Saakshi Khattri

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.

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.

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

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Spreadability of Five Vehicles on Five Surfaces

There are many factors that determine the type of vehicle chosen for a topical medication. Physician considerations include the body region where the agent will be applied, the thickness of the skin, and the amount of surface area in question. Patient considerations include ease of application and removal and aesthetic appeal. We compared the spreadability of five delivery systems used for topical medications (cream, lotion, ointment, gel, and foam) on five types of surfaces (synthetic skin, cardboard, aluminum foil, hard plastic, and soft plastic). In our study (for a set quantity of medication), the foam had the highest spreadability on all tested surfaces, and the ointment the lowest, with the foam covering nine times the surface area of the ointment. This quality makes foam agents ideal for large surface areas. Spreadability can help improve patient tolerability and compliance.

A Review of Current Evidence for TNF Inhibitor Switching in Psoriatic Arthritis

TNF inhibitors have been proven to be effective in treating psoriatic arthritis, however not every patient responds to or tolerates treatment. Between 20% and 40% of patients are switched to a different TNF inhibitor, and 5% to 15% are eventually treated with three different TNF inhibitors. Loss of efficacy is the most common reason patients fail TNF inhibitor therapy, followed by adverse effects. Less than a quarter of patients who switched TNF inhibitors did so due to lack of primary response. The majority of data demonstrates that switching can be clinically beneficial after failure of one TNF inhibitor, but is associated with lower response rates compared to initial treatment. Drug survival rates also decrease with multiple courses of treatment. If a psoriatic arthritis patient fails two TNF inhibitors, it may be more efficacious to switch to one of the newer biologics with an alternate mechanism of action.

Acitretin for the Treatment of Psoriasis: A Case Report of Long-Lasting Alopecia:

Acitretin has been associated with alopecia and hair shaft abnormalities such as hair kinking, hair curling, poliosis, and re-pigmentation of hair color. In the majority of patients, these side effects are dose-dependent, mild, and only temporary, with hair growth reoccurring after cessation of treatment. A 65-year-old male developed severe hair loss over his entire body seven weeks into treatment. He presented to us more than six months after discontinuation of acitretin without evidence of substantial hair regrowth. Here we report one of the rare cases of long-lasting alopecia after therapy with acitretin that we believe to be a case of generalized telogen effluvium.