Brodalumab: 5-Year US Pharmacovigilance Report.

INTRODUCTION: Brodalumab is a human interleukin-17 receptor A antagonist indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. Although the US prescribing information for brodalumab includes a boxed warning regarding suicidal ideation and behavior, no causal association has been demonstrated. Here, we summarize 5 years of pharmacovigilance data, from August 15, 2017, through August 14, 2022, reported to Ortho Dermatologics by US patients and healthcare providers. METHODS: Prevalence of the most common adverse events (AEs) listed in the brodalumab package insert (incidence ≥ 1%) and AEs of special interest are described. Brodalumab exposure was estimated as the time from the first to last prescription-dispensing authorization dates. Data were collected from 4744 patients in the USA, with an estimated exposure of 5815 patient-years. RESULTS: Over 5 years, 11 cases of adjudicated major adverse cardiovascular events were reported (0.23 events/100 patients), a rate lower than that experienced by patients in the international Psoriasis Longitudinal Assessment and Registry. There were 106 serious infections. No serious fungal infections were reported. There were 40 confirmed and 2 suspected COVID-19 cases, with no new COVID-19-related deaths. Of 49 reported malignancies among 42 patients, 3 were deemed possibly related to brodalumab. No completed suicides and no new suicidal attempts were reported. CONCLUSION: Five-year pharmacovigilance data are consistent with the established safety profile reported in long-term clinical trials and previous pharmacovigilance reports, with no new safety signals.

Brodalumab is an injectable treatment approved for moderate-to-severe plaque psoriasis in adults who lacked response to previous treatments. In the USA, brodalumab is only available under a Risk Evaluation and Mitigation Strategy for increased suicidality risks; however, findings from 5 years of real-world safety data have demonstrated a lack of association. In this report, we discuss safety findings reported by US patients and healthcare providers for 4744 patients treated with brodalumab over 5 years. Joint pain (known as arthralgia) was the most common safety finding, with 122 cases reported over 5 years. Other safety findings of interest across 5 years included 106 serious infections (defined as prolonged infections or infections requiring treatment), 54 cases of depression, 49 cases of cancer (in 42 patients), 40 confirmed cases of COVID-19, and 11 cases of major cardiovascular events (such as stroke or heart attack). No completed suicides occurred throughout 5 years, and no new suicidal attempts were reported in year 5. In indirect comparisons with safety data from patients with psoriasis receiving or eligible to receive similar treatments, brodalumab was not associated with an increased risk of serious infection, cancer, major cardiovascular events, or inflammatory bowel disease. Taken together, these data are consistent with safety findings from long-term clinical trials and previous safety reports of brodalumab.

Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. Objective: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. Evidence Review: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. Findings: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. Conclusions and Relevance: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

Vaccination recommendations for adults receiving biologics and oral therapies for psoriasis and psoriatic arthritis: Delphi consensus from the medical board of the National Psoriasis Foundation.

BACKGROUND: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis. OBJECTIVE: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines. METHODS: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts. RESULTS: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination. LIMITATIONS: Studies regarding infection rates after vaccination are lacking. CONCLUSION: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases.

Tapinarof Cream 1% Once Daily for the Treatment of Plaque Psoriasis: Case Photography of Clinical Outcomes from Three Phase 3 Trials.

Tapinarof cream 1% (VTAMA®; Dermavant Sciences, Inc.) is a non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis in adults and under investigation for the treatment of psoriasis in children down to 2 years of age, and for atopic dermatitis in adults and children down to 2 years of age. The PSOARING phase 3 clinical trial program evaluated tapinarof cream 1% once daily (QD) in adults with mild to severe plaque psoriasis for up to 52 weeks (NCT03956355, NCT03983980, NCT04053387). Here we present case photography documenting outcomes in the PSOARING trials. Cases illustrate various outcomes across different body areas, including responses meeting the formal FDA-mandated regulatory endpoint of a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points from baseline at week 12, meaningful clinical improvement not meeting this formal endpoint, patient-reported outcomes, and pre-specified adverse events of special interest (AESIs). Tapinarof cream 1% QD demonstrated rapid and highly statistically significant efficacy, with improvements in disease activity and quality of life. In addition, a high rate (40.9%; n = 312/763) of complete disease clearance (PGA = 0) was achieved, and improvements exceeding National Psoriasis Foundation treatment goals were demonstrated. After first achieving complete disease clearance (PGA = 0), patients treated with tapinarof experienced an approximately 4-month remittive effect off therapy. Incidence and severity of folliculitis and contact dermatitis AESIs were generally mild or moderate, localized to the site of application, and associated with low discontinuation rates. Medical images are of importance in trials of dermatologic therapies to inform clinical decision-making and enhance patient assessment. Tapinarof cream 1% QD is efficacious and well tolerated in patients with mild to severe plaque psoriasis, with clinically relevant improvements seen early in the course of treatment.Clinicaltrials.gov numbers: NCT03956355, NCT03983980, NCT04053387.

Tapinarof, a Novel, First-in-Class, Topical Therapeutic Aryl Hydrocarbon Receptor Agonist for the Management of Psoriasis.

Topical treatments remain the foundation of psoriasis management. Tapinarof (VTAMA®; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical, aryl hydrocarbon receptor (AhR) agonist approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults and is under investigation for the treatment of psoriasis in children, and atopic dermatitis in adults and children down to 2 years old. Here, we review the mechanism of action of tapinarof and the PSOARING phase 3 trial program in mild to severe psoriasis. AhR is a ligand-dependent transcription factor involved in maintaining skin homeostasis. Tapinarof specifically binds to AhR to decrease proinflammatory cytokines, decrease oxidative stress, and promote skin barrier normalization. In two identical, randomized, 12-week pivotal phase 3 trials, PSOARING 1 and 2, tapinarof cream 1% once daily (QD) demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe psoriasis. In the PSOARING 3 long-term extension trial of repeated, intermittent tapinarof cream in eligible patients completing the pivotal trials, a high rate of complete disease clearance (40.9%) and a remittive effect of approximately 4 months off therapy were demonstrated over 52 weeks, with no tachyphylaxis. The most common adverse event, folliculitis, was mostly mild or moderate and resulted in a low trial discontinuation rate in PSOARING 1 and 2 (≤1.8%). Tapinarof cream 1% QD provides a novel, non-steroidal, topical treatment option for patients with psoriasis and is highly effective and well tolerated with long-term use including when applied to sensitive and intertriginous skin. Bobonich M, Gorelick J, Aldredge L, et al. Tapinarof, a novel, first-in-class, topical therapeutic aryl hydrocarbon receptor agonist for the management of psoriasis. J Drugs Dermatol. 2023;22(8):779-784. doi:10.36849/JDD.7317.

A Novel CD206 Targeting Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice.

Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense Peptide (HDP), RP-832c, to decrease profibrotic cytokines. RP-832c selectively binds to CD206 on M2-polarized bone marrow-derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression and a transient increase in M1-macrophage marker TNF-α. To elucidate the antifibrotic effects of RP-832c, we used a murine model of bleomycin (BLM)-induced early-stage pulmonary fibrosis. RP-832c significantly reduced fibrosis in a dose-dependent manner, and decreased CD206, TGF-ß1, and α-SMA expression in mouse lungs. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased lung fibrosis and significantly decreased inflammatory cytokines TNF-α, IL-6, IL-10, IFN-γ, CXCL1/2, and fibrosis markers TGF-ß1 and MMP-13. In comparison with the FDA-approved drugs Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed. In summary, our findings showed that inhibiting the profibrotic alternatively activated M2-like macrophages using a novel peptide, RP-832c, could reduce BLM-induced pulmonary fibrosis in mice, warranting the therapeutic potential of this peptide for patients with pulmonary fibrosis.

Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors.

Plaque psoriasis is a systemic immune-mediated disease driven by interleukin-17 producing cells under the regulation of interleukin-23. Interleukin-23 signaling is mediated by the intracellular kinase tyrosine kinase 2, a Janus kinase family member. Tyrosine kinase 2 is a potential target for oral small-molecule therapies to treat psoriasis and psoriatic arthritis. A number of tyrosine kinase 2 inhibitors are in development or approved for the treatment of psoriasis or psoriatic arthritis. Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US Food and Drug Administration as a first-in-class treatment for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and is approved by Pharmaceuticals and Medical Devices Agency (PDMA) in Japan for patients with plaque psoriasis, generalized pustular psoriasis, and erythrodermic psoriasis who have had an inadequate response to conventional therapies. Deucravacitinib selectively binds to the unique tyrosine kinase 2 regulatory pseudokinase domain in an allosteric fashion, preventing a conformational change in the catalytic domain required for ATP substrate binding, thus effectively locking tyrosine kinase 2 in an inactive state. Two other tyrosine kinase 2 inhibitors in later stage clinical development, brepocitinib (PF-06700841) and ropsacitinib (PF-06826647), are orthosteric inhibitors that target the highly conserved catalytic domain. This selective allosteric tyrosine kinase 2 inhibition may explain the improved safety profile of deucravacitinib versus orthosteric Janus kinase and tyrosine kinase 2 inhibitors. Two phase 3 psoriasis trials demonstrated deucravacitinib was efficacious and not associated with safety concerns characteristic of Janus kinase inhibitors, hence the new class designation (TYK2 inhibitor) by health authorities in the USA and Japan. Allosteric tyrosine kinase 2 inhibitors represent a promising new class of molecules for the treatment of psoriasis and psoriatic arthritis, and longer-term trials will establish their place in therapy.

Accelerated epigenetic aging and DNA methylation alterations in Berardinelli-Seip congenital lipodystrophy.

Berardinelli-Seip congenital lipodystrophy type 2 (CGL2) is a very rare human genetic disorder with potential significance to the understanding of the pathobiology of aging. CGL2 patients display characteristic progeroid features and suffer from type 2 diabetes, insulin resistance and fatty liver. In this study, we profiled genome-wide DNA methylation levels in CGL2 patients with BSCL2 mutations to study epigenetic age acceleration and DNA methylation alterations. This analysis revealed significant age acceleration in blood DNA of CGL2 patients using both first- and second-generation epigenetic clocks. We also observed a shortened lifespan of Caenorhabditis elegans following knockdown of the BSCL2 homolog seip-1 on a daf-16/forkhead box, class O mutant background. DNA methylation analysis revealed significant differentially methylated sites enriched for lyase activity, kinase regulator activity, protein kinase regulator activity and kinase activator activity. We could also observe significant hypomethylation in the promoter of the dual specificity phosphatase 22 gene when comparing CGL2 patients versus controls. We conclude that in line with the observed progeroid features, CGL2 patients exhibit significant epigenetic age acceleration and DNA methylation alterations that might affect pathways/genes of potential relevance to the disease.

TNF-α/IFN-γ synergy amplifies senescence-associated inflammation and SARS-CoV-2 receptor expression via hyper-activated JAK/STAT1.

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID-19 infection. The pathogenesis of COVID-19-related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS-CoV-2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF-α + IFN-γ or a cocktail of TNF-α + IFN-γ + IL-6, increased expression of ACE2/DPP4, accentuated the pro-inflammatory senescence-associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence-like state. IL-6 by itself failed to induce substantial effects on viral entry receptors or SASP-related genes, while synergy between TNF-α and IFN-γ initiated a positive feedback loop via hyper-activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper-inflammation, normalized SARS-CoV-2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine-mediated viral entry receptor activation and links with senescence and hyper-inflammation.

Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases.

BACKGROUND: Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by variants in WRN. The International Registry of Werner Syndrome has identified biallelic pathogenic variants in 179/188 cases of classical WS. In the remaining nine cases, only one heterozygous pathogenic variant has been identified. METHODS: Targeted long-read sequencing (T-LRS) on an Oxford Nanopore platform was used to search for a second pathogenic variant in WRN. Previously, T-LRS was successfully used to identify missing variants and analyse complex rearrangements. RESULTS: We identified a second pathogenic variant in eight of nine unsolved WS cases. In five cases, T-LRS identified intronic splice variants that were confirmed by either RT-PCR or exon trapping to affect splicing; in one case, T-LRS identified a 339 kbp deletion, and in two cases, pathogenic missense variants. Phasing of long reads predicted all newly identified variants were on a different haplotype than the previously known variant. Finally, in one case, RT-PCR previously identified skipping of exon 20; however, T-LRS did not detect a pathogenic DNA sequence variant. CONCLUSION: T-LRS is an effective method for identifying missing pathogenic variants. Although limitations with computational prediction algorithms can hinder the interpretation of variants, T-LRS is particularly effective in identifying intronic variants.

A United States expert consensus to standardise definitions, follow-up, and treatment targets for extra-intestinal manifestations in inflammatory bowel disease.

BACKGROUND AND AIMS: Extra-intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited. METHODS: As a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty-four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds. RESULTS: For use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence. CONCLUSIONS: Consensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician-reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.

2020 IDEOM Annual Meeting: Actinic Keratosis Stakeholders Survey Identifies Gaps in Research and Care.

This is a report of the survey results from the International Dermatology Outcome Measures (IDEOM) actinic keratosis (AK) workgroup. The purpose of the survey was to compile a list of gaps within AK care and management that require refinement. The results were discussed at the IDEOM annual meeting held virtually on October 23–24, 2020. This built a framework with which the AK workgroup, which consisted of physicians, patients, and pharmaceutical scientists, discussed at length in their breakout session at the meeting. The electronic survey was distributed to patients, pharmaceutical scientists, and leading physician experts in the field via email on September 22, 2020, with a deadline of October 2, 2020. The survey consisted of three open-ended prompts concerning key gaps and/or unmet needs in (1) the care of AKs, (2) outcome measurement of AKs in clinical trials and, (3) the measurement of AKs in clinical practice. The results were qualitative, with a response rate of 47%. Responses included reform of outcome measures for clinical trials, a methodology for evaluating the efficacy of preventative measures, and a comparison of treatments to establish a treatment protocol, among other efforts. This paper will also provide a brief overview of the current state of the AK outcome measures, emphasizing the heterogeneity of the measures and detailing the AK workgroup's future efforts to create a reliable and applicable core outcome measure set. J Drugs Dermatol. 2022;21(2):128-134. doi:10.36849/JDD.6360.

DNA methylation signatures in Blood DNA of Hutchinson-Gilford Progeria syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder caused by mutations in the LMNA gene and characterized by premature and accelerated aging beginning in childhood. In this study, we performed the first genome-wide methylation analysis on blood DNA of 15 patients with progeroid laminopathies using Infinium Methylation EPIC arrays including 8 patients with classical HGPS. We could observe DNA methylation alterations at 61 CpG sites as well as 32 significant regions following a 5 Kb tiling analysis. Differentially methylated probes were enriched for phosphatidylinositol biosynthetic process, phospholipid biosynthetic process, sarcoplasm, sarcoplasmic reticulum, phosphatase regulator activity, glycerolipid biosynthetic process, glycerophospholipid biosynthetic process, and phosphatidylinositol metabolic process. Differential methylation analysis at the level of promoters and CpG islands revealed no significant methylation changes in blood DNA of progeroid laminopathy patients. Nevertheless, we could observe significant methylation differences in classic HGPS when specifically looking at probes overlapping solo-WCGW partially methylated domains. Comparing aberrantly methylated sites in progeroid laminopathies, classic Werner syndrome, and Down syndrome revealed a common significantly hypermethylated region in close vicinity to the transcription start site of a long non-coding RNA located anti-sense to the Catenin Beta Interacting Protein 1 gene (CTNNBIP1). By characterizing epigenetically altered sites, we identify possible pathways/mechanisms that might have a role in the accelerated aging of progeroid laminopathies.

Matrigel: history/background, uses, and future applications.

Basement membranes are thin sheets of extracellular matrix with many diverse roles in the body. Those in normal tissue are also highly insoluble and resist attempts to extract and characterize their components. A mouse tumor, the EHS tumor, has provided large amounts of basement membrane material, which has facilitated the structural and functional characterization of its components. An extract of the tumor, known as Matrigel, contains components which reconstitute into a solid gel at 37°. This solid basement membrane matrix has been used in both cell culture and in vivo. Matrigel has been utilized in some 12,000-plus publications for a variety of studies with embryonic, normal, and stem or malignant cells. Evidence presented in this Commentary suggests that Matrigel isolated from tumors grown in diverse hosts could exert unique effects that could be helpful in analyzing the causes of various pathologies and for screening possible therapeutic agents.

Cell-to-cell variation in gene expression and the aging process.

There is tremendous variation in biological traits, and much of it is not accounted for by variation in DNA sequence, including human diseases and lifespan. Emerging evidence points to differences in the execution of the genetic program as a key source of variation, be it stochastic variation or programmed variation. Here we discuss variation in gene expression as an intrinsic property and how it could contribute to variation in traits, including the rate of aging. The review is divided into sections describing the historical context and evidence to date for nongenetic variation, the different approaches that may be used to detect nongenetic variation, and recent findings showing that the amount of variation in gene expression can be both genetically programmed and epigenetically controlled. Finally, we present evidence that changes in cell-to-cell variation in gene expression emerge as part of the aging process and may be linked to disease vulnerability as a function of age. These emerging concepts are likely to be important across the spectrum of biomedical research and may well underpin what we understand as biological aging.

Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis.

BACKGROUND: The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma. METHODS: In two identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm2 contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 [absent] to 3 [severe]). RESULTS: A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved. CONCLUSIONS: In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.).

SMAD4 mutations and cross-talk between TGF-ß/IFNγ signaling accelerate rates of DNA damage and cellular senescence, resulting in a segmental progeroid syndrome-the Myhre syndrome.

SMAD4 encodes a member of the SMAD family of proteins involved in the TGF-ß signaling pathway. Potentially heritable, autosomal dominant, gain-of-function heterozygous variants of SMAD4 cause a rare developmental disorder, the Myhre syndrome, which is associated with a wide range of developmental and post-developmental phenotypes that we now characterize as a novel segmental progeroid syndrome. Whole-exome sequencing of a patient referred to our International Registry of Werner Syndrome revealed a heterozygous p.Arg496Cys variant of the SMAD4 gene. To investigate the role of SMAD4 mutations in accelerated senescence, we generated cellular models overexpressing either wild-type SMAD4 or mutant SMAD4-R496C in normal skin fibroblasts. We found that cells expressing the SMAD4-R496C mutant exhibited decreased proliferation and elevated expression of cellular senescence and inflammatory markers, including IL-6, IFNγ, and a TGF-ß target gene, PAI-1. Here we show that transient exposure to TGF-ß, an inflammatory cytokine, followed by chronic IFNγ stimulation, accelerated rates of senescence that were associated with increased DNA damage foci and SMAD4 expression. TGF-ß, IFNγ, or combinations of both were not sufficient to reduce proliferation rates of fibroblasts. In contrast, TGF-ß alone was able to induce preadipocyte senescence via induction of the mTOR protein. The mTOR inhibitor rapamycin mitigated TGF-ß-induced expression of p21, p16, and DNA damage foci and improved replicative potential of preadipocytes, supporting the cell-specific response to this cytokine. These findings collectively suggest that persistent DNA damage and cross-talk between TGF-ß/IFNγ pathways contribute to a series of molecular events leading to cellular senescence and a segmental progeroid syndrome.

National Psoriasis Foundation COVID-19 Task Force guidance for management of psoriatic disease during the pandemic: Version 2-Advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments.

OBJECTIVE: To update guidance regarding the management of psoriatic disease during the COVID-19 pandemic. STUDY DESIGN: The task force (TF) includes 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation staff. Clinical questions relevant to the psoriatic disease community were informed by inquiries received by the National Psoriasis Foundation. A Delphi process was conducted. RESULTS: The TF updated evidence for the original 22 statements and added 5 new recommendations. The average of the votes was within the category of agreement for all statements, 13 with high consensus and 14 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is variable in quality and/or quantity. CONCLUSIONS: These statements provide guidance for the treatment of patients with psoriatic disease on topics including how the disease and its treatments affect COVID-19 risk, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 (including novel vaccination), and what they should do if they develop COVID-19. The guidance is a living document that is continuously updated by the TF as data emerge.

Promoting Interfacial Interactions with the Addition of Lignin in Poly(Lactic Acid) Hybrid Nanocomposites.

In this paper, the calorimetric response of the amorphous phase was examined in hybrid nanocomposites which were prepared thanks to a facile synthetic route, by adding reduced graphene oxide (rGO), Cloisite 30B (C30B), or multiwalled carbon nanotubes (MWCNT) to lignin-filled poly(lactic acid) (PLA). The dispersion of both lignin and nanofillers was successful, according to a field-emission scanning-electron microscopy (FESEM) analysis. Lignin alone essentially acted as a crystallization retardant for PLA, and the nanocomposites shared this feature, except when MWCNT was used as nanofiller. All systems exhibiting a curtailed crystallization also showed better thermal stability than neat PLA, as assessed from thermogravimetric measurements. As a consequence of favorable interactions between the PLA matrix, lignin, and the nanofillers, homogeneous dispersion or exfoliation was assumed in amorphous samples from the increase of the cooperative rearranging region (CRR) size, being even more remarkable when increasing the lignin content. The amorphous nanocomposites showed a signature of successful filler inclusion, since no rigid amorphous fraction (RAF) was reported at the filler/matrix interface. Finally, the nanocomposites were crystallized up to their maximum extent from the glassy state in nonisothermal conditions. Despite similar degrees of crystallinity and RAF, significant variations in the CRR size were observed among samples, revealing different levels of mobility constraining in the amorphous phase, probably linked to a filler-dimension dependence of space filling.