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.

Efficacy and safety of oral minoxidil in female androgenetic alopecia.

Oral minoxidil (OM) has been reported to be effective for androgenetic alopecia (AGA). In this retrospective study, we share our experience of using OM for >24 weeks in 12 patients with female AGA (Ludwig scale I-3-III). Twelve women (aged 18-66 years; mean age 36.66 ± 18.79 years) with AGA (Ludwig scale I-3-III) were recruited. The starting dose of minoxidil was 0.50 mg daily; at 3 months, the dose was increased to 1.50 to 2 mg daily. Efficacy outcome measures were evaluated at baseline and after 24 weeks and included global clinical photography, quantitative digital videotrichoscopic assessment and quality-of-life evaluation. An overall improvement of 38% and 23% in hair density in the frontal and vertex area, respectively, was observed after 24 weeks. The quantitative digital videotrichoscopic evaluation highlighted a statistically significant improvement in the frontal area of the total average hair density and of the total number of hairs per unit area at 24 weeks (131.47 ± 36.11 vs 181.40 ± 57.38; P = .025 and 118.72 ± 32.61 vs 163.81 ± 51.82; P = .025, respectively). In conclusion, OM was effective and had an acceptable safety profile in treating female AGA. The low number of patients and retrospective design of this study are limitations.

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.

Urea-containing topical formulations.

Urea is a well-known moisturiser and keratolytic topical agent. As it is widely used in dermatology, several formulations at different concentrations have been marketed: lotions, creams, foams, ointments, gels and lacquers. Availability of different vehicles and concentration may vary in different countries, but in general products at low, medium and high urea concentration are accessible worldwide. The proper formulation should be chosen according to the disorder to treat, its severity, body areas involved and patients' preference.

Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling.

FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. Herein, we discuss on the selective phosphorylation of Serine/Threonine-protein kinase N2, Serine/Threonine-protein kinase PRP4 homolog, Serine/Threonine-protein kinase MARK2, Serine/Threonine-protein kinase PAK4, Serine/Threonine-protein kinase 10, Dual specificity mitogen-activated protein kinase kinase 2, and Protein phosphatase 1 regulatory subunit 14A, triggered by FPR2 stimulation. We also describe the putative FPR2-dependent signaling cascades upstream to these specific phospho-sites.

Confocal microscopy can assess the efficacy of combined microneedling and skinbooster for striae rubrae.

Striae distensae or stretch marks are dermal scars characterized by flattening and atrophy of the epidermis. They develop particularly during adolescence but they can also appear in other situations such as pregnancy, the use of prolonged therapies with topical or systemic corticosteroids, Cushing's syndrome, Marfan's syndrome, prolonged use of lightening creams, cachexia, rapid weight loss or the use of androgenic and anabolic substances. Treatment options often take a long time, and the results are often disappointing, causing significant psychological distress in patients. We propose a completely innovative approach, combining the skinbooster technique with the microneedling technique. These minivasive methods work by inducing tissue remodeling and stimulating the synthesis of new collagen. Confocal microscopy can show and follow the skin changes made by these therapies, thus becoming an important and valid therapeutic monitoring tool for aesthetic dermatology.

Adalimumab versus Rifampicin Plus Clindamycin for the Treatment of Moderate to Severe Hidradenitis Suppurativa: A Retrospective Study

In the present single-center retrospective study, we investigated our data to evaluate the efficacy of the classic antibiotic combination (rifampicin and clindamycin) compared to adalimumab treatment in patients affected by moderate-to-severe hidradenitis suppurativa. Disease severity and quality of life were registered using the modified Sartorious score and Hidradisk, respectively. Data were collected before starting treatment (T0) and after ten weeks of therapy (T10). The Mann-Whitney test was used to calculate statistical differences between baseline and week 10. P values less than 0.05 were considered to be statistically significant. A spearman test was used to evaluate the correlation among the parameters under study. Thirty patients (20 females, 10 males; mean age, 23.73 ± 4.57) were given the antibiotics: instead of starting the treatment by combining the two antibiotics, we recommend patients to start the therapy taking only rifampicin 300 mg twice a day for 7 days, and after the first week, to add clindamycin at a dose of 300 mg twice a day. The mean modified Sartorius Score before starting treatment was 68.8 while the value at week 10 was 57.8 (P equals 0.0052). The mean Hidradisk value before starting treatment was 74,73 while the value at week 10 was 62 (P equals 0.0095). Ten patients (10/30) achieved the HiSCR. On the other hand, thirty subjects (22 females, 8 males; mean age, 26.2±7.25) were treated with subcutaneous injections of adalimumab (160 mg at baseline, 80 mg at week 2, 40 mg at week 4, and 40 mg weekly thereafter). The mean modified Sartorius Score before starting treatment was 74.93 while the value at week 10 was 39.86 (P less than 0.0001). The mean Hidradisk value before starting treatment was 77.73 while the value at week 10 decreased to 51.86 (P less than 0.0001). Eighteen patients (18/30) achieved the HiSCR. J Drugs Dermatol. 2019;18(5):437-438.

Secukinumab for Severe Hidradenitis Suppurativa in a Patient on Haemodialysis: Efficacy and Safety on 300 mg Every 2 Weeks Administration - A Case Report.

This case study outlines the management of a 24-year-old male with a history of juvenile nephronophthisis who underwent renal transplantation at age 12 and later required dialysis at 18 due to chronic rejection and hypertension. Subsequently, the patient developed severe Hidradenitis Suppurativa (HS) affecting the axillary, groin, and gluteal regions. Despite undergoing various systemic and intravenous antibiotic therapies, as well as Adalimumab treatment, the HS remained refractory. Adalimumab was discontinued due to a detected ejection fraction of 45% during cardiologic follow-up, likely due to COVID-19 related myocarditis. Following this, the patient was initiated on secukinumab therapy, initially undergoing an induction phase followed by maintenance dosing. Significant improvements were observed in quality of life, pain scores, and HS activity after 5 weeks of secukinumab therapy, with sustained benefits at the 6-month follow-up. Secukinumab was well tolerated, with no reported adverse events. This case underscores the effectiveness and safety of secukinumab as a therapeutic option for refractory HS, particularly in patients with comorbidities such as renal transplant recipients.

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.

Adalimumab, Ustekinumab, and Secukinumab in the Management of Hidradenitis Suppurativa: A Review of the Real-Life Experience.

To date, adalimumab (ADA) is the only biotechnology drug approved for the management of hidradenitis suppurativa (HS), an inflammatory skin condition. However, it quickly became apparent that the efficacy of adalimumab in daily practice was highly variable. In our review, we highlighted the current evidence from literature on the use of biologics in HS in a real-life setting, particularly adalimumab, secukinumab and ustekinumab. Data on the effectiveness and safety of biologic drugs in HS management have been analyzed. Even if the results are promising, more studies are needed. In our opinion, the armamentarium of drugs for HS management is increasing, and treatment will be based on a tailored-tail approach, minimizing the risk of adverse events. In this context, we want to point out the reported effectiveness and safety data concerning adalimumab, ustekinumab and secukinumab as well as ixekizumab.

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 isotretinoin for acne: a complete overview.

INTRODUCTION: Acne is one of the most common and widespread skin conditions, affecting the health as much as patients' quality of life. A wide variety of treatments for acne, topical and systemics, could be prescribed, depending on its degree of severity. Isotretinoin, a derivative of retinol, has been widely used for the treatment of severe forms of acne and those forms not responding to conventional treatments. In literature, there are several studies describing its efficacy, also reporting side-effects related to the drug; therefore, this has led the scientific community to request further studies qualifying its characteristics and comparing its efficacy and safety with other classic acne treatments, as well as with different treatment regimes, in order to find the dose with the best efficacy/safety ratio. AREAS COVERED: The aim of this article is to provide a complete overview on the use of oral isotretinoin for the treatment of acne describing the efficacy, safety, and tolerability of the drug. EXPERT OPINION: Oral isotretinoin represents a valid therapeutic alternative in treating severe and mild-to-moderate acne lesions, also reducing scarring damage. There are no standardized protocols regarding the use of oral isotretinoin and its association with other therapies; however, the correct patient selection and a tailored treatment protocol according to acne lesions severity and type should be considered in order to obtain optimal results.