A retrospective multicentric cohort study of checkpoint inhibitors-induced pruritus with focus on management.

BACKGROUND: Limited data on immune checkpoint inhibitor (ICI)-induced pruritus per se and efficacy of different therapeutic modalities in its management exist. OBJECTIVE: To study the quantitative and qualitative characteristics of ICI-induced pruritus per se and to assess the efficacy of the therapeutic modalities usually applied. METHODS: We retrospectively reviewed the records of 91 patients who were under treatment with ICIs for any kind of neoplasia and developed pruritus during treatment. RESULTS: Twenty out of 91 individuals (22.0%) with ICI-induced pruritus had pruritus as the only symptom, while 71/91 (78.0%) presented with pruritus coexisting with an additional cutaneous toxicity. Pruritus was treated with antihistamines (18/20, 90.0%) and/or topical regimens, as first-line choice. In resistant cases, as a second therapeutic intervention, narrow-band UVB (NBUVB), oral steroids and GABA analogs were added (70.0%). Statistical analysis revealed a significant difference in mean pruritus Numerical Rating Scale (NRS) scores between baseline and sequential visits. Moreover, subgroup analysis revealed a significant reduction in mean NRS scores in those treated with phototherapy. LIMITATIONS: Retrospective design, low number of patients and survivorship bias. CONCLUSION: Pruritus per se was present in a substantial portion of our cohort (22.0%). Our study confirms the efficacy of current treatment strategies and suggests NBUVB as a potential steroid-sparing therapeutic alternative.

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.

Topical immunotherapy treatment of alopecia areata with diphenylcyclopropenone: Regulatory T cells as biomarkers for treatment response.

Treatment of alopecia areata is often challenging, especially for patients with extended disease. Contact immunotherapy with diphenylcyclopropenone (DPCP) has been reported as an effective topical treatment but the exact immunologic mechanism of diverting the immune response is still unknown. We investigated the efficacy of topical immunotherapy with DPCD in acute, intermediate, and chronic lesions of AA and the response rate was associated with perifollicular infiltrate of T regulatory cells. Approximately two-thirds of our patients (67.5%) had a response rate > 50% after 6 months of DPCP therapy. Patients with acute and intermediate onset of the disease were more likely to respond to the therapy. Although responders demonstrated FOXP3+ positive lymphocytes in immunohistochemistry, this association could not be confirmed by statistical significance (p = 0.052). In patients with multiple lesions, that had different chronological onset, the lesions with more recent onset responded faster than lesions of longer duration.

Challenges in sarcoidosis and sarcoid-like reactions associated to immune checkpoint inhibitors: A narrative review apropos of a case.

Sarcoidosis and sarcoid-like reactions (SLRs) may develop in association with various malignancies, as well as in association to certain oncologic drugs, including immune checkpoint inhibitors (ICIs). We aimed to perform a narrative review with regard to the development of ICIs-associated sarcoidosis or SLRs, and to discuss the corresponding diagnostic and therapeutic challenges raised in this scenario. Apropos of a melanoma patient developing SLRs while treated with ipilimumab and nivolumab, we searched for clinically evident, ICIs-associated sarcoidosis or SLRs in the English literature. We recorded the oncologic characteristics, including type of malignancy and type of ICI, the phenotypic characteristics of sarcoidosis/SLRs, as well as the impact on immunotherapy. Including our patient, we identified 80 ICIs-associated sarcoidosis or SLRs cases. Both sexes were equally affected (40 F/40 M) and the most common malignancy was melanoma (65/80, 81.3%). Concerning the oncologic treatment, there was a predilection for pembrolizumab (23/80, 28.7%), followed by the ipilimumab/nivolumab combination (21/80, 26.3%), ipilimumab (18/80, 22.5%), nivolumab (16/80, 20.0%). Although in the majority of the cases (52/80, 65.0%) there was no need for systemic prednisolone for the management of sarcoidosis, a significant proportion of patients finally discontinued ICIs treatment (44/80, 55.0%). Phenotypically, sarcoidosis and SLRs highly imitate oncologic progression posing diagnostic difficulties. A therapeutic dilemma is also raised when there is a need for systemic prednisolone, since the latter may jeopardize the therapeutic efficacy of immunotherapy. Sarcoidosis and SLRs, though rare, can present in oncologic patients treated with ICIs. Clinicians should be aware of this possibility and the related diagnostic and therapeutic challenges they have to face in this scenario.

A Real-Life 208 Week Single-Centred, Register-Based Retrospective Study Assessing Secukinumab Survival and Long-Term Efficacy and Safety Among Greek Patients with Moderate to Severe Plaque Psoriasis, Including Difficult-to-Treat Manifestations Such as Genitals and Scalp.

INTRODUCTION: Psoriasis is a chronic inflammatory disease with multiple skin manifestations, and in case of lesions affecting the genital area, sexual health impairment and psychological distress can furthermore impair the patients quality of life. Secukinumab is a fully humanized immunoglobulin G1 kappa antagonist of IL-17A and is indicated for the treatment of moderate-to-severe psoriasis, since it shows a significant efficacy in clinical outcomes, with rapid onset of remission, prolonged treatment response rate, advantageous safety profile and a valuable improvement of the patients quality of life. OBJECTIVES: This study was conducted in order to gather retrospective real-world data regarding the efficacy of secukinumab in treating patients with moderate-to-severe plaque psoriasis in Greece. To fill the relevant literature gap, we included difficult-to-treat manifestations in our analysis, specifically regarding the efficacy in the genital area and on the skin folds where relevant data are missing both from the drug clinical program as well as from the real-world setting. METHODS: All adult patients receiving 300 mg secukinumab and attending follow-up visits on a regular basis, according to routine medical practice were included. The timeline of the study was from 2015 to 2020. Primary endpoint of the study was the percentage of patients who achieved a psoriasis area and severity index (PASI) 75 response rate at week 16 and week 52 post baseline. Secondary endpoints were the evaluation at baseline (week 0), week 4 (±1), week 16 (±1), week52 (±1), and week 104 (±1), week 156 (±1), week 208 (±1) of clinical outcomes, incidence of adverse events and potential predictive variables influencing response rate. RESULTS: Ninety-nine patients were included in the study population, from whom sixty six patients (66.67%) were bio-naive, whereas 33 patients had never received systemic treatment. Regarding difficult-to-treat manifestations, we recorded scalp involvement in 74.74% (74/99) of our patients, genital psoriasis in 27.27% (27/99) and skin folds involvement (psoriasis inversa) in 17% (17/99). At week 16, PASI75/PASI90/PASI100 were observed in 87.5%/69.8%/49%, respectively. At week 4 lesions affecting the genital area and patients with skin fold involvement experienced a rapid regression and 84.1% of patients achieved sPGA 0/1 (Physician Global Assessment). Treatment with secukinumab during the 208 weeks of observation did not reveal any major adverse event or systemic infection and generally it was well tolerated. CONCLUSIONS: According to our outcomes secukinumab is an effective treatment choice for treating chronic plaque psoriasis, but, additionally, it can be efficacious in the subgroups of patients with difficult-to-treat manifestations, as our patients experienced great improvement starting even 5 weeks after treatment initiation. This real-life study offers information about clinical efficacy, retention and safety profile of secukinumab in patients from everyday clinical practice over a long-term, 4-year, follow-up period in Greece.

The Impact of Immune Checkpoint Inhibitors-Induced Skin Toxicity on Patients Quality of Life and the Role of Dermatologic Intervention.

INTRODUCTION: Data regarding quality of life (QoL) of oncologic patients experiencing dermatologic immune-related adverse events (dirAEs) and their course after dermatologic intervention are scarce. OBJECTIVES: To assess the impact of dirAEs on patients QoL and to investigate the correlation between dermatologic and oncologic indexes used for estimating QoL. METHODS: We enrolled oncologic patients with dirAEs managed in two supportive onco-dermatology outpatient clinics in Greece. Patient-reported outcomes included DLQI, EORTC-QLQ-C30 and Numerical Rating Scale for pruritus (pNRS). RESULTS: Overall, 110 patients were enrolled in the study. Mean (standard deviation) DLQI and pNRS scores were 15.54 (5.44) and 7.25 (2.95), correspondingly, while functional, symptom and summary scores of EORTC-C30 were 79.17 (2.11), 17.66 (3.60) and 80.67 (3.08), respectively. After therapeutic interventions, there was a statistically significant decrease in DLQI scores after first intervention compared to baseline, and second intervention compared to first (mean decrease 4.38 (2.91), P < 0.001 and 5.16 (3.99), P < 0.001, respectively). DLQI showed no correlation with global health status/QoLs (rho 0.01, P = 0.90) of EORTC-C30. CONCLUSIONS: DirAEs negatively affect QoL. Dermatologic intervention improves patients QoL, facilitating an unimpaired oncologic treatment. Poor correlation between DLQI and EORTC-QLQ-30 highlights the need for adapted QoL measurement tools in the context of immune checkpoint inhibitors treatment.

Effect of a novel "emollient plus" formulation on mild-to-severe atopic dermatitis and other dry skin-related diseases as monotherapy or adjunctive therapy: an observational study on efficacy, tolerance and quality of life in adult patients.

BACKGROUND: Atopic dermatitis (AD), psoriasis and senile xerosis comprise common chronic and relapsing inflammatory skin disorders with clinical symptoms such as lichenification, pruritus and inflammatory lesions that affect the quality of life of patients. OBJECTIVES: In this study, we aimed to evaluate the efficacy of a novel "emollient plus" formulation (Lipikar baume AP+M), containing non-living lysates of non-pathogenic Vitreoscilla Filiformis bacteria from LaRoche-Posay Thermal Spring water, in improving quality of life, alleviating skin pain, and managing symptoms of mild-to-severe AD or skin disorders associated with dryness or severe xerosis in adults. MATERIALS & METHODS: The study included 1,399 adult patients, who participated in a two-month observational study over two visits, conducted at dermatologists' practices. Visits included clinical assessment of skin disease before and after administration of the product as well as completion of the 10-question Dermatology Life Quality Index. Questionnaires were used to evaluate efficacy, safety, satisfaction and tolerance of the product both by the dermatologists and patients, as well as assess quality of life of patients. RESULTS: Statistically significant improvement (p<0.001) by at least one grade was observed by more than 90% based on patients' evaluation of efficacy regarding intensity of the skin disease, skin dryness, surface affected by inflammatory lesions, pruritus, quality of sleep, daily discomfort, dryness and desquamation. Quality of life after two months improved by 82.6%. CONCLUSION: This study demonstrated significant reduction in symptoms of mild-to-severe skin dryness after application of the "emollient plus" formulation over two months, either alone or as adjunctive therapy.

Eccrine Poroma: Pathogenesis, New Diagnostic Tools and Association with Porocarcinoma-A Review.

Eccrine poroma (EP) is a relatively rare benign adnexal neoplasm that usually affects elderly patients. Its pathogenesis is still under investigation, but recent gene studies have revealed gene fusions as key incidences resulting in oncogenetic pathways. It often presents as a solitary, firm papule, mostly asymptomatic, located on the soles or palms. Due to its clinical and dermoscopic variability, it is characterized as the great imitator. We performed a literature review, aiming to summarize current data on the pathogenetic mechanisms, new dermoscopic features, and novel diagnostic tools that may aid in early diagnosis and proper management of this rare adnexal tumor. Furthermore, we reviewed the possible pathogenetic associations between EP and its malignant counterpart, namely eccrine porocarcinoma. This systematic approach may aid in understanding the pathogenetic mechanisms and how to use novel histopathologic markers and imaging methods to overcome the diagnostic dilemma of this rare tumor.

Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients.

INTRODUCTION: Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy. OBJECTIVES: We aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management. METHODS: Retrieved literature from PubMed registry database was reviewed to include all articles published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The internet was searched for relevant studies. RESULTS: A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents remains unknown and patients with different cancer types receiving different regimens may develop the same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treatment may develop different types of nail alterations. The underlying mechanisms of the varying individual susceptibility and the diverse nail responses to various anticancer treatments need further investigation. CONCLUSION: Early recognition and treatment of nail toxicities can minimize their impact, allowing better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and other implicated physicians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients' quality of life.

Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Literature Review.

Immune checkpoints assist with self-tolerance and minimize collateral tissue damage when immune responses are activated. Although immune checkpoint inhibitors (CPIs) are characterized by a favorable risk/benefit ratio, immune checkpoint blockade has been associated with a new subset of autoimmune-like toxicities, named immune-related adverse events (irAEs). Dermatologic reactions are among the most prevalent irAEs triggered by CPIs. In a majority of cases they are self-limiting and readily manageable. However, it is not uncommon that they result in severe skin involvement and impairment of patients' quality of life. Awareness of the spectrum of cutaneous irAEs is mandatory for every clinician involved in the management of oncologic patients. The role of the dermatologists is essential because early recognition and appropriate management of skin toxicity may prevent dose modifications and discontinuation of CPIs. The latter is particularly relevant, considering that recent data suggest favorable oncologic response in patients developing irAEs.

Rosacea and Helicobacter pylori: links and risks.

Rosacea is a chronic skin disease characterized by facial erythema and telangiectasia. Despite the fact that many hypotheses have been proposed, its etiology remains unknown. In the present review, the possible link and clinical significance of Helicobacter pylori in the pathogenesis of rosacea are being sought. A PubMed and Google Scholar search was performed using the terms "rosacea", "H.pylori", "gastrointestinal disorders and H.pylori", "microorganisms and rosacea", "pathogenesis and treatment of rosacea", and "risk factors of rosacea", and selected publications were studied and referenced in text. Although a possible pathogenetic link between H. pylori and rosacea is advocated by many authors, evidence is still interpreted differently by others. We conclude that further studies are needed in order to fully elucidate the pathogenesis of rosacea.

Recalcitrant psoriatic uveitis and anti-tumor necrosis factor-α monoclonal antibodies: experience from a psoriasis referral center.

BACKGROUND: The incidence of non-infectious uveitis on a background of psoriasis is estimated to be 7-20%. The use of tumor necrosis factor-α (TNF-α) inhibitors as a treatment for refractory uveitis is emerging. METHODS: The psoriasis outpatient database at our referral center was searched for patients with concurrent diagnoses of psoriasis and uveitis. The medical records of the patients identified were reviewed for the use of TNF-α inhibitors. RESULTS: Five patients (three women and two men) were identified. All of them suffered moderate to severe psoriasis and chronic, bilateral uveitis. The patient with the most severe ocular inflammation was the only patient positive for human leukocyte antigen B27 (HLA-B27) and the only one to suffer from psoriatic arthritis. All patients had received treatment with adalimumab and had been evaluated at three and six months. Their psoriasis had responded excellently, and in four patients, uveitis had shown the complete remission of inflammation at six months. The fifth patient (HLA-B27+) exhibited improved uveitis activity but not complete remission at six months. CONCLUSIONS: Uveitis is an entity that should be considered when evaluating psoriasis patients with ocular complaints, even in the absence of arthritis. Anti-TNF-α monoclonal antibodies and adalimumab in particular seem to represent a promising therapeutic avenue for the treatment of refractory psoriatic uveitis. Larger randomized clinical trials are needed to confirm our conclusions.

Solitary trichoepithelioma in an 8-year-old child: clinical, dermoscopic and histopathologic findings.

Solitary trichoepithelioma (TE) is a rare, benign tumor of follicular origin that in certain cases is difficult to differentiate from basal cell carcinoma (BCC). We report the case of an 8-year-old girl with a pale pink, soft lesion on the neck. The clinical image of the lesion was equivocal, while some dermoscopic findings-blue-gray globules and arborizing vessels-could not exclude the presence of BCC from the differential diagnosis, although that would have been a very unlikely case considering the age of the patient. The histopathologic examination established the diagnosis of TE. Given the occasion of this challenging case we try to list the key clinical, dermoscopic and histopathological characteristics of TE and BCC in order to elucidate the differential diagnosis of these two entities.