Correction: Safety and efficacy of nemolizumab for patients with pruritus: a systematic review and meta-regression analysis of randomized controlled trial

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