Sandra Garcet

Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis.

Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate‐to‐severe disease are limited. Ustekinumab is an IL‐12/IL‐23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. We sought to assess efficacy and safety of ustekinumab in patients with moderate‐to‐severe AD. In this phase II, double‐blind, placebo‐controlled study, 33 patients with moderate‐to‐severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy‐based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2‐related AD genes was seen after 4 weeks of ustekinumab treatment (i.e. MMP12, IL‐22, IL‐13, IFN‐γ, elafin/PI3, CXCL1 and CCL17; P<.05). Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long‐term regulation (32 weeks) from baseline in the ustekinumab group. No severe adverse events were observed. Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound “placebo” effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.

An Integrated Model of Atopic Dermatitis Biomarkers Highlights the Systemic Nature of the Disease

Current atopic dermatitis (AD) models link epidermal abnormalities in lesional skin to cytokine activation. However, there is evolving evidence of systemic immune activation and detectable abnormalities in nonlesional skin. Because some of the best single correlations with severity (Scoring of AD, or SCORAD) are detected not only in lesional but also nonlesional skin and blood, more complex biomarker models of AD are needed. We thus performed extensive biomarker measures in these compartments using univariate and multivariate approaches to correlate disease biomarkers with SCORAD and with a combined hyperplasia score [thickness and keratin 16 (K16) mRNA] at baseline and after cyclosporine A treatment in 25 moderate to severe AD patients. Increases in serum cytokines and chemokines (IL-13, IL-22, CCL17) were found in AD versus healthy individuals and were reduced with treatment. SCORAD correlated with immune (IL-13, IL-22) and epidermal (thickness, K16) measures in lesional and, even more strongly, in nonlesional AD. Serum cytokines also had higher correlations with nonlesional markers at baseline and with treatment. Multivariate U statistics improved baseline and treatment-response SCORAD correlations. Nonlesional models showed the strongest correlations, with further improvement upon integration of serum markers. Even better correlations were obtained between biomarkers and the hyperplasia score. Larger cohorts are needed to confirm these preliminary data.

Autoantigens ADAMTSL5 and LL37 are significantly upregulated in active Psoriasis and localized with keratinocytes, dendritic cells and other leukocytes

Psoriasis is a common immune‐mediated disease that affects 2%‐4% of individuals in North America and Europe. In the past decade, advances in research have led to an improved understanding of immune pathways involved in the pathogenesis of psoriasis and has spurred the development of targeted therapeutics. Recently, three psoriasis autoantigens have been described: cathelicidin (LL37), a disintegrin and metalloprotease domain containing thrombospondin type 1 motif‐like 5 (ADAMTSL5), and lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D). It is important to establish the expression, regulation and therapeutic modulation of these psoriasis autoantigens. In this study, we performed immunohistochemistry and two‐colour immunofluorescence on non‐lesional and lesional psoriasis skin to characterize ADAMTSL5 and LL37, and their co‐expression with T cells, dendritic cells, neutrophils and macrophages, which are the main immune cells that drive this disease. Our results showed that ADAMTSL5 and LL37 are significantly (P<.05) increased in lesional skin and are co‐expressed by many dendritic cells, macrophages and some T cells in the dermis. Gene expression analysis showed significant (P<.05) upregulation of LL37 in lesional skin and significant downregulation following treatment with etanercept. ADAMTSL5 and LL37 are also significantly decreased by IL‐17 or TNF‐α blockade, suggesting feed‐forward induction of psoriasis autoantigens by disease‐related cytokines.

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.

Reduction of Inflammatory and Cardiovascular Proteins in the Blood of Patients with Psoriasis: Differential Responses between Tofacitinib and Etanercept after 4 Weeks of Treatment

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks.

Dust mite induces multiple polar T cell axes in human skin

House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new‐onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model ADs emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown.

Nonlesional atopic dermatitis skin shares similar T‐cell clones with lesional tissues

Atopic dermatitis (AD) is characterized by robust immune activation. Various T‐cell subsets, including Th2/Th22 cells, are increased in lesional and nonlesional skin. However, there is conflicting literature on the diversity of the T‐cell receptor (TCR) repertoire in lesional AD, and its relation to nonlesional skin remains unclear.

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.

Novel immune signatures associated with dysplastic nevi and primary cutaneous melanoma in human skin

Dysplastic naevi (DN) are benign lesions with atypical features intermediate between that of common melanocytic naevi (CMN) and malignant melanoma (MM). Debate remains over whether DN represent progressive lesions from CMN. Through gene expression profiling and analysis of molecular gene signatures, our study revealed progressive increases in immune activation and regulation, along with pathways implicated in melanomagenesis, from CMN to DN to MM. Using criteria of 1.5‐fold change and false discovery rate ≤0.05, we found differential expression of 7186 probes (6370 unique genes) with the largest difference detected between DN and MM from the standpoint of genomic melanoma progression. Despite progressive increases in the T‐helper type 1 (Th1)‐inducing gene (IL‐12), RT‐PCR indicated impaired Th1 or cytotoxic T‐cell response (decreased IFN‐γ) in MM. Concordantly, our results indicated progressive increases in molecular markers associated with regulatory T cells, exhausted T cells and tolerogenic dendritic cells, including detection of increased expression of suppressor of cytokine signalling 3 (SOCS3) in dendritic cells associated with MM. All together, our findings suggest that the increased immunosuppressive microenvironment of melanoma may contribute to unhampered proliferation of neoplastic cells. In addition, the detection of increased markers associated with tolerogenic dendritic cells in MM suggests that targeting these suppressive immune cell types may represent an alternative avenue for future immunotherapy.

Aberrant connective tissue differentiation towards cartilage and bone underlies human keloids in African Americans

Keloids are benign fibroproliferative tumors more frequently found among African Americans. Until now, keloid etiopathogenesis is not fully understood. To characterize keloids in African Americans, we performed transcriptional profiling of biopsies from large chronic keloids, adjacent non‐lesional (NL) skin (n=3) and a newly formed keloid lesion using Affymetrix HGU133 2.0 plus arrays. Quantitative RT‐PCR (qRT‐PCR) and immunohistochemistry (IHC) staining were performed to confirm increased expression of relevant genes. We identified 1202 upregulated and 961 downregulated differentially expressed genes (DEGs) between keloid and NL skin; 1819 up‐ and 1867 downregulated DEGs between newly formed keloid and NL skin; and 492 up‐ and 775 downregulated DEGs between chronic and newly formed keloid (fold change >2, false discovery rate <0.05). Many of the top upregulated DEGs between chronic keloid and NL skin and between newly formed keloid and NL skin are involved in bone/cartilage formation including Fibrillin 2 (FBN2), Collagen type X alpha 1, Asporin (ASPN), Cadherin 11 (CDH11), Bone morphogenic protein 1 (BMP1), Secreted phosphoprotein 1 and Runt‐related transcription factor 2 (RUNX2). qRT‐PCR confirmed significant (P<.05) upregulation of BMP1, RUNX2, CDH11 and FBN2 in chronic keloid compared to NL skin. IHC staining showed increased protein expression of ASPN, CDH11, BMP1 and RUNX2 on chronic and newly formed keloid compared to NL skin. Our study shows that large keloids in African Americans represent a dysplasia of cutaneous connective tissue towards immature cartilage or bone differentiation. The phenotype is potentially regulated by overexpression of RUNX2. This knowledge may give insights to guide the development of better treatment for the disease in the future.