Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: A meta-analysis of randomized clinical trials

Dupilumab is a recently commercialized human mAb against the IL-4 receptor α subunit, blocking both IL-4 and IL-13, which have been shown to play important roles in the pathogenesis of atopic dermatitis (AD).1Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 2Kaesler S. Volz T. Skabytska Y. Koberle M. Hein U. Chen K.M. et al.Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10.J Allergy Clin Immunol. 2014; 134: 92-99Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 3Wenzel S. Castro M. Corren J. Maspero J. Wang L. Zhang B. et al.Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet. 2016; 388: 31-34Abstract Full Text Full Text PDF PubMed Scopus (635) Google Scholar This study is a meta-analysis evaluating the efficacy and safety of dupilumab for the treatment of AD. On December 1, 2016, we conducted a systematic search of PubMed, MEDLINE, Embase, and Web of Science databases for randomized controlled trials (RCTs) (published between May 1, 2000, and December 1, 2016; English publication only) using the search terms “dupilumab” and “atopic dermatitis” or “atopic eczema.” A total of 7 randomized, double-blinded, placebo-controlled clinical trials (2 phase I, 2 phase IIa, 1 phase IIb, and 2 phase III) including 1965 (1364/601) patients diagnosed with moderate-to-severe AD were selected from 167 publications (see Fig E1 in this article's Online Repository at www.jacionline.org). In the phase I trial M4A, patients received weekly administration of 75, 150, 300 mg dupilumab or placebo for 4 weeks, respectively, and in M4B, patients received weekly doses of 150 or 300 mg dupilumab for 4 weeks. In the phase IIa trial M12, patients received 300 mg dupilumab weekly for 12 weeks,4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar whereas in study C4, patients received a combination treatment of 300 mg dupilumab and topical glucocorticoids for 4 weeks.4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar In the phase IIb study, patients received dupilumab 300 mg once a week (300 mg q1w), 300 mg every 2 weeks (300 mg q2w), 200 mg every 2 weeks (200 mg q2w), 300 mg every 4 weeks (300 mg q4w), 100 mg every 4 weeks (100 mg q4w), or placebo once a week (qw).5Thaci D. Simpson E.L. Beck L.A. Bieber T. Blauvelt A. Papp K. et al.Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.Lancet. 2016; 387: 40-52Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 6Simpson E.L. Gadkari A. Worm M. Soong W. Blauvelt A. Eckert L. et al.Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): a phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD).J Am Acad Dermatol. 2016; 75: 506-515Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar In the 2 latest phase III trials, SOLO1 and SOLO2, patients received 300 mg dupilumab or placebo at either weekly or biweekly basis for 16 weeks.7Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (50) Google Scholar All patients were adults (≥18 years old), had eczema area and severity index (EASI) score of more than 16, investigator's global assessment (IGA) score of more than 3, body surface area affected of more than 10%, and a diagnosis of AD for more than 3 years. The characteristics of the selected studies are presented in Table I. The study qualities of each RCT or subgroup were evaluated using the Jadad scale, and all 7 studies included in the meta-analysis were considered to be of high quality (see Table E1 in this article's Online Repository at www.jacionline.org).4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar, 5Thaci D. Simpson E.L. Beck L.A. Bieber T. Blauvelt A. Papp K. et al.Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.Lancet. 2016; 387: 40-52Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 6Simpson E.L. Gadkari A. Worm M. Soong W. Blauvelt A. Eckert L. et al.Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): a phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD).J Am Acad Dermatol. 2016; 75: 506-515Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 7Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (50) Google Scholar All 7 trials reported adequate randomization, none was stopped early, and M4B, phase IIb, SOLO1, and SOLO2 trials were conducted in multinational study centers. All 7 studies showed a low risk of bias (see Fig E2, A, in this article's Online Repository at www.jacionline.org). Begg funnel plot and Egger test showed that there did not seem to be bias in the publication (Fig E2, B).Table ICharacteristics of studies included in the meta-analysisReferenceYearStudyPhaseCountryCTGTreatment/control, nRegimen (dose of dupilumab)Age of dupilumab/placebo groupAD severity of baseline EASI score, treatment/controlOutcome summaryBeck et al4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar2012M4AIUSANCT0125932324/675 mg qw, 150 mg qw, 300 mg qw for 4 wk42.6 ± 1.9/37.4 ± 4.3∗Mean ± SE.30.0 ± 2.0/22.8 ± 3.0∗Mean ± SE.Rapid and dose-depedent improvements in all clinical indexesBeck et al4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar2013M4BIMultinationalNCT0138565727/10150 mg qw, 300 mg qw for 4 wk42.6 ± 1.9/37.4 ± 4.3∗Mean ± SE.30.0 ± 2.0/22.8 ± 3.0∗Mean ± SE.Rapid and dose-dependent improvements in all clinical indexesBeck et al4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar2013M12IIaEuropeNCT0154840455/54300 mg qw for 12 wk33.7 ± 1.4/39.4 ± 1.7∗Mean ± SE.28.4 ± 1.8/30.8 ± 1.9∗Mean ± SE.Improvement in all clinical indexes in the dupilumab groupBeck et al4Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (242) Google Scholar2013C4IIaEuropeNCT0163904021/10300 mg dupilumab and topic glucocorticoids qw for 4 wk36.0 ± 2.5/37.8 ± 5.3∗Mean ± SE.23.1 ± 2.7/24.1 ± 4.0∗Mean ± SE.Associated with a rapid and sustained reduction in pruritus NRS scoreThaci et al5Thaci D. Simpson E.L. Beck L.A. Bieber T. Blauvelt A. Papp K. et al.Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.Lancet. 2016; 387: 40-52Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar2014Phase IlbIIbMultinationalNCT01859988318/61300 mg qw, 300 mg q2w, 200 mg q2w, 300 mg q4w, 100 mg q4w for 12 wk37.0 (18.0-75.0)/37.2 (18.0-69.0)†Mean (range).31.7 ± 0.8/32.9 ± 1.8∗Mean ± SE.Greater EASI score improvements in the dupilumab groupSimpson et al7Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (50) Google Scholar2015SOLO1IIIMultinationalNCT02277743447/224300 mg qw for 16 wk, 300 mg q2w for 16 wk38.0 (27.5-48.0)/39.0 (27.0-50.5)‡Median (range).300 mg qw: 30.4 (21.5-40.8), 300 mg q2w: 29.8 (22.0-41.2)/31.8 (22.2-43.8)‡Median (range).Clinical index improvement in the dupilumab groupSimpson et al7Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (50) Google Scholar2016SOLO2IIIMultinationalNCT02277769472/236300 mg qw for 16 wk, 300 mg q2w for 16 wk34.0 (25.0-46.0)/35.0 (25.0-47.0)‡Median (range).300 mg qw: 28.6 (21.0-40.1), 300 mg q2w: 29.0 (21.2-41.8)/30.5 (22.1-41.7)‡Median (range).Clinical index improvement in the dupilumab groupCTG, Clinicaltrials.gov identification number; NRS, numerical-rating scale.∗ Mean ± SE.† Mean (range).‡ Median (range). Open table in a new tab CTG, Clinicaltrials.gov identification number; NRS, numerical-rating scale. In the pooled analysis of all 7 trials, significant improvement in efficacy of dupilumab for the treatment of AD was observed in various clinical indexes. Compared with the placebo control, dupilumab treatment significantly reduced the EASI score (standardized mean difference [SMD], −0.91; 95% CI, −0.99 to −0.83; P < .001) (Fig 1, A), although 3 studies did not show a substantial reduction in the EASI score, including M4, C4, and phase IIb 100 mg q4w group. A higher percentage of IGA response (IGA score turned to 0 or 1) was revealed in dupilumab treatment groups compared with the placebo group (relative risk [RR] = 4.64; 95% CI, 3.81-5.66; P < .001) (Fig 1, B). In dupilumab treatment groups, the SMD of pruritus numerical-rating scale score was −0.76 (95% CI, −0.84 to −0.68; P < .001) (Fig 1, C), indicating that dupilumab treatment improved the relief and the life quality of the patients. The results also showed a significant decrease in the mean difference in body surface area score within the dupilumab groups compared with the control group (SMD, −0.77; 95% CI, −0.84 to −0.69; P < .001) (Fig 1, D). Furthermore, the dose-dependent efficacy of dupilumab was shown. The results indicated that the most effective clinical improvement was achieved by the doses of 300 mg qw and 300 mg q2w, and the doses of 300 mg q4w and 200 mg q2w also showed significant clinical improvement, but were less effective; meanwhile, the dose of 100 mg q4w was almost ineffective. Moreover, the group receiving 100 mg q4w was the major source of heterogeneity in this meta-analysis (see Fig E3 in this article's Online Repository at www.jacionline.org), confirming that low dose of dupilumab was less likely to achieve satisfactory therapeutic effects as high doses of dupilumab. Overall, dupilumab was well tolerated and had a favorable safety profile that was substantially better than that of most systemic agents. The commonly reported adverse events (AEs) in patients treated with dupilumab were nasopharyngitis, headache, and injection-site reaction. We found that AEs occurred at a similar rate among different trials without statistical significance (RR = 0.99; 95% CI, 0.95-1.04; P = .827) (see Fig E4, A, in this article's Online Repository at www.jacionline.org). Dupilumab treatment was associated with lower risk of severe adverse events (SAEs) compared with the placebo group (RR = 0.44; 95% CI, 0.30-0.65; P < .001) (Fig E4, B). Indeed, the frequency of SAE in the pooled dupilumab group was 2.56%, whereas that of the pooled control group was 6.26%. The major SAEs in the placebo group included skin infection, inflammatory lesion, impetigo, and eczema herpeticum, which possibly resulted from the exacerbation of AD due to the lack of effective treatment. Of note, there was a high incidence (12%) of herpes virus infection in the 100 mg dupilumab group of the phase IIb trial.5Thaci D. Simpson E.L. Beck L.A. Bieber T. Blauvelt A. Papp K. et al.Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.Lancet. 2016; 387: 40-52Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Finally, similar risks of study discontinuation between dupilumab and placebo groups were observed (RR = 0.95; 95% CI, 0.61-1.50; P = .839) (Fig E4, C). To our knowledge, this is the first systematic analysis and comparison of all published dupilumab RCTs data for the treatment of moderate-to-severe AD. The trials included had high consistency in the patients enrolled, randomization and masking, and treatment outcomes. Dupilumab was shown to be consistently more effective than placebo, with a trend of a dose-dependent effect, and had a placebo-like safety profile.8Hamilton J.D. Suarez-Farinas M. Dhingra N. Cardinale I. Li X. Kostic A. et al.Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 1293-1300Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar Combination of dupilumab with topical glucocorticoids seemed to improve the effects.9Roekevisch E. Spuls P.I. Kuester D. Limpens J. Schmitt J. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: a systematic review.J Allergy Clin Immunol. 2014; 133: 429-438Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Limitations of this meta-analysis included the limited number of clinical trials (only 7) in this study and the risks of bias, for example, funding from pharmaceutical industry, might exist. Our findings suggest that dupilumab is a promising anti-AD medication, due to its specific action directed at the underlying mechanisms of AD, resulting in its good efficacy and safety profile in patients with severe AD. However, further investigations still need to be performed in future studies to evaluate the long-term efficacy and safety of dupilumab for the treatment of AD. All the research work was conducted in Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs. We thank Xiangdong Gong for help in manipulation of the results. This meta-analysis was performed and written according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement as a guideline (http://www.prisma-statement.org/). On December 1, 2016, we conducted a systematic search of PubMed, MEDLINE, Embase, and Web of Science databases for RCTs (published between May 1, 2000, and December 1, 2016; English publication only) using the search terms “dupilumab” and “atopic dermatitis” or “atopic eczema.” A 2-step approach was applied, and all the studies selected using the strategy were reviewed independently by 2 researchers (H.Y. and C.Y.X.); finally, the reports that met all inclusion criteria were included in our meta-analysis. The inclusion criteria were as follows: (1) patients given a diagnosis of AD and treated with dupilumab; (2) double-blind, randomized, placebo-controlled studies; (3) outcome measures including EASI, IGA, and pruritus numerical-rating scale (NRS) score, as well as rates of patients with AEs and the percentage of study discontinuation. We performed the Q test (to show statistically significant heterogeneity when P < .1) and the I2 test (measures the proportion of the overall variation that is attributable to between-study heterogeneity [range from 0% to 100%, >50% is considered as evidence of heterogeneity]) to analyze the heterogeneity of the studies included in our meta-analysis. The Galbraith plot was applied to indicate studies that caused heterogeneity. Each study was described as a single dot with a central regression line through the plot. On the y-axis, the log-transformed effect size divided by the SE (z score) was shown, and on the x-axis the inverse of the SE was shown. Moreover, we analyzed the methodological quality of the included studies and the risk of bias using Cochrane collaboration tool, and we also performed the Egger test, which is a linear regression method, to evaluate the bias in publication in this meta-analysis. For our meta-analysis, we extracted the following predefined variables: authors, year of publication, study type, name of the study, clinicaltrials.gov number, dupilumab doses used, number of dupilumab-treated patients and control subjects, duration of study periods, and outcome measures. The focus of our analysis was to compare the treatment effects of dupilumab and placebo across studies. The outcomes included in our meta-analysis were EASI, IGA, NRS score, rate of patients with AEs and SAEs, and study discontinuation rate. From studies included in this analysis, we extracted, for dupilumab and placebo, EASI, IGA, NRS score, and the RR for the occurrence of at least 1 AE (along with the corresponding 95% CI). The overall summary effect sizes were estimated using a random-effects model. A P value of less than .05 was considered statistically significant. Review Manager (RevMan version 5.2.5; Nordic Cochrane Centre, Copenhagen, Denmark) and STATA (version 12.0; StataCorp, College Station, Tex) software were used for statistical analysis.Fig E2A, Risk of bias summary for each included study. B, Begg funnel plot. Studies with larger scale have been spread around the average, and publications with smaller scale were plodded evenly on each side of the average. Deviation from such funnel-like distribution is able to point out the bias of the studies. Both the funnel plot and Egger test showed no evidence of bias in the publication.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Galbraith radial plot. The figure shows the contribution of results from the patient groups treated with different doses of dupilumab in the different studies to the heterogeneity of efficacy of treatment. The following studies were included: phase IIb 300qw (1), phase IIb 200q2w (2), phase IIb 300q2w (3), phase IIb 100q4w (4), phase IIb 300q4w (5), M4 (6), M12 (7), C4 (8), SOLO1 300q2w (9), SOLO1 300qw (10), SOLO2 300q2w (11), and SOLO2 300qw (12). The group receiving 100 mg every 4 week (100q4w) in phase IIb study was found to be the main cause of the heterogeneity.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E4Forest plot of rate of AEs, SAEs, and study discontinuation in 7 RCTs. A, AE rates and RR of AE rates between dupilumab- and placebo-treated patients. B, SAE rates and RR of SAE rates between dupilumab- and placebo-treated patients. C, Rates of study discontinuation and RR of study discontinuation between dupilumab- and placebo-treated patients. Diamonds stand for the meta-analysis summary effect estimate. Blue dots represent the RR, and horizontal lines represent 95% CIs of the RR estimates.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Quality assessment of included RCTs using the Jadad scaleReferenceYearStudyRepresentation of randomizationAppropriateness of method for randomizationRepresentation of double blindingAppropriateness of method for double blindingRepresentation of withdrawalsTotal scoreBeck et alE1Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (936) Google Scholar2012M4A111115Beck et alE1Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (936) Google Scholar2013M4B111115Beck et alE1Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (936) Google Scholar2013M12111115Beck et alE1Beck L.A. Thaci D. Hamilton J.D. Graham N.M. Bieber T. Rocklin R. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (936) Google Scholar2013C4111115Thaci et alE2Thaci D. Simpson E.L. Beck L.A. Bieber T. Blauvelt A. Papp K. et al.Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.Lancet. 2016; 387: 40-52Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar2014Phase IIb111115Simpson et alE4Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (1106) Google Scholar2015SOLO1111115Simpson et alE4Simpson E.L. Bieber T. Guttman-Yassky E. Beck L.A. Blauvelt A. Cork M.J. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (1106) Google Scholar2016SOLO2111115 Open table in a new tab