Correction: Safety and efficacy of nemolizumab for patients with pruritus: a systematic review and meta-regression analysis of randomized controlled trial
Year: 2026
Type: erratum
Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a current worldwide prevalence of 5-25% (Deckers, I. A., et al. 2012). Moderate-to-severe AD is often refractory to first-line topical treatments, while systemic immunosuppressants are commonly used in clinical treatment (Wollenberg, A., et al. 2016). However, the use of traditional systemic treatments including systemic corticosteroids, phototherapy, and immunosuppressants are limited by the safety risk (Rademaker, M., et al. 2020). Due to the undesired adverse effects (AEs) of traditional systemic treatment, there is still an unmet need for safe and effective long-term therapy for moderate-to-severe AD. The symptom of AD characterized by pruritus and skin barrier dysfunction, which are triggered by an immune response to antigenic substances and mechanical irritation (Furue, K., et al. 2019, Suá rez-Fariñas, M., et al. 2015, Czarnowicki, T., et al. 2019, Arora, C.J., et al. 2020). Some patients have pruritus even if other symptoms are well controlled by topical glucocorticoids and antihistamines, their effects in AD are limited or associated with long-term side effects (Hong, J., et al. 2011, Yosipovitch, G. and J.D. Bernhard 2013). Thus, among patients with AD, the primary therapeutic objective should be to relieve pruritus, improve dermatitis, and enhance quality of life. Interleukin-31 (IL-31) is believed to play a key role in the pathogenesis of AD Kabashima, K., et al. 2020). Therefore, nemolizumab is deemed as a promising drug for AD patients with pruritus. When nemolizumab is administered in a hospital, the body weight-normalized dose is not problematic. However, considering an auto-injection situation might be warranted in the future, there were still no consensus on the flat-dose regimen of the utilization of nemolizumab. Despite several previous clinical trials have attempted to investigate an appropriate self-injection regimen, the results remained inconclusive (Nemoto, O., et al. 2016, Kinugasa, E., et al. 2021). Although a recently published meta-analysis demonstrated the efficacy of nemolizumab for patients with AD by pooling the results from 4 randomized controlled trials (RCT), it failed to assess the effect of dosage or the times of injections on the study outcomes (Xuemin, X., et al. 2021). Moreover, several additional RCTs implemented with different dose or times of injections were published recently. Therefore, this meta-analysis aimed to evaluate the efficacy of nemolizumab in treating patients with pruritusAD by assessing the amelioration of pruritus, and in addition, to investigate the association between dosage or regimen of nemolizumab with the improvement in clinical indices.Literature search This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Selcuk, A.A. 2019). This study does not contain any participants and ethics approval is not applicable. The literature search was performed based on the PICO principle (Aslam, S. and P. Emmanuel 2010). PubMed, Embase, and the Cochrane library were searched for available papers published up to August 2021 for potentially eligible studies, using the MeSH terms 'Pruritus', 'Dermatitis, Atopic', as well as 'nemolizumab' and relevant key words. The eligibility criteria were 1) population: patients with atopic dermatitis andor pruritus, 2) intervention: nemolizumab, 3) control: placebo, 4) randomized controlled trial, and 6), full-text in English.Quality appraisal The level of evidence of the included studies was assessed independently by two authors (Fengxia Hu and Maoli Dan) according to the version 2 of the Cochrane tool for assessing risk of bias in randomized trials (ROB 2) (Sterne, J.A.C., et al. 2019). The included studies were assessed respectively in five domains regarding the 1) Bias arising from the randomization process; 2) bias due to deviations from intended interventions; 3) bias due to missing outcome data; 4) bias in measurement of the outcome; and 5) bias in selection of the reported result. Finally, an overall evaluation was concluded per study based on the assessments of each individual aspect. Any discrepancy in the assessment was resolved by discussion until a consensus was reached.Data extraction The study characteristics (authors, year of publication, country, study phase, study duration, sample size, gender, and age of the patients), treatment parameters (the regimen of desired treatment, and the dose of each injection), and the outcomes were extracted by two authors (Kailibinuer Abulikemu and Yongzhen Hong) independently. Any discrepancy was resolved by discussion.Outcomes Pruritus visual analog scale (VAS) is a commonly used scoring scale to evaluate the pruritus severity which ranged from 0 to 100 with higher scores indicating worse pruritus (Reich, A., et al. 2012). Eczema Area and Severity Index (EASI) (Barbier, N., et al. 2004), and adverse events (AEs) were also extracted as the study outcomes. The primary outcome in the present meta-analysis was the mean change in pruritus VAS score from baseline to the end of study. The secondary outcomes were mean change in EASI score from baseline to the end of study, and the occurrence of any AEs.Data synthesis This study was designed to directly compare the treatment of nemolizumab with placebo. Some included studies contained more than one treatment arm to compare the effects of different doses of nemolizumab. In such instances, we split the participants into several cohorts of patients to directly compare the efficacy of each dosage of nemolizumab with placebo. To avoids arbitrary omission of relevant groups and double-counting of participants, we included each pair-wise comparison separately, but with placebo group divided out approximately evenly among the comparisons (Higgins JPT, T.J., Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors) 2021). Pruritus VAS and EASI at the last follow-up were extracted for the nemolizumab group and placebo groups, respectively. If the results were not presented as means and standard deviations, the means and standard deviations were estimated based on the reported parameters (median, range, or standard error) (Hozo, S.P., et al. 2005).Statistical analysis All analyses were performed using STATA SE 14.0 (StataCorp, College Station, Texas, USA). Effects (weighted mean difference (WMD) or standardized mean difference (SMD), as appropriate) and the corresponding 95% confidence intervals (CIs) were used to compare the outcomes. Statistical heterogeneity among the studies was evaluated using Cochran's Q-test and the I 2 index. I 2 >50% and Q-test p<0.10 indicated high heterogeneity, and the random-effects model was used; otherwise, the fixed-effects model was applied. p<0.05 was considered statistically significant. The odds ratio (OR) was used to assess the differences in the number of AEs for each group. in which case the funnel plots and Egger's test can yield misleading results (Higgins, J.P.T., et al. 2019). According to the Cochrane Handbook, the publication bias was analyzed only when the number of cohorts included in each metaanalysis was more than 10. Funnel plots, Begg's test and Egger's test were conducted respectively to assess the potential publication bias. Subgroup analysis and meta-regression were applied to analyze the impact of covariates to the study outcomes.Selection of the studies The initial search yielded 271 entries. After removing the duplicates, 207 records were screened, and 189 were excluded. Eighteen full-text papers were assessed for eligibility, and 12 were excluded (In vivo study, n=5; population, n=1; intervention, n=2; meta-analyses, n=4). Finally, 14 cohorts of participants consisting of six randomized controlled studies were included in the meta-analysis (Figure 1).This meta-analysis finally included 569 and 240 patients who received nemolizumab and placebo, respectively. Of the six included studies, there were 1 phase I trial ( 1a), whereas the results of subgroups analysis in three times (WMD=-34.35, 95%CI: -45.77 to -22.94, p<0.001; I 2 =0%, pheterogeneity=0.572) and four times injections (WMD=-22.22, 95%CI: -30.33 to -14.10, p<0.001; I 2 =0%, pheterogeneity=0.946) of nemolizumab showed significantly reduction in pruritus VAS score compared to placebo.Eczema Area and Severity Index score Seven cohorts of patients retrieved from three studies reported the mean change of EASI score from baseline. There was significant difference in the reduction of EASI score between nemolizumab and placebo (WMD=-11.76, 95%CI: -20.55 to -2.96, p=0.009; I 2 =0%, pheterogeneity=0.978, Figure 3). Subgroup analysis (Table 2 & Supplementary Figure 1b) suggested no significant difference in the reduction of EASI score when there were only three injections of nemolizumab during treatment (WMD=-8.75, 95%CI: -26.72 to 9.22, p=0.340; I 2 =0%, pheterogeneity=0.630). However, significantly more reduction of EASI was observed in patients who were injected four times during the study period (WMD=-12.71, 95%CI: -22.79 to -2.62, p=0.014; I 2 =0%, pheterogeneity=0.991).Adverse events There was no significant difference in the occurrence of any AEs between nemolizumab and placebo (RR=1.03, 95%CI: 0.93 to 1.13, p=0.593; I 2 =0%, pheterogeneity=0.980, Figure 4). The comparable results were consistent regardless of the frequency of injection (Supplementary Figure 1c). The most frequently reported AEs from patients treated with nemolizumab were infections and skin or subcutaneous tissue disorders, including nasopharyngitis (occurred in 10-32.7% of the patients) and exacerbated AD (occurred in 15-28.1% of the patients). Several studies also reported that a few patients developed gastrointestinal disorders, respiratory disorders, thoracic disorders, mediastinal disorders, and administration site conditions after been treated with both nemolizumab and placebo, with relatively small and even percentile in the occurrences between groups (Supplementary Table 2). Besides, the severity of the AEs was generally mild, with only a few severe AEs were reported in both nemolizumab group and placebo (Data not shown).Sensitivity analysis, publication bias, and meta-regression The results of the sensitivity analysis suggested that the results of the meta-analysis were robust (Supplementary Figure 2a&b). No publication bias on pruritus VAS and AEs were detected according to the results of both Begg's test and Egger's test (Supplementary Table 3). The funnel plots were presented in Supplementary Figure 3a&b. Despite no significant heterogeneity was observed between the included studies, meta-regression was performed to assess the possible effect of the dose of nemolizumab and length of study duration on the outcomes. The univariate meta-regression showed that both the dosage (Beta=-0.61, 95%CI: -15.77 to 14.54, p=0.931) and study duration (Beta=2.04, 95%CI: -1.13 to 5.20, p=0.186) had no association with change of pruritus VAS score. This insignificant association was also observed in EASI and AE (Supplementary Table 4).The results in this meta-analysis demonstrated the promising efficacy and safety of nemolizumab in treating patients with AD and pruritus. Compared to patients in placebo group, the difference in average change of pruritus VAS score was significant, indicating its efficacious in relieving pruritus and in improving patients' quality of life. In addition, the significantly greater reduction in the average change of EASI score comparing nemolizumab and placebo suggested a considerable remission in the severity of AD. And the comparable occurrences of any AEs in treatment and placebo group indicated a tolerable safety concern of nemolizumab for the treatment of AD. The results of our analysis are congruent with the previous meta-analysis, albeit differed a bit in the extent of reduction in the clinical indices. In the previous meta-analysis (Xuemin, X., et al. 2021), compared to placebo, the average differences in the reduction of pruritus VAS score and EASI score from patients in nemolizumab group are -3.96 (95%CI: -5.56 to -2.37, p<0.001) and -0.31 (95%CI: -0.45 to -0.17, p<0.001), respectively. And the relative risk of developing any AEs comparing nemolizumab and placebo was 0.84 (95%CI: 0.69 to 1.01, p=0.069). It seems that previous meta-analysis used a 10-point scale in pruritus VAS and EASI. Besides, previous meta-analysis used the standardized mean difference to measure the pooled effect size. Instead, we used a 100-point scale to assess the differences in the change of pruritus VAS score and EASI score with weighted mean difference. Moreover, we included two newly published RCT and composed a total of six RCTs in this analysis. The variation in the extent of the results might be explained by the according differences. This meta-analysis also intended to evaluate how the differences in regimen would potentially affect the efficacy of nemolizumab in ameliorating the symptom of AD and pruritus. However, the exact total dose of nemolizumab was hard to assessed due to the limited information in each study, and the dose of each single injection varied significantly from 0.1 mg/kg to 3.0 mg/kg. So, instead of calculating the total dose of nemolizumab during the treatment period, we performed a subgroup analysis on the total frequency of injections to estimate the effect of dosage. The results showed that the change of pruritus VAS score was not significantly different between the single injection of nemolizumab and placebo, and the occurrence of AEs was not different from placebo as well. A total of 3 times of injection could significantly outperform the placebo in the change of pruritus VAS score, but not differed in the EASI score. And a total of 4 times of injection could yield better reduction in both pruritus VAS and EASI compared to placebo. These results might indicate a total of monthly 4 times injections should be considered in future clinical designs. Despite we failed to conclude the best dosage of nemolizumab in each injection, we did a meta-regression to analyze the association between the single dosage as well as the study duration with the differences in change of pruritus VAS, EASI and the occurrence of AEs. However, our results did not reveal a significant association between these two indicators. An improved understanding of AD pathophysiology resulted in an explosion of researches to discover a novel and efficient agent for this population. Nemolizumab was developed as an inhibitor of IL-31 signaling, and several studies have presented findings that indicated a direct effect of IL-31 in the generation of pruritus in patients with atopic dermatitis (Oyama, S. Targeting interleukin-31 aims to decrease pruritus and signs of skin inflammation, which may result in the reduced severity of AD. Serum IL-31 concentration in patients receiving maintenance hemodialysis were reported to be higher in those with pruritus than in those without pruritus (Ko, M.J., et al. 2014). Kinugasa et al. also discovered a tendency for patients with higher serum IL-31 levels at baseline to have greater pruritus VAS reductions following nemolizumab treatment (Kinugasa, E., et al. 2021). Indeed, baseline IL-31 is a significant indicator which might influence the effect of nemolizumab. Future studies could focus on the role of IL-31 and its inhibition for the control of pruritus. The present meta-analysis has limitations that must be considered when weighing the results. First, only six studies with a total of 809 patients were included in the analysis. Fortunately, all studies were sophisticated designed RCT with low risk of bias, and the sensitivity analyses showed that the estimated parameters did not affect the conclusions. Besides, several studies did not report the parameters in a standard of mean and standard deviation. In such instances, reasonable estimates were used under the instruction of Cochrane Handbook for systematic review. In conclusion, the promising effect of nemolizumab reflected by the difference in average change in pruritus VAS score and EASI compared to placebo indicated its efficacious in relieving pruritus and the severity of AD and improving patients' quality of life. And the comparable occurrences of any AEs in treatment and placebo group indicated a tolerable safety concern of nemolizumab for the treatment of AD.Contribution to the Field Statement Atopic dermatitis (AD) is a chronic inflammatory skin disease with a current worldwide prevalence of 5-25%. Nemolizumab is deemed as a promising drug for AD patients with pruritus. However, there were still no consensus on the flat-dose regimen of the utilization of nemolizumab. This meta-analysis has evaluated the efficacy of nemolizumab in treating patients with AD by assessing the amelioration of pruritus, and has investigated the association between dosage or regimen of nemolizumab with the improvement in clinical indices. We found that the promising effect of nemolizumab reflected by the difference in average change in pruritus VAS score and EASI compared to placebo indicated its efficacious in relieving pruritus and the severity of AD and improving patients' quality of life. And the comparable occurrences of any AEs in treatment and placebo group indicated a tolerable safety concern of nemolizumab for the treatment of AD.
Source: Frontiers in Immunology
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7127394432
Cites:
Cited by:
Related to: