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.

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.).

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.

Effect of Reactive Oxygen Species Photoproduced in Different Water Matrices on the Photostability of Gadusolate and Mycosporine-Serinol.

In the past few years, there has been an increasing interest in mycosporines-UV-absorbing molecules-bringing important insights into their intrinsic properties as natural sunscreens. Herein, mycosporine-serinol and gadusol (enolate form)/gadusolate were exposed to UV radiation via a solar simulator and the photostability was assessed in pure water and different natural matrices like river, estuary and ocean water. In general, this study revealed that the photodegradation of gadusolate and mycosporine-serinol was higher in natural matrices than in pure water due to the generation of singlet oxygen on UV irradiation. In pure water, in terms of photostability, both gadusolate and mycosporine-serinol were found to offer good protection and high performance in terms of photodegradation quantum yield ((0.8 ± 0.2) × 10-4 and (1.1 ± 0.6) × 10-4, respectively). Nonetheless, the photostability of mycosporine-serinol was found to be superior to that of gadusolate in natural water, namely, ocean, estuary and river. The present work highlights how mycosporine-serinol and gadusolate resist photodegradation, and supports their role as effective and stable UV-B sunscreens.

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.

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.

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.

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.

National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1.

OBJECTIVE: To provide guidance about management of psoriatic disease during the coronavirus disease 2019 (COVID-19) pandemic. STUDY DESIGN: A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. RESULTS: The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus and 13 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is limited in quality. CONCLUSION: These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, 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 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge.

Case Study-Spiking Neural Network Hardware System for Structural Health Monitoring.

This case study provides feasibility analysis of adapting Spiking Neural Networks (SNN) based Structural Health Monitoring (SHM) system to explore low-cost solution for inspection of structural health of damaged buildings which survived after natural disaster that is, earthquakes or similar activities. Various techniques are used to detect the structural health status of a building for performance benchmarking, including different feature extraction methods and classification techniques (e.g., SNN, K-means and artificial neural network etc.). The SNN is utilized to process the sensory data generated from full-scale seven-story reinforced concrete building to verify the classification performances. Results show that the proposed SNN hardware has high classification accuracy, reliability, longevity and low hardware area overhead.

ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

High incidence of BSCL2 intragenic recombinational mutation in Peruvian type 2 Berardinelli-Seip syndrome.

Congenital generalized lipodystrophy (CGL) is a genetically heterogeneous group of disorders characterized by the absence of functional adipose tissue. We identified two pedigrees with CGL in the community of the Mestizo tribe in the northern region of Peru. Five cases, ranging from 15 months to 7 years of age, presented with generalized lipodystrophy, muscular prominence, mild intellectual disability, and a striking aged appearance. Sequencing of the BSCL2 gene, known to be mutated in type 2 CGL (CGL2; Berardinelli-Seip syndrome), revealed a homozygous deletion of exon 3 in all five patients examined, suggesting the presence of a founder mutation. This intragenic deletion appeared to be mediated by recombination between Alu sequences in introns 2 and 3. CGL2 in this population is likely underdiagnosed and undertreated because of its geographical, socio-economic, and cultural isolation.© 2016 Wiley Periodicals, Inc.

Analysis of non-melanoma skin cancer across the tofacitinib rheumatoid arthritis clinical programme.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the incidence of non-melanoma skin cancer (NMSC) across the tofacitinib RA development programme. METHODS: NMSC events (through August 2013) were identified in patients receiving tofacitinib in two Phase (P)1, eight P2, six P3 and two long-term extension (LTE) studies. In P123 studies, tofacitinib was administered at various doses (1-30 mg twice daily [BID], 20 mg once daily), as monotherapy or with conventional synthetic disease-modifying anti-rheumatic drugs, mainly methotrexate. In LTE studies, patients from qualifying P123 studies received tofacitinib 5 or 10 mg BID. Crude incidence rates (IRs; patients with events/100 patient-years) for first NMSC event were evaluated across doses and over time. RESULTS: In the overall population, comprising data from 18 studies (15,103 patient-years), 83 of 6092 tofacitinib-treated patients had NMSC events. The IR for NMSC (0.55 [95% confidence interval, 0.45-0.69] overall population) was stable up to 84 months of observation. IRs for tofacitinib 5 and 10 mg BID in combined P123 trials were 0.61 (0.34-1.10) and 0.47 (0.24-0.90), respectively. Corresponding IRs for LTE studies were 0.41 (0.26-0.66) and 0.79 (0.60-1.05). CONCLUSIONS: The IR for NMSC across the tofacitinib RA clinical development programme was low and remained stable over time. The IR for NMSC in LTE studies was numerically but not significantly higher with tofacitinib 10 versus 5 mg BID; an inverse dose relationship was observed in P123 trials. Longer follow-up is required to confirm these results.

Photodynamic Therapy: A Clinical Consensus Guide.

BACKGROUND: The American Society of Dermatologic Surgery (ASDS) periodically develops consensus documents for its members concerning various aspects of dermatologic surgery. Advances in photodynamic therapy (PDT) have been many and PDT use has been established in a variety of skin conditions. OBJECTIVE: The ASDS board of directors proposed a committee of experts in the field to develop consensus documents on different treatments. An expert panel reviewed the literature on PDT and discussed the findings. The consensus was reached with evidence-based recommendations on different clinical applications for PDT. PATIENTS AND METHODS: This consensus document includes discussions regarding PDT, including different photosensitizers and various light source activators, historical perspective, mechanism of action, various therapeutic indications and expected outcomes, pre- and post-care, and management of adverse outcomes. RESULTS: Photodynamic therapy is highly effective for pre-cancerous lesions, superficial nonmelanoma skin cancers, inflammatory acne vulgaris and other conditions. New protocols including laser mediated PDT significantly improve results for several indications. CONCLUSION: The ASDS consensus document on PDT will be helpful for educating members on safe and effective PDT for a variety of indications.

POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?

We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.

Basal cell carcinoma.

Basal cell carcinoma (BCC) is a relatively common form of cancer with a favorable prognosis when treated early. Although most BCCs are easily treated by surgical methods, these lesions occasionally progress to an advanced state that is no longer conducive to surgery or radiation therapy. Even more rarely, the lesions spread to distant sites. Until recently, treatment for locally advanced and metastatic BCC were restricted to chemotherapy and radiation; however, the effectiveness of traditional chemotherapeutic methods in treating locally advanced or metastatic BCC is limited at best. Recent discoveries in the fields of molecular biology have found important pathways implicated in the pathogenesis of BCC. Among these are the epidermal growth factor receptor and hedgehog pathways, which are now being targeted by new biologic therapies. Despite a paucity of phase II and III trial data, preliminary evidence demonstrating the disease-stabilizing ability of biologic therapies in locally advanced and metastatic BCC appears promising.

Comparison of therapeutic agents' short-term effects on facial and scalp actinic keratosis: A network meta-analysis.

BACKGROUND: Care for actinic keratosis (AK) can be improved with more knowledge on the relative of effect of indicated therapies. OBJECTIVES: Using network meta-analyses, we quantitatively determined the comparative "short-term" effects of interventions in adults with facial and scalp AK. METHODS: On February 28, 2023, evidence from the peer-reviewed literature was systematically obtained from OVID, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. We analyzed data from studies published in English, of a trial design, and investigating the effect of an actinic keratosis monotherapy. Patient complete clearance, patient partial clearance or lesion-specific clearance across adults were analyzed at 8-12 weeks after therapy. Patient complete clearance pertained to proportion of participants who experienced complete clearance of actinic keratosis lesions; patient partial clearance corresponded to percentage of subjects who achieved at least 75% clearance of actinic keratosis lesions; lesion-specific clearance represented the percentage of all lesions that were cleared. In the main (i.e., base) analyses, nodes were analyzed only at the level of the agent. RESULTS: Data from a total of 84 studies were used-across which 22 active agents were identified. Estimates of interventions' surface under the cumulative ranking curve rankings and (pairwise) relative effects were estimated. Across the three outcomes, fluorouracil 5% was ranked the most effective. CONCLUSIONS: Our work is the first to provide information on covariate-adjusted relative effects of actinic keratosis therapies- including the more recently reported treatments-for the face and scalp; this knowledge may help physicians and patients make more informed decisions.