Cutaneous Adverse Events Research Articles

Cutaneous Adverse Events of Osimertinib in Diverse Patient Populations with EGFR-mutated Non-Small Cell Lung Cancer: A Retrospective Cohort Analysis.

Cutaneous Adverse Events of Osimertinib in Diverse Patient Populations with EGFR-mutated Non-Small Cell Lung Cancer: A Retrospective Cohort Analysis.

Cardiodermatology: the heart of the connection between the skin and cardiovascular disease.

The skin and cardiovascular systems are connected in unique and meaningful ways, and many diseases conventionally considered as being limited to one organ system are more closely related than previously believed. Major cardiovascular diseases and phenomena such as infective endocarditis, congestive heart failure, Kawasaki disease and thromboembolism are associated with specific skin findings, and advances in genetics, immunology and clinical epidemiology show that inflammatory dermatological diseases, such as psoriasis, have serious cardiovascular and cardiometabolic consequences. Additionally, commonly used cardiovascular therapies, such as antihypertensive medications, are associated with important cutaneous adverse effects, including photosensitivity, photocarcinogenesis and eczematous skin reactions. Moreover, systemic dermatological therapies, including retinoids, Janus kinase inhibitors and biologics, can alter the risk of cardiovascular and cardiometabolic diseases. In this Review on cardiodermatology, we provide interdisciplinary insights from dermatology and cardiology that will be of practical use to both cardiologists and generalists who manage cardiovascular and cardiometabolic diseases in patients with dermatological findings or histories. We discuss specific skin findings associated with cardiovascular diseases to aid in diagnosis; important cutaneous adverse effects of common cardiovascular therapies, for the purpose of treatment monitoring; and the effect of dermatological diseases and dermatological treatment on cardiovascular risk.

INNV-12. CUTANEOUS TOXICITIES OF MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS IN CHILDREN AND YOUNG ADULTS WITH NEUROFIBROMATOSIS-1

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. Cutaneous adverse events (CAEs) are common and may hinder patients’ abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS We reviewed institutional medical records of patients under 30 years with a diagnosis of “NF1,” “NF2,” or “other neurofibromatoses” on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS The median age of 40 patients with NF1 was 14 years old. Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%) (Table 1). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%) (Figure 1). Twenty-three out of the 28 cases of acneiform eruption were in post-pubertal patients (82.1%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi (Table 2). There was no significant association between CAE presence and tumor response (p=0.39). CONCLUSIONS MEK inhibitors have been demonstrated as a valuable treatment, but CAEs complicate the ability to stay on the treatment. Most patients in our cohort developed a CAE, demonstrating its prevalence in this population. Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Delayed and immediate cutaneous adverse events during pembrolizumab combination chemotherapy against cervical cancer: Case series.

Immune checkpoint inhibitors (ICIs), such as pembrolizumab (PEM), are widely recognized for their antitumor efficacy, but they can also lead to various cutaneous adverse events (CAEs). While most CAEs can be managed with topical corticosteroids, severe cases may necessitate halting immunotherapy. The incidence of severe CAEs is notably higher in combination therapies involving ICIs than in monotherapies, emphasizing the need for stringent, long-term management strategies. This includes potential modifications or discontinuations of the combination therapy. PEM, when added to the conventional paclitaxel + cisplatin (or carboplatin) ± bevacizumab regimen, has shown significant improvements in overall and progression-free survival for patients with Stage IVB metastatic or locally uncontrolled recurrent cervical cancer. This case series retrospectively examined the incidence and management of CAEs in 19 female patients treated with this combination therapy between October 2022 and May 2023. Four patients exhibiting CTCAE grade 3 were identified. The four cases of severe CAEs involved erythema multiforme after the initial course of PEM combination chemotherapy. Notably, three patients experienced immediate hypersensitivity reactions, including anaphylaxis, during subsequent treatments. This observation underscores the necessity for rigorous dermatological monitoring of patients undergoing PEM combination chemotherapy. Such vigilance is crucial for early detection of adverse reactions and timely adjustment of treatment regimens, thereby enhancing patient safety.

Cutaneous Toxicities of MEK Inhibitor Use in Children: AComparison of Binimetinib and Selumetinib.

Binimetinib and selumetinib are two mitogen-activated protein kinase kinase (MEK) inhibitors used to treat low-grade gliomas and plexiform neurofibromas. Cutaneous toxicities are commonly associated with MEK inhibitors; however, limited studies have examined cutaneous effects in a pediatric population or whether toxicities vary between MEK inhibitors. We conducted an IRB-approved, single-center, retrospective review of pediatric neuro-oncology patients on binimetinib or selumetinib who presented to NYU from April 2016 through July 2022. Forty-six children met inclusion criteria (23 females, 23 males) with a mean age of 11.7 years. Thirty-three were treated with binimetinib and 13 with selumetinib. Dermatologic adverse events were encountered in 97.8% of the cohort, and the most common were acneiform eruption (63.0%), paronychia (58.7%), and xerosis (54.3%). Children 12 years and older were more likely to have acneiform eruption (p < 0.001) and seborrheic dermatitis (p < 0.001), while children under 12 were more likely to have xerosis (p = 0.037). The incidence of cutaneous adverse events was significantly different between MEK inhibitors for folliculitis and hair pigment dilution (39.4% binimetinib, 0% selumetinib, p = 0.009). Significantly, more patients required MEK inhibitor dose reduction/hold on binimetinib (87.9%) than selumetinib (46.2%) (p = 0.006). Severity of cutaneous disease was not associated with tumor response. Our study confirms dermatologic adverse events are common in children on MEK inhibitors. Age appears to be associated with increased likelihood of certain cutaneous reactions. Overall, the selumetinib patients in our cohort presented with less severe adverse events and decreased risk of MEK inhibitor dose reduction/hold. Our results will aid clinicians in providing appropriate counseling, treatments, and improved preventive care.

Successful use of dupilumab to manage a grade 3 cutaneous adverse effect from enfortumab vedotin/pembrolizumab treatment in a patient with metastatic urothelial carcinoma

Successful use of dupilumab to manage a grade 3 cutaneous adverse effect from enfortumab vedotin/pembrolizumab treatment in a patient with metastatic urothelial carcinoma

Langerhans cells directly interact with resident T cells in the human epidermis

Adult human skin contains nearly twice as many T cells as the peripheral blood, which include tissue-resident memory T (TRM) cells. However, the precise mechanisms maintaining TRM cells in the healthy skin remain unclear. Using normal human skin samples, we find that Langerhans cells (LCs) contact T cells in the epidermis of the elderly. LCs with high human leukocyte antigen (HLA)-II, CD86, and PD-L2 expression directly contacted PD-1+ TRM cells and CTLA-4+ regulatory T cells in the epidermis, indicating an axis of peripheral tolerance in a steady state. Environmental insults, ultraviolet B radiation and hapten, downregulated HLA-II and CD86 on LCs in the epidermis, suggesting that disruption of LC-T cell tolerogenic axis contributes to skin inflammation. Interestingly, immune checkpoint blockade therapy was associated with decreased epidermal LC-T cell contact in the normal skin of cancer patients affected by cutaneous immune-related adverse events. Collectively, our findings indicate that LCs may contribute to T cell tolerance in the epidermis.

Frequency of androgenic cutaneous adverse events associated with levonorgestrel intrauterine devices: an analysis of the Food and Drug Administration Adverse Events Reporting System database

Frequency of androgenic cutaneous adverse events associated with levonorgestrel intrauterine devices: an analysis of the Food and Drug Administration Adverse Events Reporting System database

Cutaneous Toxicities of Advanced Treatment for Cutaneous Melanoma: A Prospective Study from a Single-Center Institution.

The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient's quality of life is of paramount importance. We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024. In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1-2] (97%) and typically occurred after 10 weeks of treatment. This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center.

Pyoderma Gangrenosum Associated With Iatrogenic Interleukin 17A Blockade: A Report of Two Cases andaReview of the Literature.

Pyoderma gangrenosum (PG) is a rare necrotizing neutrophilic dermatosis driven by monokines and cytokines elaborated by monocytes and autoreactive T cells, respectively. Th1-mediated autoimmune disorders and myeloproliferative disease are among the potential disease associations. More recently, certain medications were implicated, including TNF-alpha inhibitors, rituximab, and IL-17A inhibitors, such as secukinumab, where the development of PG is held to represent a cutaneous immune adverse effect. We present two patients who developed an autoinflammatory syndrome resembling PG in the setting of drug therapy with agents exhibiting an IL-17A inhibitory effect. The drugs were erunumab in one and secukinumab in the other. One patient received the anti-calcitonin gene-related peptide targeted therapy, erenumab, for migraine prophylaxis. While this drug has not been previously implicated in the development of PG, it can cause IL-17A blockade. The other patient was on secukinumab, a monoclonal antibody that selectively targets IL-17A. We documented a microenvironment enriched in IL-17A, emphasizing that the blockade impacts the functionality of the receptor as opposed to a quantitative reduction in IL-17A production by T cells. Qualitative functional IL-17A blockade could result in a paradoxical increase in IL-23, a pro-inflammatory cytokine that may contribute to the influx of neutrophils pathogenetically implicated in PG.

Clinical characteristics, treatment and outcome of subacute cutaneous lupus erythematosus induced by PD-1/PD-L1 inhibitors.

PD-1/PD-L1 inhibitors have increasingly been associated with the occurrence of subacute cutaneous lupus erythematosus (SCLE), but the clinical characteristics and outcomes remain under-explored. Literature on PD-1/PD-L1 inhibitors induced SCLE was retrieved from Chinese and English databases until June 31, 2024, and clinical data of patients were extracted for retrospective analysis. Twenty-nine patients participated, with a median age of 63 years (range 43, 80). The most frequently reported drugs were Nivolumab (51.7%) and pembrolizumab (31.0%). The median time from treatment initiation to SCLE onset was 3 months (range 0.5, 47). Cutaneous manifestations presented primarily as papulosquamous lesions (65.5%) and erythema annulare (31.0%), predominantly occurring on the trunk (51.7%) and arms (51.7%). Serological analysis revealed positive anti-Ro antibodies in 91.7% of patients, positive antinuclear antibodies in 75.0%, and positive anti-La antibodies in 50.0%. Skin biopsies showed interface dermatitis in 65.5% of cases and lymphocyte infiltration in 82.8%. Treatment with topical corticosteroids, systemic corticosteroids, and hydroxychloroquine led to gradual improvement or resolution of the rash, with a median recovery time of 1 month (range 0.5, 11). As the use of PD-1/PD-L1 inhibitors in oncology increases, SCLE should be recognized as a rare cutaneous adverse effect. Histological and serological evaluations play a critical role in diagnosing SCLE. Typically, SCLE resolves on its own with appropriate local and systemic treatment.

Immunohistochemical Expression of Immune Regulatory Proteins in Interface Dermatoses.

Cutaneous immune-related adverse events (irAEs) of immunotherapies, such as anti-programmed cell death protein-1 (PD-1), suggest that immune checkpoint factors may contribute to the pathobiology of lichenoid interface dermatitis in immunotherapy-naïve patients. Our study aimed to describe innate and adaptive immune markers via immunohistochemical (IHC) staining of lichenoid interface dermatoses. We studied the staining patterns of PD-L1, STING, IL-36 gamma, CD8, PD-1, and LAG-3 in five interface dermatoses: oral lichen planus (LP) (n = 10), cutaneous LP (n = 10), chronic cutaneous lupus erythematosus (CLE) (n = 11), erythema multiforme (EM) (n = 11), and toxic epidermal necrolysis (TEN) (n = 13), by immunohistochemistry (IHC) analysis. Expression was evaluated semi-quantitively according to the percentage of keratinocytes and dermal lymphocytes stained compared to keratinocytes and resident pericapillary lymphocytes in normal human skin. All interface dermatoses evaluated showed increased expression of PD-L1 on keratinocytes and LAG-3 in lymphocytes. STING was increased on the keratinocytes of most specimens. Expression of IL-36 gamma, in basal layer keratinocytes was more extensive in oral LP and cutaneous LP and varied in CLE, EM, and TEN. Lymphocytic infiltration expressing PD-1 was elevated in oral LP, cutaneous LP, and CLE. Current thinking is that interface dermatitis is the result of a cell-mediated immune reaction involving cytotoxic CD8+ T-cell-mediated apoptosis of keratinocytes. The findings of this study suggest that in addition to cell-mediated immunity, innate immune factors may contribute to pathobiology.

Facial edema and necrotic ulcers: a cutaneous reaction to liraglutide.

Due to rising obesity rates, new drugs like liraglutide, a GLP-1 receptor agonist, are increasingly used for weight loss. While liraglutide-related skin reactions are rare, this case report describes a 44-year-old male with severe facial edema and necrotic ulcers following liraglutide administration. Despite having taken the drug five years earlier without issue, the patient developed symptoms after receiving two doses. A skin biopsy revealed necrosis and inflammation, and the condition was successfully treated with steroids. The report underscores the need to consider cutaneous adverse effects in patients using liraglutide.

Kaposi Sarcoma as a Possible Cutaneous Adverse Effect of ChAdOx1 nCov-19 Vaccine: A Case Report

The COVID-19 pandemic prompted the rapid development of vaccines, including the ChAdOx1 nCov-19 (AstraZeneca) vaccine. While effective, adverse effects have been reported, including cutaneous manifestations. Kaposi sarcoma (KS), a vascular tumor linked to Kaposi sarcoma herpesvirus/human herpesvirus 8 (HHV-8), has seen increased detection during the pandemic. This study reports a case of classic cutaneous KS in a 79-year-old male following the first dose of the ChAdOx1 nCov-19 vaccine, without prior SARS-CoV-2 infection. The patient developed multiple reddish-blue papules on his legs and feet, confirmed as KS through histopathology. Treatment included radiotherapy and sequential chemotherapy with Doxorubicin. The potential reactivation of latent HHV-8 by the vaccine is explored through mechanisms involving the SARS-CoV-2 spike protein and adenovirus vector, which may induce immune responses and inflammatory pathways. Although establishing a direct causal link remains challenging, the case highlights the need for vigilance regarding KS reactivation post-vaccination. Further large-scale studies are warranted to elucidate the relationship between COVID-19 vaccines and latent virus reactivation, ensuring comprehensive safety assessments and informed public health decisions.

Dermatologist's role in managing cutaneous adverse events of anticancer drugs: A retrospective analysis of 538 hospital dermatology consultations in Japan.

Dermatologist's role in managing cutaneous adverse events of anticancer drugs: A retrospective analysis of 538 hospital dermatology consultations in Japan.

Pre-procedural Topical Antisepsis in the Neonate: A Systematic Review Evaluating Risk Factors for Skin Injury.

Pre-procedural antisepsis is a critical component of hospital-acquired infection prevention in the neonatal intensive care unit (NICU). However, broadly utilized topical antiseptic agents pose an elevated risk of disruption to neonatal skin integrity, and evidence-based guidelines are lacking. This systematic review of the literature sought to assess and characterize the predisposing risk factors for and types of neonatal skin injury from topical antiseptic agents. A systematic search of Medline Ovid, Embase, Web of Science, CINAHL, and Cochrane Library was conducted, including academic literature providing data on neonatal skin injuries related to topical antisepsis in the NICU. A total of 19 articles (99 patients) met the inclusion criteria. Of the available data, most reported skin injuries were described in extremely preterm (98.1%) and very low birth weight (98.4%) infants. The majority of reported adverse cutaneous events were attributed to chlorhexidine preparations (74.8%), followed by octenidine (18.2%), povidone-iodine (6.1%), and isopropyl alcohol (2.0%). Erythema (40.1%), skin breakdown (23.4%), and chemical burns (17.5%) were the skin reactions reported most frequently, followed by skin irritation (8.3%), and skin necrosis (2.8%). Our findings indicate that both extremely preterm and very low birth weight infants are particularly susceptible to skin toxicities from pre-procedural antiseptic preparations. These data underscore the need for future research to support the development of guidelines which minimize iatrogenic cutaneous injuries in the neonatal population, specifically for the care of infants under 2 months of age, for whom current recommendations are lacking due to a paucity of data.

Clinical Features of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Induced by Immune Checkpoint Inhibitor versus Non-Immune Checkpoint Inhibitor Drugs in China: A Cross-Sectional Study and Literature Review.

Immune checkpoint inhibitors (ICIs) can cause life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Large-scale original research on ICI-induced SJS/TEN is limited. This study aimed to explore the unique clinical characteristics and potential pathophysiological mechanisms of SJS/TEN induced by ICIs. This cross-sectional study compared the clinical features of SJS/TEN induced by ICIs and non-ICIs, and reviewed the case characteristics of ICI-induced SJS/TEN. Clinical features were analyzed using independent t-tests, Mann-Whitney U-tests, and multivariable regression models. This study enrolled 41 cases of ICI-induced SJS/TEN and 107 non-ICI-induced cases from January 22, 2015, to May 28, 2024. ICI-induced SJS/TEN patients exhibited a trend towards a longer latency period (β: 17, 95% CI: -1.49 to 35.48), a smaller affected body surface area (BSA) (β: -40.68, 95% CI: -71.59 to -9.77), and milder oral and ocular mucositis than non-ICI-induced cases. A literature review identified PD-1 inhibitors as the primary ICIs involved and systemic corticosteroids as the most frequent intervention. No statistically significant difference in mortality rate was observed between patients treated with systemic corticosteroids alone and those receiving combination therapies (P= 0.85). The mortality rate for ICI-induced SJS/TEN was 24.5%. This study offered the largest comparative analysis to date, highlighting the unique clinical features of ICI-induced SJS/TEN, including a smaller affected BSA, a prolonged latency period trend, and milder oral and ocular mucositis. We described the epidemiology, clinical presentation, and therapeutic strategies for ICI-induced SJS/TEN. These findings not only contribute to a deeper understanding of the complex immune-inflammatory pathways in severe immune-related cutaneous adverse events (ircAEs) but also may inform the development of more targeted and effective treatments.

Three Cases of Cutaneous Adverse Events Caused by Enfortumab Vedotin

Three Cases of Cutaneous Adverse Events Caused by Enfortumab Vedotin

Cutaneous and Systemic Adverse Effect of Topical Corticosteroid Misuse on Iraqi Women

Topical corticosteroids (TCS) are the most widely prescribed and abused topical medications worldwide. TCs have melanogenic, anti-pruritic, atrophogenic, immunosuppressive effects on the epidermis and sex-hormone-like, in addition to anti-inflammatory activity. Several of these, if used without judgment, may have serious local and systemic negative repercussions. The current study was designed to evaluate the possible local and systemic effects of topical corticosteroid misuse among women in Basrah City and Amara city, Iraq. Totally 125 participants were categorized into three major groups: control individuals, patients who utilize TCs for 1–3 months, and patients with long-term TC use for more than 3 months. A questionnaire was filled out, and a full skin examination was performed by a special dermatologist. Blood was drawn for hematological, hormonal, and biochemical analysis. TCS abuse was linked to the development of skin conditions with various percentages and frequencies, such as erythema, photosensitivity, dryness, acne, atrophy, infections, pigmentation, hirsutism, and rosacea. TCs also have systemic adverse effects in addition to their cutaneous ones, especially with prolonged use. TCS prolongs bleeding time compared to control group. Long-term TCS suppresses ACTH and decreases cortisol concentrations significantly while having no effect on insulin or testosterone levels. Interestingly, TCS significantly reduced serum vitamin D and serum interleukin 6 compared to the normal control group. TCS misuse is a big disaster in Iraq, associated with huge skin impacts and systemic deterioration, including hormonal and hematological consequences that require medical intervention and educational and legal approaches for successful treatment.

Benefits of High-Dose Vitamin D in Managing Cutaneous Adverse Events Induced by Chemotherapy and Radiation Therapy.

The use of chemotherapy and radiation for cancer treatment can result in cutaneous adverse events (AEs) such as toxic erythema of chemotherapy (TEC) and radiation-induced dermatitis. High-dose vitamin D supplementation has been suggested to potentially improve and shorten recovery for these AEs, primarily based on data from case reports and case series. In this article, we discuss the role of vitamin D in the most prevalent cancers (breast and colorectal cancer) and changes in vitamin D levels after chemotherapy or radiation treatments. We also summarize reports on high-dose vitamin D supplementation for treating chemotherapy-induced and radiation-induced skin toxicity. Larger studies and randomized controlled trials are essential to clarify the roles of vitamin D in malignancy and in cutaneous AEs associated with cancer treatment. The existing studies we reviewed lack standardized dosing regimens and exhibited heterogeneity across study populations, making it challenging to draw generalizable conclusions.