Kunal Malik

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.

The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins

Beyond classic “allergic”/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n = 59) compared to psoriasis (n = 22) and healthy controls (n = 18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-γ, CXCL9, TNF-β) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.

Leiomyoma Cutis: A Focused Review on Presentation, Management, and Association with Malignancy

Cutaneous leiomyomas (CLs) are rare, sporadic, or inherited tumors of smooth muscle origin associated with various disorders. Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the primary tumor predisposition syndrome associated with inherited CLs, affecting 180 families worldwide, with significant mortality. CLs are subdivided into piloleiomyomas, genital leiomyomas, and angioleiomyomas based on their smooth muscle of origin, as well as their clinicopathologic features. Piloleiomyomas, derived from arrector pili muscle, are solitary or multiple firm papulonodules located typically on the extremities and trunk; genital leiomyomas, derived from dartoic, vulvar, or mammary smooth muscle, are solitary papulonodules or pedunculated papules located on the scrotum, vulva, or nipple; and angioleiomyomas, which include solid, cavernous, or venous subtypes, are derived from the tunica media of small arteries and veins and typically present on the extremities. Partial/excisional biopsy is required for diagnosing all CLs. Histology shows interlacing fascicles of spindle cells with moderate amounts of eosinophilic cytoplasm and a blunt-ended, elongated nucleus with perinuclear halos. Surgical excision is curative for CLs, with other management options including medical or destructive therapy; active surveillance is advised to monitor HLRCC-associated neoplasms, with pharmacological therapies under active research.

Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis

Background: Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The “plaque model” has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis. Objective: We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics. Methods: We enrolled 30 patients with mild‐to‐moderate AD in a randomized, double‐blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT‐PCR and immunohistochemistry) were evaluated. Results: TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL‐13, IL‐22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers. Conclusion: We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.

Cutaneous Adverse Events in Chronic Hepatitis C Patients Treated With New Direct-Acting Antivirals: A Systematic Review and Meta-Analysis.

Background: Direct-acting antivirals (DAAs) are known to present with additional dermatological events over pegylated-interferon/ribavirin (Peg-IFN/RBV). Objective: A systematic review and meta-analysis was conducted to assess the incidence/risk of cutaneous adverse events (AEs) for simeprevir, sofosbuvir, ABT450/r-ombitasvir, dasabuvir, ledipasvir, daclatasvir, and asunaprevir. Methods: The databases searched included PubMed, Clinicaltrials.gov, and Clinicaloptions.com. Data on telaprevir and boceprevir were obtained from a previous study. Results: The incidences of cutaneous AEs were 34.3% (95% CI 18.4%-54.8%) for the old DAAs + Peg-IFN/RBV, 22.0% (95% CI 17.9%-26.8%) for the new DAAs + Peg-IFN/RBV, 9.8% (95% CI 8.6%-11.2%) for the DAAs + RBV, and 3.8% (95% CI 2.4%-6.1%) for DAAs only. Simeprevir + Peg-IFN/RBV was associated with an increased relative risk over Peg-IFN/RBV; RR = 1.319 (95% CI 1.026-1.697). Conclusion: Dermatological events are still an important issue for many of the new DAAs. Appropriate monitoring, management, and patient education are needed to minimize AEs and achieve HCV cure.

Sebaceus and Becker’s Nevus: Overview of Their Presentation, Pathogenesis, Associations, and Treatment

Nevus sebaceus (NS) and Becker’s nevus (BN) are two variants of epidermal nevi. NS clinically presents as a yellowish-orange, hairless plaque on the scalp, face, or neck, while BN presents as a tan-to-brown hyperpigmented, sometimes hypertrichotic, plaque typically on the chest and shoulder. Histologically, NS displays mature or nearly mature sebaceus glands as well as acanthosis and fibroplasia of the papillary dermis. BN shows variable papillomatosis, acanthosis, and hyperkeratosis, with hyperpigmentation of the basal/suprabasal layer. While the genetic basis of NS is thought to be due to post-zygotic mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS)/Kristen rat sarcoma viral oncogene homolog (KRAS) genes, the genetic basis of BN is relatively unknown and is implicated with paradominant inheritance. In some patients, NS and BN can each be associated with additional cutaneous and extra-cutaneous anomalies, ranging from benign or malignant tumors to multiple organ irregularities. Due to the wide range of possible associations, treatment for NS and BN is devised on a case-by-case basis. In this article, we review the features, etiology, and diagnosis/management of NS and BN, with a focus on associations. We also report a patient who concomitantly presents with both lesions.

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.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

Background: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much‐needed pathogenesis‐based therapy. Objective: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age‐matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL‐17 and TNF‐&agr;–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity‐related manner, patients with Netherton syndrome showed the greatest T‐cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN‐&ggr;, OASL, and TH2/IL‐4 receptor/IL‐5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL‐17–regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis‐like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL‐17/IL‐36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.

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.