RESUMEN
The peripheral T cell repertoire of healthy individuals contains self-reactive T cells1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells3-10. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors11. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-specific effector CD8 T cells from (1) acquiring a fully functional, pathogenic differentiation state, (2) secreting significant amounts of effector molecules, and (3) gaining access to epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.
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Antígenos , Linfocitos T CD8-positivos , Tolerancia Inmunológica , Receptor de Muerte Celular Programada 1 , Piel , Animales , Humanos , Ratones , Antígenos/inmunología , Biopsia , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Epidermis/inmunología , Epidermis/metabolismo , Perfilación de la Expresión Génica , Liquen Plano/inmunología , Liquen Plano/patología , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Piel/citología , Piel/inmunología , Piel/metabolismo , Piel/patologíaRESUMEN
PURPOSE: Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. METHODS: Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. RESULTS: Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. CONCLUSION: Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.
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Neoplasias de la Mama , Nitrilos , Pirazoles , Pirimidinas , Vitíligo , Humanos , Femenino , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Aminopiridinas , Piridinas/efectos adversos , Vitíligo/tratamiento farmacológico , Vitíligo/inducido químicamente , Estudios Retrospectivos , Quinasa 4 Dependiente de la Ciclina , Calidad de Vida , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: In 2023, nearly 2 million patients will be diagnosed with cancer in the United States and at least 40% will be eligible for treatment with an immune checkpoint inhibitor (ICI). Cutaneous immune related adverse events (cirAEs) from ICIs are common and include pruritus as well as maculopapular, eczematous, bullous, lichenoid, and psoriasiform reactions. All clinicians interfacing with cancer patients must expedite proper evaluation and diagnosis, treatment, and/or consultation that supports the need for evidence-directed guidelines. MATERIALS AND METHODS: A panel of advisors was selected, and a systematic literature review generated foundational evidence to develop a treatment algorithm for cirAEs via a modified Delphi process. Iterations of the algorithm were performed until the group met consensus. RESULTS: An algorithm that tailors the management of cirAEs was developed based on the CTCAE v.5 grading of skin disorders. Representative clinical images and suggested diagnostic measures, supplement the algorithm. CONCLUSION: Recognition and treatment of cirAEs guided through a multidisciplinary, physician-developed algorithm will limit disruption of immunotherapy, optimize quality of life, and enhance overall outcomes in patients treated with ICIs. J Drugs Dermatol. 2023;22:11(Suppl 1):s3-10.
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Neoplasias , Calidad de Vida , Humanos , Algoritmos , Inmunoterapia/efectos adversos , Prurito , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Among the 1,918,030 patients in the United States estimated to be diagnosed with cancer in 2022, approximately 50% will require radiation therapy (RT) as part of their treatment plan. Radiation dermatitis (RD) is the most common side effect of RT, particularly in patients with breast, head, neck, and anal cancers, with a wide spectrum in the severity and degree of RD that develops in an individual and considerable heterogeneity in the management of RD. In addition, few contemporaneous treatment algorithms exist for the prevention and treatment of RD, underscoring the need to develop uniform, evidence-directed guidelines. MATERIALS AND METHODS: A modified Delphi process was used to develop a treatment algorithm (USCOM II) that expanded upon a previous algorithm (USCOM I) for the management of RD. A panel of multidisciplinary advisors was selected, and a systematic literature search with key terms was conducted to identify publications on RD. Subsequently, the literature was graded according to the strength of evidence for the recommendation. The advisors convened to review the results and assemble the algorithm. Further iterations on the algorithm were obtained until 100% group consensus was achieved. RESULTS: An algorithm that tailors the management of RD, based on the CTCAE v.5 grading of RD and the presence of moist desquamation, was developed. Unique features include photographs illustrating the clinical spectrum of RD to supplement the algorithm and the integration of medically based recommendations with over-the-counter (OTC) skincare regimens that include cleansing, moisturizing, and photoprotection. CONCLUSION: Acute RD, when suboptimally managed, can lead to symptoms of pruritus and pain, decreased quality of life and morbidity, and treatment interruptions. When RD is severe or prolonged, it can delay the receipt of a full therapeutic course of RT. Enhanced patient education on the prevention of RD and clarity of treatment recommendations through a multidisciplinary, physician-developed algorithm may help prevent and manage the various adverse effects and improve the overall care of patients receiving RT. J Drugs Dermatol. 2022;21:11(Suppl 1):s3-14.
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Dermatitis , Neoplasias , Humanos , Estados Unidos/epidemiología , Calidad de Vida , Administración Cutánea , AlgoritmosRESUMEN
Fibroblast growth factor receptor (FGFR) tyrosine kinases, which are expressed on the cell membrane, are involved in a wide range of biological functions such as cell proliferation, survival, migration, and differentiation. The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. In addition to the typical adverse events associated with tyrosine kinases, the FGFR inhibitors appear to give rise to a number of adverse events affecting the skin. Here we describe these skin events, which include the more common nail adverse events (e.g., onycholysis), palmar-plantar erythrodysesthesia syndrome, and stomatitis, as well as less common reactions such as calciphylaxis. This review aims to provide oncologists with an understanding of these dermatologic events and proposes guidelines for the management of treatment-emergent dermatologic adverse events. Awareness of possible adverse events associated with specific drugs should allow physicians to educate patients as to what to expect and implement effective management plans at the earliest possible opportunity, thereby preventing premature discontinuation while maintaining patient quality of life. IMPLICATIONS FOR PRACTICE: Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles. The most frequent adverse events (AEs) include those affecting skin, hair, and nails, a unique class effect of these agents. These are usually mild to moderate in severity. This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies. Early intervention and effective management may improve treatment adherence, optimize outcomes, and improve quality of life.
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Antineoplásicos , Neoplasias de los Conductos Biliares , Antineoplásicos/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Humanos , Morfolinas , Pirimidinas , Pirroles , Calidad de Vida , Receptores de Factores de Crecimiento de Fibroblastos/uso terapéuticoRESUMEN
BACKGROUND: An increasing number of patients survive or are living with cancer. Anticancer treatments frequently have cutaneous adverse events (cAEs) that may severely impact patients' quality of life and interrupt anticancer treatment. The US Cutaneous Oncodermatology Management (USCOM) project aims to improve cancer patients' and survivors' quality of life by offering tools for preventing and managing cAEs. METHODS: An algorithm was designed to reduce the incidence of cAEs, treat cAEs, and maintain healthy skin using general measures and over-the-counter agents to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and advanced providers. The panel used a modified Delphi approach, developed, discussed, and reached a consensus on statements and an evidence-based algorithm. RESULTS: The USCOM algorithm includes education on cAEs for patients and clinicians supporting prevention, treatment, and maintenance using skincare measures before, during, and after cancer treatment. A skincare regimen including hygiene, moisturization, and sun protection products should be safe and effective in helping to minimize cAEs and improving skin conditions such as erythema, xerosis, pruritus, and photosensitivity. The number and quality of studies evaluating skincare formulations and regimens for cAEs are increasing, but the evidence on the benefits of specific formulations is still scarce. CONCLUSIONS: The algorithm focuses on general measures and skincare to prevent or reduce the severity of cAEs. Increased awareness of cAEs by the multidisciplinary team treating and guiding the cancer patient throughout their care may improve patient outcomes. J Drugs Dermatol. 2021;20:9(Suppl):s3-19.
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Calidad de Vida , Cuidados de la Piel , Administración Cutánea , Algoritmos , Humanos , PielRESUMEN
BACKGROUND: Sarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective. OBJECTIVE: To evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA. METHODS: A prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation. RESULTS: Tofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein α may explain the differences in JAK-STAT signaling between sarcoidosis and GA. LIMITATIONS: The study is limited by the small number of participants. CONCLUSIONS: Tofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.
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Granuloma Anular/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Inducción de Remisión/métodos , Sarcoidosis/tratamiento farmacológico , Adulto , Anciano , Biopsia , Femenino , Granuloma Anular/diagnóstico , Granuloma Anular/patología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sarcoidosis/diagnóstico , Sarcoidosis/patología , Índice de Severidad de la Enfermedad , Piel/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy. We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis. OBJECTIVE: To study the efficacy of topical cholesterol/lovastatin in different variants of porokeratosis. METHODS: We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis. Patients were genotyped before initiation of therapy. Patients then applied topical cholesterol/lovastatin twice daily to a unilaterally defined treatment area for up to 3 months. The response was evaluated and patients photographed at every visit. RESULTS: Three patients had MVD mutations, and 2 patients had PMVK mutations. Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear porokeratosis lesions. There were no adverse events. LIMITATIONS: Case series design with a small number of patients. CONCLUSION: Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors.
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Anticolesterolemiantes/administración & dosificación , Carboxiliasas/genética , Colesterol/administración & dosificación , Lovastatina/administración & dosificación , Poroqueratosis/tratamiento farmacológico , Poroqueratosis/genética , Administración Cutánea , Adulto , Preescolar , Combinación de Medicamentos , Genotipo , Humanos , Persona de Mediana Edad , Mutación , Pomadas , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Adulto JovenRESUMEN
The advent of immune checkpoint inhibition represents a paradigm shift in the treatment of an increasing number of cancers. However, the incredible therapeutic promise of immunotherapy brings with it the need to understand and manage its diverse array of potential adverse events. The skin is the most common site of immune-related adverse vents (irAEs), which can present with a wide variety of disparate morphologies and severities. These toxicities can endanger patient health and the ability to continue on therapy. This review summarizes our current understanding of the presentation and management of the most common and clinically significant cutaneous irAEs associated with immune checkpoint inhibitor (ICI) therapy. Effective management of these cutaneous irAEs requires an understanding of their morphology, their appropriate clinical characterization, and their potential prognostic significance. Their treatment is additionally complicated by the desire to minimize compromise of the patient's anti-neoplastic regimen and emphasizes the use of non-immunosuppressive interventions whenever possible. However, though cutaneous irAEs represent a challenge to both oncologist and dermatologist alike, they offer a unique glimpse into the mechanisms that underlie not only carcinogenesis, but many primary dermatoses, and may provide clues to the treatment of disease even beyond cancer.
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Erupciones por Medicamentos , Inhibidores de Puntos de Control Inmunológico , Terapia Molecular Dirigida/métodos , Neoplasias Cutáneas , Dermatología/métodos , Dermatología/tendencias , Erupciones por Medicamentos/inmunología , Erupciones por Medicamentos/terapia , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/terapiaRESUMEN
BACKGROUND: There is increasing recognition of distinct inflammatory eruptions associated with checkpoint inhibitors. A better understanding of their severity, therapeutic response, and impact on cancer treatment is needed. OBJECTIVE: To analyze the different rashes associated with immunotherapy referred to our institution's oncodermatology clinic and inpatient consultative service and to evaluate their therapeutic response and impact on immunotherapy. METHODS: We retrospectively reviewed the medical records of patients referred to the oncodermatology clinic or inpatient dermatology service during 2016-2018 at Yale-New Haven Hospital for eruptions that developed during immunotherapy. RESULTS: In total, 98 patients (51 men, 47 women) treated with checkpoint inhibitors developed 103 inflammatory eruptions, with a range of mean latency of 0.2-17.7 months. A minority of patients (25/103; 24.3%) required immunotherapy interruption; most of these cases involved immunobullous (7/8; 87.5%), lichenoid (8/26; 30.8%), maculopapular (6/18; 33.3%), and Stevens-Johnson syndrome-like (2/2, 100%) reactions. Only 3 of 16 (18.8%) patients who had their immunotherapy interrupted had a grade 2 or 3 flare on rechallenge. Most reactions (93/103; 90.3%) responded to dermatologic therapy or immunotherapy interruption. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSION: A variety of inflammatory reactions might occur from immunotherapy with differing degrees of severity. While most rashes responded to topical treatment, immunobullous and exfoliative presentations frequently interrupted immunotherapy. Increased awareness and early recognition could reduce the need for unnecessary immunotherapy interruption.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Erupciones por Medicamentos/etiología , Exantema/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/terapia , Exantema/patología , Exantema/terapia , Femenino , Humanos , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Erupciones Liquenoides/inducido químicamente , Erupciones Liquenoides/patología , Erupciones Liquenoides/terapia , Masculino , Persona de Mediana Edad , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Estudios Retrospectivos , Síndrome de Stevens-Johnson/etiología , Síndrome de Stevens-Johnson/patología , Síndrome de Stevens-Johnson/terapia , Privación de TratamientoRESUMEN
Cutaneous toxicities to DNA methyltransferase inhibitors are variable and include localized injection site reactions, ecchymoses, maculopapular eruptions, and neutrophilic dermatoses including pyoderma gangrenosum, Sweet syndrome, and neutrophilic eccrine hidradenitis. This series describes two patients diagnosed with lobular neutrophilic panniculitis arising during treatment of acute myelogenous leukemia with "hypomethylating drugs," including the first report of its occurrence with a next-generation agent. Differential diagnoses, histopathologic characteristics, treatment considerations, and proposed pathogenesis will be discussed.
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Antineoplásicos/toxicidad , Azacitidina/análogos & derivados , Azacitidina/toxicidad , Inhibidores Enzimáticos/toxicidad , Paniculitis/inducido químicamente , Enfermedades de la Piel/inducido químicamente , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Azacitidina/administración & dosificación , Azacitidina/uso terapéutico , ADN , Diagnóstico Diferencial , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Metiltransferasas/antagonistas & inhibidores , Persona de Mediana Edad , Neutrófilos/patología , Paniculitis/patología , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Enfermedades de la Piel/patología , Resultado del TratamientoAsunto(s)
Melanoma , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/inducido químicamente , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/inmunología , Melanoma/tratamiento farmacológico , Interleucina-13 , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Interleucinas , Inmunoterapia/efectos adversosAsunto(s)
Neoplasias , Pigmentación de la Piel , Humanos , Piel , Administración Cutánea , PacientesRESUMEN
BACKGROUND: Bullous disorders associated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established. OBJECTIVE: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy. METHODS: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018. RESULTS: We identified 9 of 853 patients who developed bullous eruptions (â¼1%) that were treated with an-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSIONS: Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents.