Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients" International Study.

BACKGROUND: The introduction of cyclin-dependent kinase inhibitors (CDK4/6i) was a great advance in therapeutics for patients with estrogen receptor+/human epidermal growth factor receptor (HER2) locally advanced and metastatic breast cancer. Despite the increasing use of these agents, their adverse drug-related events have not yet been fully characterized. We describe the spectrum of cutaneous adverse reactions occurring in advanced breast cancer patients treated with cyclin-dependent kinase inhibitors, analyzing types, severity, time to onset, and possible treatment outcomes. METHODS: We performed a multicentric retrospective study including patients with advanced breast cancer who developed cutaneous lesions during treatment with CDK4/6i in the period from June 2020 to June 2021. Patients > 18 years were recruited at eleven onco-dermatology units located in Albania (1), Argentina (1), France (1), Greece (3), Italy (3), and Spain (2). We evaluated patients' epidemiological and clinical characteristics, types of cutaneous adverse events, their time to onset, and treatment outcomes. The severity of the skin reactions was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 score. RESULTS: Seventy-nine patients (median age: 62.3 years; range 39-83 years) were included in the study, and, collectively, we recorded a total of 165 cutaneous adverse events during follow-up visits. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and eczematous lesions (24/79). Cutaneous toxicities were usually mild in severity (>65%) and occurred after a median of 6.5 months. Only four patients (5%) required treatment discontinuation due to the severity of the skin lesions. The majority of the skin reactions were managed with topical treatments. CONCLUSIONS: To the best of our knowledge, we present the largest case series of cutaneous adverse events developing in advanced breast cancer patients treated with CDK4/6i. We showed that cutaneous toxicities are usually mild in severity, and manageable with standard supportive care; however, in selected cases, they can lead to treatment discontinuation with possible implications for patients' clinical outcomes.

Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.

BACKGROUND: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). OBJECTIVES: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. METHODS: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. RESULTS: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01-0·76] and vitiligo (OR 0·07, 95% CI 0·006-0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02-0·31), lichenoid reactions (OR 0·15, 95% CI 0·03-0·77) and eczematous reactions (OR 0·24, 95% CI 0·07-0·78), all compared with pruritic rash. CONCLUSIONS: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy. Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer. The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus. Clinical awareness and specialized dermatological consultation should be advocated.

Severe blistering eruptions induced by immune checkpoint inhibitors: a multicentre international study of 32 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), bullous life-threatening reactions are rare. To better define the clinical and histological features, treatment, and prognosis of ICI-related severe blistering cutaneous eruptions. This retrospective case series was conducted between 2014/05/15 and 2021/04/15 by the dermatology departments of four international registries involved in drug reactions. Inclusion criteria were age ≥18 years old, skin eruption with blisters with detachment covering ≥1% body surface area and at least one mucous membrane involved, available pictures, and ICI as suspect drug. Autoimmune bullous disorders were excluded. Each participant medical team gave his own diagnosis conclusion: epidermal necrolysis (EN), severe lichenoid dermatosis (LD), or unclassified dermatosis (UD). After a standardized review of pictures, cases were reclassified by four experts in EN or LD/UD. Skin biopsies were blindly reviewed. Thirty-two patients were included. Median time to onset was 52 days (3-420 days). Cases were originally diagnosed as EN in 21 cases and LD/UD in 11 cases. After review by experts, 10/21 EN were reclassified as LD/UD. The following manifestations were more frequent or severe in EN: fever, purpuric macules, blisters, ocular involvement, and maximal detachment. Most patients were treated with topical with or without systemic corticosteroids. Eight patients (25%) died in the acute phase. The culprit ICI was not resumed in 92% of cases. In three patients, another ICI was given with a good tolerance. Histology did not reveal significant differences between groups. Severe blistering cutaneous drug reactions induced by ICI are often overdiagnosed as EN. Consensus for management is pending.

Reacción a fármacos con eosinofilia y síntomas sistémicos (DRESS) / Drug reaction with eosinophilia and systemic symptoms (DRESS)

La reacción a fármacos con eosinofilia y síntomas sistémicos (del acrónimo en inglés DRESS: drug reaction with eosinophilia and systemic symptoms) o síndrome de hipersensibilidad inducida por fármacos (del acrónimo en inglés DIHS: drug induced hypersensitivity syndrome), es una reacción adversa a fármacos (RAF) grave e infrecuente. Los mecanismos involucrados en su fisiopatogenia incluyen diversas alteraciones de las enzimas metabolizadoras de fármacos, con la consecuente acumulación de metabolitos reactivos, la reactivación secuencial de virus de la familia del herpes, la predisposición genética asociada a ciertos alelos de antígenos leucocitarios humanos (HLA) y una respuesta de hipersensibilidad retardada de tipo IV. En la actualidad, se han ido incorporando nuevos fármacos responsables de este cuadro como medicamentos biológicos, inmunosupresores y quimioterápicos. La presentación clínica del DRESS es variable. Tiene una morbimortalidad alta y supone costos elevados en la atención médica. Su tratamiento consiste, en primer lugar, en la suspensión de los fármacos causales o sospechosos de desencadenar el síndrome. Luego, según la gravedad del cuadro, se pueden indicar corticosteroides sistémicos o inmunoglobulina (IGIV) combinada con corticosteroides, plasmaféresis, ciclosporina, micofenolato de mofetilo y rituximab. El objetivo de este trabajo fue realizar una revisión sobre el DRESS y destacar los aspectos nuevos y relevantes de los últimos 5 años.

Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), is a serious and rare adverse drug reaction. Among the mechanisms involved in its pathophysiology, there are various alterations in drugmetabolizing enzymes with the consequent accumulation of reactive metabolites, sequential reactivation of viruses of the herpes family, genetic predis-position associated with certain HLA, and a type IV hypersensitivity response. Currently, new drugs responsible for this pathology have been incorporated, such as biologicals, immunosuppressants and chemotherapy. The clinical presentation of DRESS is variable. It has a high morbidity and mortality and involves high costs in medical care. Its treatment consists, in the first place, in the suspension of the causal or suspected drugs. Then, depending on severity, systemic corticosteroids or IVIG combined with corticosteroids, plasmapheresis, cyclosporine, mycophenolate mofetil, and rituximab may be indicated.The objective of this work was review DRESS and highlight the new and relevant aspects of the last 5 years.

Immune checkpoint-mediated psoriasis: A multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group.

BACKGROUND: Immune checkpoint inhibitor (ICI)-mediated psoriasis poses significant diagnostic and therapeutic challenges. OBJECTIVE: To report data on ICI-mediated psoriasis, emerging from the largest cohort to date, to our knowledge, and to propose a step-by-step management algorithm. METHODS: The medical records of all patients with ICI-mediated psoriasis were retrospectively reviewed across 9 institutions. RESULTS: We included a cohort of 115 individuals. Grade 1, 2, and 3 disease severity was reported in 60 of 105 (57.1%, 10 missing data), 34 of 105 (32.4%), and 11 of 105 (10.5%), respectively. The ratio between exacerbation and de novo cases was 1:4.3. The most common systemic therapy was acitretin (23 patients, 20.1%), followed by systemic steroids (8 patients, 7%), apremilast (7 patients, 6.1%), methotrexate (5 patients, 4.3%) and biologics (4 patients, 3.6%). Overall, 29 of 112 patients (25.9%) interrupted and 20 of 111 (18%) permanently discontinued ICIs because of psoriasis. Body surface area of greater than 10% at baseline had a 3.6 increased risk for ICI treatment modification (odds ratio, 3.64; 95% confidence interval, 1.27-10.45; P = .03) and a 6.4 increased risk for permanent discontinuation (odds ratio, 6.41; 95% confidence interval, 2.40-17.11; P < .001). Guttate psoriasis and grade 2 or 3 disease were significant positive predictors for antitumor response of ICI, whereas pruritus was a negative predictor. LIMITATIONS: Retrospective design. CONCLUSION: Acitretin, apremilast, and methotrexate are safe and effective modalities for ICI-mediated psoriasis. In most cases, ICI can be completed unhindered. A therapeutic algorithm is proposed.

Erupción variceliforme de Kaposi y enfermedad de Darier / Kaposi's varicelliform rash and Darier's disease

La erupción variceliforme de Kaposi es una infección cutánea diseminada, causada en la mayor parte de los casos por el virus Herpes simple tipo 1. Se suele presentar en pacientes con alteraciones preexistentes de la barrera cutánea, especialmente en niños con dermatitis atópica. Se comunica el caso de un paciente de 84 años, quien negaba enfermedades cutáneas previas, que consultó por lesiones dolorosas y pruriginosas, en la piel del tórax y el abdomen, de 3 semanas de evolución. Con sospecha de una enfermedad infecciosa viral, bacteriana, ampollar o neutrofílica, se realizó inmunofluorescencia directa para herpes, cultivo y biopsia de piel para estudio histológico. La inmunofluorescencia fue positiva para Herpes simple tipo 1 y el estudio histopatológico mostró cambios compatibles con infección herpética y enfermedad de Darier. La enfermedad de Darier es una genodermatosis infrecuente que se suele manifestar en la adolescencia. Si bien su diagnóstico en la ancianidad es excepcional, este caso ilustra que se debe considerar en todos los pacientes que presenten erupción variceliforme. (AU)

Kaposi's varicelliform rash is a disseminated cutaneous infection, caused by Herpes virus 1. It usually presents in patients with pre-existing skin barrier disorders, especially in children with atopic dermatitis. We report the case of an 84-year-old patient, who reported having no previous skin diseases, who consulted for painful, itchy, 3-week-old skin lesions. As we suspected viral, bacterial, bullous or neutrophilic disease, direct immunofluorescence, culture, and skin biopsy for histological study were performed. Immunofluorescence was positive for Herpes simplex type 1 and the histopathological study showed changes compatible with herpetic infection and Darier's disease. Darier's disease is a rare genodermatosis that usually manifests in adolescence. Although its diagnosis in old age is anecdotal, it should be considered in patients with a varicelliform rash. (AU)

Efectos adversos inmunomediados por inhibidores de PD-1 / PD-1 inhibitors immune-mediated side effects

Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)

Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)

Lingual ulceration associated with retinoic acid syndrome during treatment of acute promyelocytic leukemia.

BACKGROUND: All-trans retinoic acid (ATRA) is routinely associated with chemotherapy for the treatment of acute promyelocytic leukemia (APL). Several reports of scrotal ulceration induced by this agent have been made in the recent years. AIMS: The aim of this article was to report the first case of a lingual ulceration associated with retinoic acid syndrome (RAS). MATHERIALS AND METHODS: We presented a 32-year-old man with a diagnosis of acute promyelocytic leukemia who received treatment with ATRA. He presented with febrile neutropenia and a lingual ulcer that did not respond to antibiotic and antifungal regimens. He developed weight gain, lower limb edema, polyserositis, and acute renal failure. Retinoic acid syndrome syndrome was diagnosed. RESULTS: An exhaustive attempt to exclude infectious causes was made performing repeated cultures, histologic examinations, and direct immunofluorescence for HSV. No causative agent was identified. Re-epithelialization of the ulcer was achieved with ATRA cessation and treatment with systemic steroids. DISCUSSION: As far as we are concerned, we report the first case of a lingual ulceration associated with RAS. CONCLUSION: It is important for dermatologists to recognize this cutaneous complication of ATRA as it poses many differential diagnoses in neutropenic patients.

El Rol de las infecciones por herpesvirus- 6, herpesvirus- 7, virus Epstein-Barr y citomegalovirus en las farmacodermias / Role of human herpesvirus 6 and 7, Epstein-Barr virus and cytomegalovirus in cutaneous drug reactions

Los herpesvirus son capaces de permanecer en el organismo de los seres humanos como infecciones crónicas latentes y evadir al sistema inmune dando lugar a reactivaciones. Existen asociaciones conocidas entre el desarrollo de cuadros de farmacodemias y la presencia previa, simultánea o subsecuente de infecciones por herpesvirus. La fisiopatogenia de estos cuadros es compleja y se encuentra en revisión permanente. El exantema inducido por ampicilina en pacientes con mononucleosis infecciosa ejemplifica cómo una infección viral puede facilitar la aparición de hipersensibilidad a un fármaco. Los herpesvirus-6 y 7, elcitomegalovirus y el virus Epstein-Barr se encuentran implicados en la etiopatogeniadel síndrome de hipersensibilidad inducido por drogas y su reactivación predice unriesgo mayor de compromiso sistémico. Se cree que en este caso es la alergia medicamentosa quién generaría un terreno propicio para su reactivación...

Reactivation of Chagas' disease: cutaneous manifestations in two immunosuppressed patients.

BACKGROUND: Chagas' disease is a zoonosis caused by a protozoan agent, Trypanosoma cruzi. Patients undergoing immunosuppressive treatment due to organ transplant, malignancies, infections, or chemotherapy may reactivate a preexisting chronic or indeterminate Trypanosoma cruzi infection. METHODS: We present two transplant patients who underwent reactivation of Chagas' disease with cutaneous manifestations after an augmentation in their immunosuppressive therapy. A 38-year-old man was hospitalized on day 69 after receiving an allogeneic bone marrow transplant; he developed multiple painful erythematous plaques with diffuse borders, confined to the right cheek, trunk, thigh, elbows, and feet. A 59-year-old woman with a 14-year history of Chagasic cardiomyopathy presented one month after heart transplantation with a painful infiltrated purpuric plaque on the back of her right leg. RESULTS: In both cases, histologic examination of skin biopsies showed dermal infiltration with intrahistiocytic amastigotes. In one of the reported cases, the Strout method detected parasitemia. Treatments with nifurtimox (600 mg/d) in case 1 and benznidazole (400 mg/d) in case 2 were started. Fever and cutaneous lesions resolved immediately after seven days of treatment. CONCLUSIONS: Reactivation of Chagas' disease is a serious complication that usually occurs in immunocompromised patients. Clinical manifestations include febrile illness occasionally associated with painful skin lesions. Early diagnosis and proper treatment can significantly improve these patients' outcome.