “Lebrikizumab (250 mg, subcutaneously, q2w)” (MD -1.6, 95%CI: -2.5 to -0.58), were the most effective drugs. According to the SUCRA analysis results, “Dupilumab (300 mg, subcutaneously, q1w)” is ranked first. Low-certainty evidence demonstrated that “Abrocitinib (100 mg, oral, qd)” (MD -0.8, 95%CI: -1.6 to -0.03) maybe inferior to the most effective, but superior to placebo. Low-certainty evidence demonstrated that “Abrocitinib (10 mg, oral, qd)” (MD -0.02, 95%CI: -2.8 to 2.8), “Abrocitinib (30 mg, oral, qd)” (MD 0.4, 95%CI: -1.9 to 2.7), “Baricitinib (1 mg, oral, qd)” (MD -0.33, 95%CI: -1.1 to 0.47), “Baricitinib (2 mg, oral, qd)” (MD -0.16, 95%CI: -0.84 to 0.56), “Dupilumab (100/200 mg, subcutaneously, q2w)” (MD -0.84, 95%CI: -2.5 to 0.8), “Dupilumab (200/300 mg, subcutaneously, q2w) (MD -0.65, 95%CI: -2.5 to 1.2), and “Dupilumab (300 mg, subcutaneously, q4w)” (MD -1.2, 95%CI: -2.4 to -0.08), were maybe not convincingly different compared to placebo.

Table 3 Summary table of anxiety and depression on Janus kinase (JAK) inhibitors for atopic dermatitis (AD)

Subgroup analysis

As described in methods, we conducted subgroup analyses based on different populations, i.e., adults and children. In the 10 trials that included only adults, the network plot for anxiety and depression analysis results are shown in appendix Figures S1. The results of subgroup analysis for adult anxiety and depression did not reveal subgroup effects (appendix Table S6). The credibility subgroup analysis results are presented in appendix Text S3-4. In the three trials that included only children, the network plot for anxiety and depression analysis results are shown in appendix Figures S2. The results indicate that the subgroup analysis for adult anxiety and depression did not reveal subgroup effects (appendix Table 7). The credibility subgroup analysis results are presented in appendix Text S5-6.

Heterogeneity assessments

The results of inconsistency testing for direct and indirect comparisons are shown in appendix Figure S3-4. We did not find substantial between-study heterogeneity for two outcomes and most comparisons (appendix Table S8-9). Since no pairwise meta-analysis included more than 10 studies, funnel plots and Egger’s regression test were not performed. The results of anxiety and depression by the fixed-effects model are shown in appendix Table S10. In other trials, the treatment duration of “Abrocitinib” was 12 weeks, whereas in the “Bieber 2021” trial, it was 16 weeks. We excluded “Bieber 2021” and conducted a sensitivity analysis, with the results presented in appendix Table S11.

Principal Findings

Our review, including 7,784 participants with primarily moderate-to-severe atopic AD in 18 trials evaluating four unique systemic immunomodulatory drugs, found that abrocitinib, baricitinib, dupilumab, and lebrikizumab, exhibit varying degrees of effectiveness on alleviating anxiety and depressive. Dupilumab, particularly at the 300 mg dose administered subcutaneously, was found to provide the most significant remission in both anxiety and depression symptoms. This finding provides important evidence for healthcare providers to simultaneously address both dermatological and mental health issues for patients with AD.

Strengths and Limitations

The strengths of our study included systematic approach and methodological rigor, adhering to PRISMA and Cochrane guidelines to ensure the reliability of the results^11,12. We conducted a comprehensive search across multiple databases and grey literature, including a diverse range of RCTs that encompass various drugs and patient characteristics, thereby providing a crucial evidence base for the impact of systemic immunomodulatory treatments on anxiety and depression. The application of the ICEMAN tool for subgroup analysis further enhances the transparency and credibility of the findings¹⁸. Despite the low credibility of the subgroup analysis, it still represents a significant improvement over the absence of clinical evidence. Additionally, the use of the GRADE framework to assess the certainty of evidence offers clear guidance for clinical practice, effectively illustrating the comparative efficacy of different interventions²¹. These strengths render our study significantly valuable within the existing evidence.

Our findings have some limitations as well. Several trials are ongoing, which may introduce potential publication bias. However, there is no cause for concern, as we will monitor ongoing developments and update this study to include the latest evidence as necessary. Five trials^38–41 included both children and adults without separately reporting outcomes for two groups, which may contribute to heterogeneity and limit the external validity of our findings. Our results indicate that the subgroup analysis did not show significant effects, which may be related to insufficient sample size. Nevertheless, we utilized the available data for subgroup analysis, despite its low reliability. Additionally, part of AD patients received basic treatments, which may influence the efficacy of immunotherapy. However, the potential impact of these medications on mental health is likely minimal, requiring little concern. The included trials used two different measurement tools to assess anxiety and depression. Although we performed a conversion¹⁶, the items of these two scales are not entirely consistent, which may impact the results. However, the analysis after conversion facilitates the interpretation of the findings. We utilized imputation techniques to address missing data, which may introduce bias and undermine the robustness of our findings. Additionally, heterogeneity in participant, such as age and sex, could potentially impact the stability of the finding, thereby necessitating that users of this evidence carefully consider the clinical context. Finally, the limited follow-up duration constrains the assessment of long-term efficacy.

Comparison with Other Studies

In recent years, several systematic reviews and meta-analyses have evaluated the efficacy of systemic immunomodulatory drugs for AD^{8–10,42−44}, but none have assessed their effectiveness on mental health in this patient population. Our study provides a critical enhancement to the existing evidence by elucidating the impact of systemic immunomodulatory drugs on anxiety and depression. The findings from our study has broaden the clinical evidence base and enriches the dimensionality of outcomes within the domain of AD treatment. Currently, Dupilumab and Abrocitinib demonstrate superior efficacy, including improvements in skin conditions, patient quality of life, and mental health outcomes. However, multiple studies have indicated that physician or dermatologist often tend to favor conservative treatment for patients with AD, especially chronic AD, primarily due to the high costs of these new drugs and the lack of long-term safety data^45–47.

In our study, the four immunomodulatory drugs demonstrated significant efficacy in alleviating anxiety and depression, including separate assessments for children and adults. This finding underscores the necessity for personalised treatment strategies, suggesting that clinicians should thoroughly consider the age, disease history, and comorbidity of patients when formulating treatment plans. The research by Adam et al.⁴⁸ revealed the favourable safety and efficacy profile of systemic treatment in special populations, indicating that age-related factors cannot be overlooked in clinical practice. Thus, the implementation of tailored treatment approaches for different age groups is particularly crucial. Li et al.⁴⁹ confirmed the adaptability of Abrocitinib in different patients, further supporting the argument for individualised treatment based on patient characteristics.

Despite our findings indicating that all evaluated medications significantly improved symptoms of anxiety and depression, with Dupilumab (300 mg, subcutaneously, q1w) achieving the highest efficacy in anxiety relief, there remains insufficient attention to the long-term efficacy of these novel treatments. Papp et al.⁵⁰ noted that the lack of long-term efficacy studies in specific populations, such as children and the elderly, could negatively impact clinical decision-making. Given the substantial physiological and psychological differences between paediatric patients and adults, long-term efficacy research focused on children is critical for assessing the suitability and safety of Dupilumab and other medications within this demographic. Furthermore, elderly patients often present with comorbidities and polypharmacy when using immunomodulatory drugs, complicating the assessment of long-term efficacy. Napolitano et al.⁵¹ emphasised that the chronicity of the disease and the complex pathogenetic mechanism, make elderly AD management challenging, further research is required to evaluate its long-term use to ensure sustained efficacy in this vulnerable population.

Therefore, future investigations should prioritise the assessment of the long-term efficacy of these new therapies across diverse populations, thereby providing more comprehensive clinical data. This approach not only facilitates informed decision-making by clinicians in practice but also aids in optimising personalised treatment plans, ensuring that patients’ mental health is continuously monitored throughout their treatment journey.

Clinical Implications and Future Research

The findings of our study are not only significant for clinical practice but also provide insights for future research. Subsequent investigations should focus on how systemic immunomodulatory drugs can enhance patients’ quality of life through the interaction of physiological and psychological factors, particularly analyzing why certain individuals experience more pronounced benefits in mental health. This understanding could foster more personalized treatment strategies. Furthermore, by leveraging data science techniques, machine learning can be utilised to analyses patient treatment responses and develop predictive models, thereby optimizing therapeutic approaches.

To address the gap in long-term data, it is advisable to establish cross-institutional collaborative networks to share experiential data regarding the use of new therapies by patients with AD in real-world settings. Given the high costs associated with emerging immunomodulatory medications, policymakers should consider implementing targeted funding programmes to support the treatment of AD patients, thus alleviating overall healthcare expenses and reducing societal burdens. These innovative research initiatives and policy recommendations have the potential to not only improve comprehensive care for AD patients but also to advance more effective public health strategies, ultimately enhancing the overall health outcomes of individuals suffering from chronic conditions.

Our study demonstrates that systemic immunomodulatory drugs significantly alleviate anxiety and depression in patients with AD, particularly with the subcutaneous administration of Dupilumab at a 300 mg dose, which markedly improves mental health. This finding underscores the importance of addressing both dermatological and psychological health issues in the management of AD, advocating for personalized treatment plans based on individual patient condition. Future research should prioritize the assessment of long-term efficacy and establish cross-institutional collaborative networks to enhance understanding and optimization of these therapies across diverse patient populations.

Atopic dermatitis, AD; Randomized controlled trials, RCTs; Eczema Area and Severity Index, EASI; Peak Pruritus Numeric Rating Scales, PP-NRS; Standard deviations, SDs; Grading of Recommendations Assessment, Development and Evaluation, GRADE; Mean differences, MDs; Confidence intervals, CIs; Minimally important difference, MID; Surface Under the Cumulative Ranking Curve, SUCRA.

Author Contributions: ML, KHZ, JHT and YZ planned and designed the study. ML developed search strategies. ML, KHZ, KLY, YG, and LZ screened potential studies and extracted data from the included studies. ML, KHZ and YG managed the data and performed the statistical analysis. YZ and JHT conducted the arbitration under disagreement and ensured that there were no errors. YZ and JHT provided methodological support and helped to interpret findings. ML wrote the first draft. ML, YZ and KLY revised the draft. All authors approved the final version of the manuscript.

Acknowledgments: None.

Conflict of Interest Disclosures: All authors declare that they have no relevant conflicts of interest.

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Table 2 is available in the Supplementary Files section.

No competing interests reported.

Effect of systemic immunomodulatory therapies on mental health in atopic dermatitis: a systematic review and network meta-analysis

Status:

Version 1

Abstract

Figures

Key Points

Introduction

Methods

Search strategy

Eligibility criteria

Data collection

Quality assessment

Data analysis

Certainty of evidence

Results

Characteristics of trials

Quality of trials

Summaries of primary outcomes

Anxiety

Depression

Heterogeneity assessments

Discussion

Principal Findings

Strengths and Limitations

Comparison with Other Studies

Clinical Implications and Future Research

Conclusion

Abbreviations

Declarations

References

Table 2

Additional Declarations

Supplementary Files

Status:

Version 1