analyses were generally consistent. For example, significant clinical improvements were reported more consistently with the 300 mg qw regimen than q2w in both weight-adjusted and unadjusted analyses. Of note, a separate population PK analysis based on a larger dataset (Kovalenko P et al., manuscript in preparation) found no meaningful effect of racial subgroup on dupilumab PK after correction for body weight.
Differential mutations in skin barrier and innate/adaptive immunity genes may impact the nature of AD in racial subgroups. Filaggrin loss-of-function mutations, which lead to deficiency of the structural protein filaggrin and resulting skin barrier defects, have been identified as a major predisposing factor for the development of AD in Europeans and Asians.6 In contrast, in individuals of African descent, the association between filaggrin mutations and AD is less clear; overall, evidence suggests these mutations occur less frequently in African Americans compared with European Americans. Loss-of-function mutations in the closely related filaggrin-2 protein were associated with African, but not European, American patients with AD. However, filaggrin as well as lipid alterations may also be influenced by cytokines, rather than by genetics.27,28 Other potential genetic factors include variants of the tight junction gene claudin and the immune-related genes TLSP and IRF2, which have been noted in patients of African descent with AD.6 Race-specific alterations in epidermal structure may contribute to molecular and histologic differences observed between White, Asian, and Black/African American individuals and may account for some differences in transepidermal water loss observed between European and African Americans.6 Racial and ethnic variations in epidermal and dermal structure and function29 may explain why the presentation of AD in individuals of African descent often differs from that in other racial subgroups, with notable extensor involvement and more frequent perifollicular accentuation and scattered distinct papules on the extensors and trunk, xerosis, Dennie–Morgan lines, hyperlinearity of the palms, periorbital dark circles, lichenification, prurigo nodularis, and post-inflammatory dyspigmentation.6 Similar differences in AD characteristics have also been observed in patients participating in studies conducted in Africa compared with other regions.7 Collectively, these differences may impact the course of AD in Black/African American patients. However, the limited current data on AD in Black/African American patients have restricted understanding of the disease and outcomes in this patient subset. For example, a recent systematic review and meta-analysis of studies evaluating the clinical features of AD in various populations found that only 4% reported the inclusion of Black/African American patients;7 while another review of US studies of systemic AD therapy found that none presented a stratification of results by racial subgroup.30
The safety data among racial subgroups were consistent with those reported in the overall populations.21,22
Differential mutations in skin barrier and innate/adaptive immunity genes may impact the nature of AD in racial subgroups. Filaggrin loss-of-function mutations, which lead to deficiency of the structural protein filaggrin and resulting skin barrier defects, have been identified as a major predisposing factor for the development of AD in Europeans and Asians.6 In contrast, in individuals of African descent, the association between filaggrin mutations and AD is less clear; overall, evidence suggests these mutations occur less frequently in African Americans compared with European Americans. Loss-of-function mutations in the closely related filaggrin-2 protein were associated with African, but not European, American patients with AD. However, filaggrin as well as lipid alterations may also be influenced by cytokines, rather than by genetics.27,28 Other potential genetic factors include variants of the tight junction gene claudin and the immune-related genes TLSP and IRF2, which have been noted in patients of African descent with AD.6 Race-specific alterations in epidermal structure may contribute to molecular and histologic differences observed between White, Asian, and Black/African American individuals and may account for some differences in transepidermal water loss observed between European and African Americans.6 Racial and ethnic variations in epidermal and dermal structure and function29 may explain why the presentation of AD in individuals of African descent often differs from that in other racial subgroups, with notable extensor involvement and more frequent perifollicular accentuation and scattered distinct papules on the extensors and trunk, xerosis, Dennie–Morgan lines, hyperlinearity of the palms, periorbital dark circles, lichenification, prurigo nodularis, and post-inflammatory dyspigmentation.6 Similar differences in AD characteristics have also been observed in patients participating in studies conducted in Africa compared with other regions.7 Collectively, these differences may impact the course of AD in Black/African American patients. However, the limited current data on AD in Black/African American patients have restricted understanding of the disease and outcomes in this patient subset. For example, a recent systematic review and meta-analysis of studies evaluating the clinical features of AD in various populations found that only 4% reported the inclusion of Black/African American patients;7 while another review of US studies of systemic AD therapy found that none presented a stratification of results by racial subgroup.30
The safety data among racial subgroups were consistent with those reported in the overall populations.21,22
Although data on racial differences are not available for other systemic therapies, the efficacy and safety observations here are generally consistent with studies of topical therapies such as pimecrolimus (Whites, Asians, Blacks, and Hispanics)31 and tacrolimus (Asians vs Caucasians),32 which showed no differences in treatment outcomes among racial subgroups. The analysis had several limitations. First, only data from a short 16-week treatment duration were presented, as the small number of patients in some racial subgroups of the CHRONOS trial at week 52 prevented robust statistical analyses. Second, the analysis did not directly compare dupilumab dose regimens. Finally, only a small number of Black/African American patients were available for analysis; therefore, differences between dupilumab and placebo did not always reach the level of nominal statistical significance (P<0.05), particularly for the q2w dose regimen.
CONCLUSIONS
Irrespective of racial subgroup, dupilumab results in significant clinical improvement and a favorable benefit-risk profile in patients with moderate-to-severe AD inadequately controlled with topical medications. Trends in this analysis suggest that dupilumab 300 mg qw may provide incremental benefits over the q2w regimen in Black/African American patients; however, interpretation is limited by the small sample size of the Black/ African American cohort and variations in mean body weight between racial subgroups. Overall, these results support the relevance of moderating type 2 inflammation by blocking IL-4 and IL-13 signaling for treatment of AD among all racial subgroups.
ACKNOWLEDGMENTS
The authors thank Thomas Hultsch for his contributions.
FUNDING STATEMENT
Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifiers: NCT02277743; NCT02277769, NCT02260986. Medical writing/editorial assistance provided by Carolyn Ellenberger, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.
DISCLOSURES
Andrew F. Alexis is an advisory board member/consultant for Almirall, Beiersdorf, BioPharmX, Celgene, Cipla, Dermavant, Dermira, Galderma, LEO Pharma, Menlo Therapeutics, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Trevi Therapeutics, Unilever, Valeant; investigator for Almirall, Bristol-Myers Squibb, Celgene, Galderma, LEO Pharma, Menlo Therapeutics, Novartis, RxL. Marta Rendon is an investigator for Regeneron Pharmaceuticals, Inc. Jonathan I. Silverberg is an investigator for AbbVie, Celgene, Eli Lilly & Co., GlaxoSmithKline, Incyte, LEO Pharma, Realm, Regeneron Pharmaceuticals, Inc., Roche; consultant for AbbVie, Anacor Pharmaceuticals, Eli Lilly &
