Autoimmune Skin Diseases and Immune Checkpoint Inhibitors.

Immune system escape is one of the major strategies required for cancer growths. In this scenario, the advent of immune checkpoint inhibitors (ICIs) revolutionized the landscape of treatment options for tumors. Despite their wide use, these agents are associated with a unique spectrum of toxicities known as immune-related adverse events (irAEs). IrAEs are cause of treatment suspension (up to 60% of all causes of treatment interruption) and potentially impact on patients' quality of life. These toxicities are the main limitations on the use of these innovative drugs. IrAEs are peculiar, due to the mechanism of actions of ICIs, and any body organs may be involved (skin, thyroid, colon, lungs, in particular). Thus, the management often requires a multidisciplinary approach. The aim of this manuscript is to review current literature on autoimmune skin diseases described in association with ICIs (i.e., vitiligo, lupus erythematosus, vasculitis, morphea/scleroderma, alopecia areata, bullous pemphigoid, dermatomyositis), in order to provide a comprehensive overview for the physician.

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.

Vitiligo-like lesions in patients with advanced breast cancer treated with cycline-dependent kinases 4 and 6 inhibitors.

PURPOSE: Introduction of cyclin-dependent inhibitors was a milestone in therapeutics for patients with estrogen receptor+/HER2- metastatic breast cancer. Despite the wide use of such agents and remarkable improvement of survival rates, drug-related adverse events are not yet fully characterized. We describe vitiligo-like lesions as a new adverse event occurring in patients with advanced breast cancer treated with cyclin-dependent inhibitors. METHODS: We performed an international retrospective study including patients with advanced breast cancer who developed vitiligo-like lesions during treatment with cyclin-dependent kinases 4 and 6 inhibitors, in the period January 2018-December 2019. Patients > 18 years, both males and females, were recruited at six Dermatology Departments located in Italy (3), France (1) and Greece (2). We evaluated epidemiological and clinical characteristics, impact on quality of life and outcome of vitiligo-like lesions in patients treated with cyclin-dependent 4 and 6 inhibitors. The percentage of skin involved by vitiligo-like lesions was assessed using the Body Surface Area (BSA) score. Changes in patients' quality of life were investigated through the evaluation of the Dermatology Life Quality Index (DLQI) questionnaire. RESULTS: Sixteen women (median age: 62.5 years; range 40-79 years) treated with cyclin-dependent kinases 4 and 6 inhibitors for advanced breast cancer presented with vitiligo-like lesions during follow-up visits. Cutaneous lesions consisted of white, irregular macules and patches located mainly on sun-exposed areas in 11/16 patients or diffuse to the entire body surface in 5/16. Cutaneous lesions clearly impaired the quality of life of patients tested (DLQI ≥ 10). CONCLUSIONS: We present for the first time, to our knowledge, a case series of vitiligo-like lesions developing in patients with advanced breast cancer treated with cyclin-dependent kinases 4 and 6 inhibitors. We showed that such lesions further impair the patients' quality of life and their treatment is challenging.

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.

Safe distance, safe patients! Therapeutic management of oncological patients affected by cutaneous and mucosal adverse events during the COVID-19 pandemic: an Italian experience.

Stringent measures have been taken to contain COVID-19 spread, limiting access only for urgent visits, surgery procedures, or hospitalizations and using teledermatology services for non-urgent cases. Management of oncological patients affected by chemo-, immune-, and radiotherapy-related cutaneous and mucosal adverse events is a challenge. Firstly because of the differential diagnosis of cutaneous rash (e.g., drug-related rash or paraviral exanthema). Secondly, oncological patients can suffer from xerosis, pruritus, and mucositis that contribute to cutaneous and mucosal barrier lesions, thus becoming vulnerable site for viral or bacterial colonization. These lesions can also be aggravated by the use of protective mask and gloves. Here, we report also our results of a teledermatological survey on 87 oncological patients, where the health status of oncological patients referred to our dedicated clinic was assessed during the COVID-19 pandemic. Therefore, it is fundamental that oncological patients are followed up by their dermatologists even if the clinics are closed. Teledermatology represents a crucial means of communication. Patients can contact the dermatological staff by emails and telephone, 24 h a day, 7 days a week, for video calls and dermatological consultations.

How to Increase Adherence and Compliance in Acne Treatment? A Combined Strategy of SMS and Visual Instruction Leaflet.

INTRODUCTION: Acne is a common skin disease with important psychosocial impact. Often inadequate compliance affects the efficacy of the therapy. Because of emerging use of mobile and electronic health technology, the recent literature evaluated the helpfulness of the tools in medication adherence. The first goal of our study was to evaluate the adherence to therapy with topical adapalene 0.3%/benzoyl peroxide (A-BPO) 2.5% in different groups of patients who received explicative information supported by different strategies. The second goal was to evaluate the patient's quality of life and skin parameters. MATERIALS AND METHODS: We enrolled 126 subjects with mild to severe acne vulgaris. They were randomized into 3 groups of 42 patients each and applied daily topical A-BPO (0.3%, 2.5%) for 12 weeks. The first group (G1) was trained on the gel application by an explicative leaflet. The second group (G2) received the same instructions as group 1 and a daily SMS to remind them of the application of the product. The third group (G3) only received standard instructions. Evaluations were performed at the beginning of treatment (T0) and after 12 weeks (T1): assessment of acne severity using the Investigator's Global Assessment (IGA) Scale for Acne Severity, quality of life by the Cardiff Acne Disability Index (CADI) and the Patient-Doctor Relationship Depth-of-Relationship Scale (PDRDS), skin pH, grade of hydration and adherence to treatment with a 7-day recall calendar were also measured. RESULTS: After 12 weeks of therapy, we observed a reduction in IGA in all groups confirming the clinical efficacy of the product. In the multiple comparison analysis of IGA score reduction, a significant difference was found in G2 versus G1 and G2 versus G3, while the G1 versus G3 comparison was not statistically significant. However, the leaflet group (G1) showed better results compared to the no-leaflet group (G3). Supporting these data, we observed that adherence days correlated positively with the improvement of the single parameters. Moreover, we observed that SMS and leaflet groups had a greater improvement in quality of life evaluated by CADI and PDRDS scores. CONCLUSIONS: According to our data, this experimental setup based on text message service and leaflet service is inexpensive and easy to use. Physicians could consider using these items in their practice to enhance patient adherence and satisfaction as well as treatment outcome.

Drug-induced photosensitivity associated with anticancer therapies.

INTRODUCTION: Despite the promising results in terms of effectiveness of anticancer treatments, a wide range of dermatologic adverse reactions have been reported. Among them, skin photosensitivity, defined as a range of dermatologic conditions caused or exacerbated by sunlight exposure, is an emerging adverse event. EVIDENCE ACQUISITION: A review of the current literature was performed to report the most characteristic phototoxic and photoallergic reactions associated with anticancer therapies, as well as other characteristic manifestations potentially related to photo-exposure, including UV recall, vitiligo-like reactions, drug-induced cutaneous lupus erythematosus, and UV-induced hyperpigmentation. EVIDENCE SYNTHESIS: A total of 30 manuscripts were collected in the present review, reporting several phototoxic and photoallergic reactions associated with anticancer therapies. CONCLUSIONS: Photosensitivity reactions are an increasing challenge in cancer management. The raising awareness about this adverse event has increased the identification of potential photosensitizing drugs as well as its prevention and the management. However, more studies are required to improve the knowledge of this cutaneous toxicity and to define a personalized treatment strategy.

Atezolizumab-Induced Acrodermatitis and Pustular Psoriasis in a Patient with Non-Small Cell Lung Cancer: A Rare Case Report.

Introduction: Immune checkpoint inhibitors are new drugs approved for the treatment of many types of malignancies. Despite their wide use and unquestionable clinical benefits, these agents have also been associated with a unique spectrum of side effects known as immune-related adverse events. In this study, we report the first case of atezolizumab-induced pustular psoriasis and acrodermatitis. Case Presentation: A 61-year-old woman presented to our department with erythematous-desquamative and pustular lesions involving all hands and feet fingers, inguinal region, and trunk, associated to severe psoriatic onychodystrophy. She was affected by non-small-cell lung carcinoma from 12 years, and 7 months before admission, she started a treatment with atezolizumab. Conclusion: Immune checkpoint inhibitors such as atezolizumab are linked to a plethora of adverse events. Identifying and treating certain adverse skin events, particularly in cancer patients, can be a challenge, leading oncologists to discontinue immunotherapy. Our case shows how it is necessary to have a shared therapeutic algorithm in order to manage serious skin reactions in cancer patients and avoid disruption of the oncotherapy.

Biological Therapy for Psoriasis in Cancer Patients: An 8-Year Retrospective Real-Life Study.

Background: It is now recognized that psoriasis plays a key role in the development of several comorbidities, such as cardiovascular disease, and metabolic syndrome. Some authors have hypothesized that patients with psoriasis may have an increased risk of developing certain types of cancer. The efficacy and safety of biologic drugs are well-documented in clinical trials and in real-life studies. However, there is limited evidence on the safety of the use of biologic treatments in cancer patients with psoriasis, and the use of this therapeutic class in patients with a pre-existing or concomitant malignancy is still debated. Methods: We have conducted a retrospective observational study of a group of oncology patients with moderate-to-severe psoriasis treated with biologic therapy at the Dermatology Clinic of the University of Naples Federico II, during the period from 2016 to 2024. We included 20 adult patients; in 15 of them the diagnosis of neoplasm preceded the start of treatment biologic, while four of these patients had been diagnosed with cancer during the course of therapy biologics. Results: The most represented neoplasms in our population were breast carcinoma, prostate carcinoma, thyroid carcinoma, and chronic lymphatic leukemia. Anti-IL17 drugs were the most frequently prescribed (47.7%), followed by anti-IL23p19 (36.8%), anti-IL-12/23 (10.5%) and anti-TNF alpha (5.26%). All patients showed improvement of psoriasis after starting the therapy. Conclusions: Our experience supports the effectiveness and safety of biological therapy for psoriasis in patients with a history of cancer or recent onset neoplasia.

A Rare Type of Radiation-Induced Alopecia: Proton-Induced Alopecia.

Introduction: Radiation-induced alopecia (RIA) is a side effect resulting from cranial radiation therapy (RT) and it can be temporary or permanent. In cancer patients, RIA is a less frequent event than chemotherapy-induced alopecia, although the former is more likely to cause permanent hair loss. It is characterized initially by intense anagen effluvium caused by acute dose-dependent damage to the matrix cells of anagen follicles. Proton therapy (PT) is a specific type of RT used in the treatment of brain tumors, which sometimes can cause proton-induced alopecia (PIA), a rare subtype of RIA. Below, we report a case of a patient who presented PIA following PT treatment of a meningioma of the frontal region. Case Presentation: A 38-year-old female patient presented to our trichology outpatient clinic for widespread hair loss in the frontal region. Following a diagnosis of meningioma of the frontal region 3 years ago, adjuvant radiotherapy treatment of the frontal region with scanning beam PT (mean dose of 45 Gy) was performed. Two weeks after the end of treatment, the patient came to our attention with diffuse hair loss at the level of the PT-treated area. Trichoscopy showed flame hairs, broken hairs, black dots, and pigtail hairs. A diagnosis of PIA was established, and topical treatment with minoxidil 5% solution twice a day was initiated. At the follow-up visit after 4 months, the patient had total hair regrowth. Conclusion: PIA is a subtype of RIA still poorly studied in the literature. Hair loss is caused by aggression by radiations of the hair follicle in the anagen phase, leading to an interruption of the mitotic activity of the matrix cells. The cells of the follicular bulb are characterized by marked mitotic activity at this stage and are consequently more susceptible to cytotoxic damage. All this causes tightening of the proximal portion of the hair shaft, increasing its fragility and susceptibility to breakage.

Trichoscopic Patterns and Confocal Microscopy Features of Chemotherapy-Induced Alopecia.

Introduction: Chemotherapy-induced alopecia (CIA) can seriously affect the quality of life of cancer patients. Trichoscopic patterns and confocal microscopy (RCM) features of CIA have been scarcely studied. This study aimed to investigate the dermoscopic and RCM features of CIA in 19 females and 5 males, with CIA due to current or recent chemotherapy. Methods: Patients with CIA and current or recent (within 2 months) history of chemotherapy treatment were enrolled. After clinical examination, standard pictures were taken by digital camera (SLR Canon PowerShot G10) and trichoscopic images were captured by the Handyscope device (20x). Images of RCM were acquired by VivaScope 3000 with the VivaStack option. The trichoscopic and confocal images were acquired by three independent observers after central parting on three areas: vertex, middle, and frontal scalp. Results: A total of 24 patients were enrolled. CIA has features of anagen effluvium at trichoscopy but with low frequency of yellow dots and prominence of black dots. The simultaneous presence of pseudo-monilethrix and black dots at trichoscopy confirms the hypothesis that chemotherapy insults the hair follicle intermittently. At RCM, the presence of abnormal hair shaft morphology highlights that the insults affect hair shaft production. Conclusion: These are the first data in this field, so further studies with a higher number of patients analyzed are needed to confirm these findings.

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.

Autoimmune bullous dermatoses in cancer patients treated by immunotherapy: a literature review and Italian multicentric experience.

Cutaneous immune-related adverse events are frequently associated with immune checkpoint inhibitors (ICIs) administration in cancer patients. In fact, these monoclonal antibodies bind the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/ligand 1 leading to a non-specific activation of the immune system against both tumoral cells and self-antigens. The skin is the most frequently affected organ system appearing involved especially by inflammatory manifestations such as maculopapular, lichenoid, psoriatic, and eczematous eruptions. Although less common, ICI-induced autoimmune blistering diseases have also been reported, with an estimated overall incidence of less than 5%. Bullous pemphigoid-like eruption is the predominant phenotype, while lichen planus pemphigoides, pemphigus vulgaris, and mucous membrane pemphigoid have been described anecdotally. Overall, they have a wide range of clinical presentations and often overlap with each other leading to a delayed diagnosis. Achieving adequate control of skin toxicity in these cases often requires immunosuppressive systemic therapies and/or interruption of ICI treatment, presenting a therapeutic challenge in the context of cancer management. In this study, we present a case series from Italy based on a multicenter, retrospective, observational study, which included 45 patients treated with ICIs who developed ICI-induced bullous pemphigoid. In addition, we performed a comprehensive review to identify the cases reported in the literature on ICI-induced autoimmune bullous diseases. Several theories seeking their underlying pathogenesis have been reported and this work aims to better understand what is known so far on this issue.

Scleroderma-like Syndrome in the Setting of Pembrolizumab Therapy for Non-Small Cell Lung Cancer: Diagnosis and Dermatologic Management.

Immune checkpoint inhibitors play an important role in the treatment of malignancies. ICIs consist of monoclonal antibodies directed against inhibitory immune receptors cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), or programmed cell death-ligand 1 (PD-L1). PD-1 is a receptor expressed by T lymphocytes and has the role of inhibiting their activation. Pembrolizumab is a humanized anti-PD-1 monoclonal antibody. It can improve the immune function of T-cells, which results in significant clinical benefit in the treatment of cancer. Despite its wide use, immunotherapy is associated with a spectrum of side effects known as immune-related adverse events. We present a case of an 82-year-old patient with widespread fibroatrophic skin areas that occurred during a treatment with pembrolizumab for non-small cell lung cancer. Clinical, serological, and histopathological examinations led to the diagnosis of generalized morphea. The patient discontinued pembrolizumab and switched to chemotherapy with pemetrexed and carboplatin. A good therapeutic response was obtained with phototherapy, corticosteroids, and topical calcineurin inhibitors. A focus on the therapeutic management of this skin toxicity in oncological patients is provided.

Oral Minoxidil for Chemotherapy-Induced Alopecia.

Introduction: Chemotherapy-induced alopecia (CIA), one of the most dramatic side effects of chemotherapy, occurs in approximately 65% of patients receiving cytotoxic drugs. Case Presentation: We report the case of a patient, 64 years old, affected by chemotherapy-induced alopecia treated with oral minoxidil with good results. Discussion/Conclusion: Our case may be useful in the literature to propose a new therapy for this pathology that is fundamentally very difficult to treat.