Dermal lesions associated with anti-tumor necrosis factor α therapy in patients with inflammatory bowel disease (IBD): findings from a tertiary IBD center in Poland.

INTRODUCTION: There are scarce data on the occurrence of dermal lesions in patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor α (anti-TNF­α) antibodies. Characteristics of the skin lesions, their clinical course, and impact on treatment are of high importance. OBJECTIVES: The aim of this study was to assess the prevalence, risk factors, and clinical sequelae of dermal lesions in IBD patients treated with anti-TNF­α antibodies. PATIENTS AND METHODS: This retrospective, single­center study evaluated 541 IBD patients treated with anti-TNF­α drugs and 688 IBD individuals with no history of anti-TNF­α treatment. RESULTS: Higher prevalence of dermal lesions was noted in the patients on anti-TNF­α therapy than in the individuals not receiving such treatment (30.9% vs 16.4%; P <0.001). Risk factors for dermal lesions included higher body mass index (BMI), Crohn disease located in the small intestine, and longer duration of therapy. Some types of dermal lesions were associated with anti-TNF­α therapy; these included infusion reactions and injection site reactions, cutaneous infection, psorasiform reactions, and lupus­like symptoms. Overall, 5.9% of the patients on anti-TNF­α therapy required treatment change or discontinuation due to dermal lesions (alopecia, lupus­like symptoms, melanoma, and psoriasis). CONCLUSIONS: We observed a higher prevalence of dermal lesions in patients with IBD undergoing anti-TNF­α therapy than in the treatment-naive group, although development of such lesions rarely necessitated a change in or discontinuation of treatment. Patients with IBD should regularly undergo follow-up dermatologic evaluation, which may improve detection of dermal lesions. Moreover, biologic therapy in IBD patients requires close collaboration with an experienced dermatologist.

The spectrum of cutaneous toxicities related to novel genitourinary cancer therapies.

CONTEXT: Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities. OBJECTIVE: To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors. EVIDENCE ACQUISITION: A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs). EVIDENCE SYNTHESIS: Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender. CONCLUSIONS: Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.

Dermatologic adverse events caused by biologic treatments - Pathogenesis and management.

Biologics are approved for various dermatologic, allergic, rheumatic, and gastroenterologic inflammatory diseases, as well as for numerous malignancies. The dermatologic adverse events from treatment with biologics may resemble primary inflammatory diseases but differ in pathogenesis. In this article, we describe five different pathogenic mechanisms of dermatologic adverse events. By studying these mechanisms, we hope to gain valuable insights into the pathogenesis of primary inflammatory diseases. In addition, in this article, we provide recommendations for the treatment and management of the dermatological adverse events induced by biologics.

Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10-4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10-2, p = 2.8 × 10-2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10-2, p = 3.2 × 10-2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10-1, p = 3.4 × 10-2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10-2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10-4-3.1 × 10-3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10-3-2.8 × 10-3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10-3), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10-4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.

Prevalence of skin problems caused by insulin pump therapy and associated factors in children with type 1 diabetes mellitus: A large cross-sectional survey in China.

AIMS: To document the prevalence of skin problems associated with insulin pump use and identify contributing factors among children with type 1 diabetes mellitus in China. METHODS: In total, 461 children were recruited from an online community (i.e., a Wechat group) of pediatric patients with T1DM. A self-developed questionnaire was filled in by parents, collecting the information on social demographics, disease, and insulin pump therapy related characteristics and skin problems. We applied the Mann-Whitney U test, Chi square test and logistic regression analysis to identify the factors associated with skin problems. RESULTS: Of the 461 responders, 308 (66.8 %) children were reported to have skin problems. More specifically, 38.8 % had pigmentation changes, 22.3 % allergy/dermatitis, 20.2 % scaring, 11.5 % pain, 10.8 % infection, 10.6 % subcutaneous lipohypertrophy, and 6.1 % lipoatrophy. Logistic regression analysis showed that independent associated factors of skin problems were the caregiver's educational level as college or above, patient having skin allergies, and using the Brand 2 insulin pump (p values < 0.05). CONCLUSIONS: The present study documents the prevalence of skin problems and identifies associated factors, such as caregiver's education, patients skin allergies, and using a specific brand of pump. Health education should address these factors in addition to the traditionally emphasized factors.

Paradoxical and bimodal immune-mediated dermatological side effects of TNF-α inhibitors: A comprehensive review.

INTRODUCTION: Due to the increasing prevalence of immune-mediated diseases such as psoriasis, lichen planus, rheumatoid arthritis and inflammatory bowel disease, dermatologists have turned to new biologic drugs known as DMARDs (disease-modifying anti-rheumatic drugs) in recent years. AREAS COVERED: In this study, we evaluate the immune-mediated dermatological side effects of DMARDS by reviewing and analyzing previous peer-reviewed research on the effects of TNF-α inhibitors in the treatment of skin diseases, as well as adverse effects of these drugs and some of the main causes of these effects. EXPERT OPINION: DMARDs are very effective in improving control of the above diseases. TNF-α inhibitors are an important group of DMARDs that are widely used. The paradoxical adverse events (PAEs) associated with the use of TNF-α inhibitors are divided into three categories: true paradoxical, borderline paradoxical, and non-paradoxical. True PAEs include conditions for which TNF-α inhibitors are approved for treatment. Borderline PAEs are considered to occur with this class of drugs for which there is no definite approval but for which there is sufficient evidence. Although these events are rare, early recognition of the accused drug and appropriate decision-making may prevent progression of complications and irreversible side effects.

Air pollution and skin diseases: A comprehensive evaluation of the associated mechanism.

Air pollutants deteriorate the survival environment and endanger human health around the world. A large number of studies have confirmed that air pollution jeopardizes multiple organs, such as the cardiovascular, respiratory, and central nervous systems. Skin is the largest organ and the first barrier that protects us from the outside world. Air pollutants such as particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) will affect the structure and function of the skin and bring about the development of inflammatory skin diseases (atopic dermatitis (AD), psoriasis), skin accessory diseases (acne, alopecia), auto-immune skin diseases (cutaneous lupus erythematosus(CLE) scleroderma), and even skin tumors (melanoma, basal cell carcinoma (BCC), squamous-cell carcinoma (SCC)). Oxidative stress, skin barrier damage, microbiome dysbiosis, and skin inflammation are the pathogenesis of air pollution stimulation. In this review, we summarize the current evidence on the effects of air pollution on skin diseases and possible mechanisms to provide strategies for future research.

Utility of hydroxychloroquine laboratory monitoring in dermatologic and rheumatologic patients.

Hydroxychloroquine (HCQ) is an immunomodulator used in dermatology and rheumatology. Side effects may be observed on routine monitoring studies before they become clinically apparent. The goal of this retrospective chart review was to assess laboratory abnormalities in dermatologic and rheumatologic patients taking HCQ. Medical records of patients prescribed HCQ were retrospectively reviewed. Demographics, reported side effects, and parameters on baseline and follow-up complete blood count (CBC) and comprehensive metabolic panel (CMP) were recorded and graded. Laboratory abnormalities were considered severe if they were grade 3 or greater according to Common Terminology Criteria for Adverse Events v3.0 and persistent if they continued beyond subsequent laboratory testing. Of 646 eligible charts, 289 had monitoring studies for review. There were 35 severe (grade 3 or 4, 35/289; 12%) adverse events that developed, as noted on CBC or CMP. Of these 35 severe adverse events, 25 self-corrected on subsequent testing, and 10 (10/289, 3%) across 9 patients were persistent, including glomerular filtration rate, alanine transferase, alkaline phosphatase, glucose, hemoglobin and lymphopenia abnormalities. Of these 10 abnormalities, 7/10 (70%) were unlikely due to hydroxychloroquine use according to the calculated Naranjo score for each patient. Severe laboratory abnormalities while taking hydroxychloroquine are rare, even in a population with a high rate of comorbidities. Among the abnormalities observed, the majority of them (70%) were likely due to disease progression or a medication other than hydroxychloroquine. CBC and CMP monitoring for the reason of observing abnormalities while on HCQ should be at the discretion of the prescribing physician.

Skin and ophthalmic complications of chloroquine and hydroxychloroquine in patients with rheumatoid arthritis and systemic lupus erythematous.

Immunosuppressive agents are routinely used to control autoimmunity. However, some adverse events are correlated to their clinical applications. The aim of this study was to study the clinical findings and ocular and cutaneous side effects of chloroquine (CQ) and hydroxychloroquine (HCQ), as current immunomodulators, in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This descriptive study was performed on 360 individuals referred to the Rheumatology clinic during 2003-2020. Demographic characteristics and other information were collected from patients with RA and SLE. Skin and ocular complications were evaluated in patients who were on treatment with CQ and HCQ. Study populations consisted of 199 subjects with RA and 161 cases with SLE. The frequencies of skin and ocular complications in all patients treated with CQ and HCQ were 32 (17.65%) and 94 (51.9%), respectively. The prevalence of skin complications in patients with RA and SLE was 20 (10.05%) and 22 (13.66%), respectively. The frequencies of ocular complications in patients with RA and SLE were, respectively, 58 (29.4%) and 36 (22.5%). Multiple logistic regression analysis revealed that ophthalmic complications of CQ and HCQ in all patients were dependent on the effects of the duration of drug uses, disease duration, and cumulative doses (p < 0.05), unlike skin complications. Disease types had no effect on ocular complications. Based on these findings, treatment with CQ and HCQ participates in some skin and ocular complications in patients with RA and SLE which are largely associated with the duration of disease and treatment.

The Use of Biologic Agents for the Treatment of Cutaneous Immune-Related Adverse Events from Immune Checkpoint Inhibitors: A Review of Reported Cases.

Cutaneous immune-related adverse events encompass a spectrum of dermatological manifestations, including lichenoid reactions, psoriasiform eruptions, eczematous dermatitis, immunobullous disorders, granulomatous reactions, pruritus, vitiligo, and severe cutaneous adverse reactions such as Stevens-Johnson syndrome. The conventional approach to treating high-grade or refractory cutaneous immune-related adverse events has involved high-dose systemic corticosteroids. However, their use is limited owing to the potential disruption of antitumor responses and associated complications. To address this, corticosteroid-sparing targeted immunomodulators have been explored as therapeutic alternatives. Biologic agents, commonly employed for non-cutaneous immune-related adverse events such as colitis, are increasingly recognized for their efficacy in treating various patterns of cutaneous immune-related adverse events, including psoriasiform, immunobullous, and Stevens-Johnson syndrome-like reactions. This review consolidates findings from the English-language literature, highlighting the use of biologic agents in managing diverse cutaneous immune-related adverse event patterns, also encompassing maculopapular, eczematous, and lichenoid eruptions, pruritus, and transient acantholytic dermatosis (Grover disease). Despite the established efficacy of these agents, further research is necessary to explore their long-term effects on antitumor responses.

Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized Actionable Pathways.

PURPOSE: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. EXPERIMENTAL DESIGN: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. RESULTS: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. CONCLUSIONS: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.

F127-SE-tLAP thermosensitive hydrogel alleviates bleomycin-induced skin fibrosis via TGF-ß/Smad pathway.

BACKGROUND: Skin fibrosis affects the normal function of the skin. TGF-ß1 is a key cytokine that affects organ fibrosis. The latency-associated peptide (LAP) is essential for TGF-ß1 activation. We previously constructed and prepared truncated LAP (tLAP), and confirmed that tLAP inhibited liver fibrosis by affecting TGF-ß1. SPACE peptide has both transdermal and transmembrane functions. SPACE promotes the delivery of macromolecules through the stratum corneum into the dermis. This study aimed to alleviate skin fibrosis through the delivery of tLAP by SPACE. METHODS: The SPACE-tLAP (SE-tLAP) recombinant plasmid was constructed. SE-tLAP was purified by nickel affinity chromatography. The effects of SE-tLAP on the proliferation, migration, and expression of fibrosis-related and inflammatory factors were evaluated in TGF-ß1-induced NIH-3T3 cells. F127-SE-tLAP hydrogel was constructed by using F127 as a carrier to load SE-tLAP polypeptide. The degradation, drug release, and biocompatibility of F127-SE-tLAP were evaluated. Bleomycin was used to induce skin fibrosis in mice. HE, Masson, and immunohistochemistry were used to observe the skin histological characteristics. RESULTS: SE-tLAP inhibited the proliferation, migration, and expression of fibrosis-related and inflammatory factors in NIH-3T3 cells. F127-SE-tLAP significantly reduced ECM production, collagen deposition, and fibrotic pathological changes, thereby alleviating skin fibrosis. CONCLUSION: F127-SE-tLAP could increase the transdermal delivery of LAP, reduce the production and deposition of ECM, inhibit the formation of dermal collagen fibers, and alleviate the progression of skin fibrosis. It may provide a new idea for the therapy of skin fibrosis.

Outcome Measurement Instruments Used to Evaluate Dermatologic Adverse Events in Cancer Trials: A Systematic Review.

Importance: Assessment of type, severity, and impact of dermatologic adverse events (DAEs) necessitates well-developed and validated clinician-reported outcome measures (ClinROMs) and patient-reported outcome measures (PROMs) that evaluate concepts specific to mucocutaneous toxic effects and that allow appropriate interpretation and comparison of DAEs across trials. Objective: To evaluate heterogeneity and quality of ClinROMs and PROMs used to assess DAEs from systemic cancer therapy. Evidence Review: Two systematic reviews were conducted by searching PubMed and Embase databases from inception through March 7, 2023, and April 12, 2023. The first search included randomized clinical trials and observational studies reporting systemic cancer treatment-induced DAEs assessed by a ClinROM or PROM. The second included studies evaluating measurement properties of frequently used ClinROM and PROM instruments. The Consensus-Based Standards for the Selection of Health Measurement Instruments risk of bias tool was used to evaluate methodologic quality of validation assessments. Findings: A total of 395 studies were included. The Common Terminology Criteria for Adverse Events (CTCAE) was utilized in 331 studies meeting inclusion criteria (83.8%). At least 1 skin-related PROM was infrequently utilized in systemic chemotherapy clinical trials (79 studies [20.0%]). Most frequently utilized PROMs were the Dermatology Life Quality Index (DLQI; 34 studies [8.6%]) and Skindex-16 (20 studies [5.1%]). Among studies capturing DAEs, 115 (29.1%) reported a nondescript term (ie, rash) as the only DAE. Eight studies described 44 property assessments of the CTCAE, DLQI, and Skindex. There were no studies evaluating content validity, intrarater reliability, or measurement error for the CTCAE, DLQI, or Skindex. There were no studies evaluating structural validity, internal consistency, and responsiveness of DLQI or Skindex. Interrater reliability and responsiveness were each assessed for 1 DAE-related component of the CTCAE. Construct validity for CTCAE, DLQI, and Skindex was evaluated in 29 (65.9%), 3 (6.8%), and 9 (20.5%) assessments, respectively. Conclusions and Relevance: In this systematic review, there was a narrow spectrum of ClinROMs and PROMs with limited validity for the measurement of DAEs in the context of systemic chemotherapy interventions in clinical trials. Report of trial DAEs often had low morphologic specificity and meaning. Based on existing gaps in measurement and report of DAEs, a frequent and impactful adverse event to chemotherapy, the framework for evaluating cutaneous toxic effects in oncology trials may need collaborative reevaluation.

Granulysin-mediated reduction of PDZRN3 induces Cx43 gap junctions activity exacerbating skin damage in trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE)-induced hypersensitivity syndrome (THS) has been a concern for many researchers in the field of environmental and occupational health. Currently, there is no specific treatment for THS, leaving patients to contend with severe infections arising from extensive skin lesions, consequently leading to serious adverse effects. However, the pathogenesis of severe skin damage in THS remains unclear. This study aims to investigate the specific danger signals and mechanisms underlying skin damage in THS through in vivo and in vitro experiments. We identified that cell supernatant containing 15 kDa granulysin (GNLY), released from activated CD3-CD56+NK cells or CD3+CD56+NKT cells in PBMC induced by TCE or its metabolite, promoted apoptosis in HaCaT cells. The apoptosis level decreased upon neutralization of GNLY in the supernatant by a GNLY-neutralizing antibody in HaCaT cells. Subcutaneous injection of recombinant 15 kDa GNLY exacerbated skin damage in the THS mouse model and better mimicked patients' disease states. Recombinant 15 kDa GNLY could directly induce cellular communication disorders, inflammation, and apoptosis in HaCaT cells. In addition to its cytotoxic effects, GNLY released from TCE-activated NK cells and NKT cells or synthesized GNLY alone could induce aberrant expression of the E3 ubiquitin ligase PDZRN3, causing dysregulation of the ubiquitination of the cell itself. Consequently, this resulted in the persistent opening of gap junctions composed of connexin43, thereby intensifying cellular inflammation and apoptosis through the "bystander effect". This study provides experimental evidence elucidating the mechanisms of THS skin damage and offers a novel theoretical foundation for the development of effective therapies targeting severe dermatitis induced by chemicals or drugs.