Ana B Pavel

Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial

Background: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. Objective: Evaluate interleukin 22 blockade in adults with moderate‐to‐severe atopic dermatitis (AD). Methods: We performed a randomized, double‐blind, placebo‐controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow‐up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. Results: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 ± 2.7 in the fezakinumab arm and 8.0 ± 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a baseline SCORAD of ≥50), SCORAD decline was significantly stronger in the drug‐treated patients than placebo‐treated patients at 12 weeks (21.6 ± 3.8 vs 9.6 ± 4.2, P = .029) and 20 weeks (27.4 ± 3.9 vs 11.5 ± 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug‐treated than placebo‐treated patients (12.4% ± 2.4 vs 6.2% ± 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug‐treated than placebo‐treated patients (0.7 ± 0.2 vs 0.3 ± 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. Limitations: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. Conclusion: Fezakinumab was well‐tolerated, with sustained clinical improvements after last drug dosing.

Asian atopic dermatitis serum is characterized by Th2/Th22-activation, highly correlated with non-lesional skin measures.

Asian AD serum is characterized by prominent Th2 and Th22 signatures that correlate with the non-lesional skin profile, suggesting that serum phenotyping can serve as a surrogate for assessing disease extent beyond apparent AD lesions.

An integrated model of alopecia areata biomarkers highlights both TH1 and TH2 upregulation

This study expands the current paradigm on AA cytokine profile in serum and scalp, identifying IL-15, and Th1 and Th2 serum cytokines that reflect both tissue activity and clinical disease severity.

Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features

Our data established the molecular fingerprints of AD and psoriasis in Han Chinese patients, and identified tissue biomarkers of disease that correlated with clinical severity.

Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

Background: IL‐22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL‐22 antagonism have not been defined in human subjects. Objective: We sought to evaluate the cellular and molecular effects of IL‐22 blockade in tissues from patients with moderate‐to‐severe AD. Methods: We assessed lesional and nonlesional skin from 59 patients with moderate‐to‐severe AD treated with anti–IL‐22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. Results: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10−5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10−19), respectively. Because IL‐22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL‐22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL‐22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL‐22–high drug‐treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL‐22–high placebo‐treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL‐22–low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100As, were restricted to the IL‐22–high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T‐cell and dendritic cell activation and differentiation. Conclusions: This is the first report showing a profound effect of IL‐22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL‐22 baseline expression, suggest a central role for IL‐22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.

Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation

BACKGROUNDnAfrican Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population.nnnOBJECTIVEnWe sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls.nnnMETHODSnWe performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls.nnnRESULTSnAfrican American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1β), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA.nnnCONCLUSIONnThe molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.