Atopic Dermatitis and Ulcerative Colitis Successfully Treated with Upadacitinib.

Background and Objectives: JAK inhibitors entered current clinical practice as treatment for several immune-related diseases and, recently, for atopic dermatitis. These drugs target the Janus Kinase intracellular cascade, rendering them suitable for treating both Th1 and Th2 immune-mediated responses. Materials and Methods: We report the case of a 36-year-old male patient presenting an overlap of ulcerative colitis, a Th1-related disease, and atopic dermatitis, a Th2-mediated condition. Treatment with upadacitinib was initiated, and laboratory and instrumental follow-ups were carried out for 8 months. Results: The complete and persistent clinical remission of both conditions was observed at a low dose of 15 mg of upadacitinib, even though ulcerative colitis guidelines usually recommend a dosage of 45 mg. No serious adverse responses to therapy were reported. Conclusions: Upadacitinib may be the most suitable management strategy in subjects with coexisting severe conditions mediated by Th1 inflammation, such as ulcerative colitis, and by Th2 cytokines, such as atopic dermatitis.

Management of patients with atopic dermatitis undergoing systemic therapy during COVID-19 pandemic in Italy: Data from the DA-COVID-19 registry.

BACKGROUND: Few and small studies have described the management of immunomodulant/immunosuppressive therapies or phototherapy in atopic dermatitis (AD) patients during coronavirus disease 2019 (COVID-19) pandemic. METHODS: A national registry, named DA-COVID-19 and involving 35 Italian dermatology units, was established in order to evaluate the impact of COVID-19 pandemic on the management of adult AD patients treated with systemic immunomodulant/immunosuppressive medications or phototherapy. Demographic and clinical data were obtained at different timepoints by teledermatology during COVID-19 pandemic, when regular visits were not allowed due to sanitary restrictions. Disease severity was assessed by both physician- and patient-reported assessment scores evaluating itch intensity, sleep disturbances, and AD severity. RESULTS: A total of 1831 patients were included, with 1580/1831 (86.3%) continuing therapy during pandemic. Most patients were treated with dupilumab (86.1%, 1576/1831) that was interrupted in only 9.9% (156/1576) of cases, while systemic immunosuppressive compounds were more frequently withdrawn. Treatment interruption was due to decision of the patient, general practitioner, or dermatologist in 39.9% (114/286), 5.6% (16/286), and 30.1% (86/286) of cases, respectively. Fear of increased susceptibility to SARS-CoV-2 infection (24.8%, 71/286) was one of the main causes of interruption. Sixteen patients (0.9%) resulted positive to SARS-CoV-2 infection; 3 of them (0.2%) were hospitalized but no cases of COVID-related death occurred. CONCLUSIONS: Most AD patients continued systemic treatments during COVID pandemic and lockdown period, without high impact on disease control, particularly dupilumab-treated patients.

It is never too late to treat chronic spontaneous urticaria with omalizumab: Real-life data from a multicenter observational study focusing on elderly patients.

Chronic spontaneous urticaria might affect elderly patients, causing a serious impairment of their quality of life. The therapeutic management of the elderly patient is challenging; in fact, the first-line recommended therapy for symptom control are antihistamines, that may have interactions or increased risk of side effects in patients with comorbidities and poly-pharmacological regimen. Omalizumab is the first biological drug approved for chronic spontaneous urticaria resistant to antihistamines. Real-life data focusing on patients >65-year-old treated with omalizumab are rare. In our retrospective study, we evaluated the efficacy and safety of this biologic therapy in patients over 65-year-old. We performed Urticaria Activity Score-7 (UAS-7) in order to evaluate the efficacy of omalizumab and the time of remission. We collected any adverse event related to the treatment. Moreover, we investigated the presence of comorbidities and their impact on the efficacy of omalizumab. Sixty-threepatients, with a mean age of 72.3 ± 5.6 years, range: 65-89) were enrolled. Of 63 subjects, 23 (36.5%) had an "early complete response" profile, which means the achievement of a UAS7 score of "0" within the first 7 days of therapy. The most frequent comorbidity was hypertension, which affected 26 of 63 (41.3%) patients; no adverse events were reported. No significant correlations were found between treatment effectiveness and comorbidities. Omalizumab is a safe and effective therapy also in elderly patients with multiple comorbidities.

Cutaneous adverse reactions after COVID-19 vaccines in a cohort of 2740 Italian subjects: An observational study.

An in-depth characterization of the incidence, morphology, and onset of COVID-19-vaccines cutaneous adverse reactions is currently lacking. The existing literature on COVID-19 vaccination-related cutaneous adverse reactions largely focused on messenger RNA vaccines and mainly included type 1 hypersensitivity reactions, such as urticaria and angioedema. Other cutaneous manifestations are still poorly characterized and have been classified as delayed hypersensitivity rash. Our prospective observational study on a sample of 2740 subjects who underwent the COVID-19 vaccination aimed at defining the prevalence of cutaneous adverse reactions and at identifying their timing of onset and their correlation with the administered dose. Vaccine-related cutaneous adverse reactions occurred in 50 subjects. Patients were asked to complete a questionnaire on the type of COVID-19 vaccine received, the time of onset of cutaneous reactions, and the dates of administration. Out of 2740 individuals who received the COVID-19 vaccination, 50 were diagnosed with cutaneous adverse reactions to vaccine, after the first dose in 28 patients, after the second in 20, and after both in two. We reported localized injection site erythema in 12 patients and generalized cutaneous reactions in 38 patients. Our study shows that cutaneous adverse reactions to COVID-19 vaccination are not common and most often occur after the first dose, recurring infrequently after the second dose. These reactions are usually easily manageable and, even in severe generalized cases, oral antihistamines and corticosteroids were sufficient for resolution. Therefore, except for immediate hypersensitivity reactions, cutaneous adverse reactions do not represent a contraindication to the completion of the vaccination cycle.

Atopic dermatitis in adolescents: Effectiveness and safety of dupilumab in a 16-week real-life experience during the COVID-19 pandemic in Italy.

Dupilumab showed significant improvement of adolescent atopic dermatitis (AD) signs and symptoms in clinical trials, with a good safety profile. Herein we report the real-word effectiveness and safety of dupilumab in adolescents with moderate to severe AD from January to October 2020, during the COVID-19 pandemic in Italy. All patients had a diagnosis of AD for a mean [SD] 12.8 [3.1] years. Baseline demographics, AD characteristics (EASI, cDLQI, NRS itch score, NRS sleep loss score) at baseline and week 16, and safety data were collected. Nineteen patients (52.6% men; mean [SD] age, 15.6 [1.4] years [range, 13-17 years]) were included in the analysis. All patients reached EASI-50 and 78.9% EASI-75, especially in those with EASI≥30 and BMI < 25 at baseline, with marked reduction for cDLQI (77.4%), NRS itch score (5.9 point), and NRS sleep loss score (87.5%). One patient contracted asymptomatic SARS-CoV-2 infection and 1 developed mild conjuntivitis, without stopping dupilumab. In this real-word experience the effectiveness of dupilumab was excellent and resulted higher than that observed in clinical trials, with a good safety profile during COVID-19 pandemic.

Living with Chronic Spontaneous Urticaria in Italy: A Narrative Medicine Project to Improve the Pathway of Patient Care.

Chronic spontaneous urticaria (CSU) is perceived as a difficult to manage disease with negative impact on quality of life. The aim of this study was to highlight how to improve the care of people with CSU, using the methodology of narrative medicine. From June 2014 to March 2015, CSU-diagnosed patients and their physicians were asked to record their experiences of the condition in writing. Fourteen healthcare teams participated: 41% considered CSU as a challenge to overcome, while 22% experienced CSU as a big commitment. The number of professional involved was evaluated as insufficient in 11 hospitals. Seventy-five percent of the 190 Italian patients had visited 3 or more physicians before receiving a final diagnosis, with a perceived waste of time and resources. The therapeutic pathways were described as unsatisfactory in 83% of cases. As a result, anger and frustration were life-dominant emotions in 92% of patients. The critical points of the care pathway are related to organizational issues and lack of awareness.

LATEX sensitization in elderly: allergological study and diagnostic protocol.

BACKGROUND: The prevalence of latex allergy varies according to the population studied from 3% to 64%. No data exist in the present literature about elderly people because they were not considered among populations at risk. We report a retrospective observational study of 88 elderly patients of our centre of Dermatology and Allergology at Policlinico Umberto I, University of Rome, Sapienza. RESULTS: First and second level diagnostic tests showed latex positivity in 11,4% of patients studied for latex allergy in the elderly population. CONCLUSIONS: Our study demonstrates a prevalence of elderly-latex sensitization of 11,4%, showing that allergy to latex is a growing disease that can occur at any age. So, we propose these patients as an additional risk category for latex allergy.

Interleukin-13 Inhibitors in the Treatment of Atopic Dermatitis: The Role of Tralokinumab.

INTRODUCTION: The advent of biotechnological drugs has significantly changed the management of atopic dermatitis (AD) and the approach to the moderate-to-severe form of this chronic relapsing disease. OBJECTIVES: The aim of our review is to summarize the current literature on anti-interleukin (IL)-13 in atopic dermatitis. METHODS: A literature search was organized and a systematic review was performed to summarize the most recent evidence supporting the efficacy and safety of tralokinumab. RESULTS: Tralokinumab (anti-IL-13) 300 mg every 2 weeks subcutaneously has proven effective in several clinical trials in adults and adolescents with moderate to severe atopic dermatitis inadequately controlled with other topical or systemic therapies. Tralokinumab was found to be significantly superior in terms of efficacy in reducing Investigator's Global Assessment (IGA), Eczema Area and Severity Index (EASI) -75, Numeric Pain Rating Scale (NRS) pruritus, and Dermatology Life Quality Index (DLQI) scale numbers. During follow-up, tralokinumab was well tolerated with limited severity of adverse events. CONCLUSIONS: Tralokinumab leads to statistically significant improvements in disease severity and outcome scores. It represents an effective treatment option for adults with moderate to severe AD, but further large-scale studies are needed to verify long-term superiority over other treatments.

Association between Vitamin D Receptor Polymorphisms, Tight Junction Proteins and Clinical Features of Adult Patients with Atopic Dermatitis.

INTRODUCTION: Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD). METHODS: From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry. RESULTS: The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and zonulin-1 (ZO-1), while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058). CONCLUSION: This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease.

Dupilumab as Therapeutic Option in Polysensitized Atopic Dermatitis Patients Suffering from Food Allergy.

IgE-mediated food allergy is characterized immunologically by a type 1 immune response triggered upon exposure to specific foods and clinically by a broad range of manifestations and variable severity. Our understanding of food allergy within the allergic march of atopic dermatitis (AD) is still incomplete despite the related risk of unpredictable and potentially severe associated reactions such as anaphylactic shock. The aim of this pilot study was to investigate the effects of dupilumab, an IL-4/IL-13 monoclonal antibody approved for AD, on the allergic sensitization profile of patients with AD and type 1 hypersensitivity-related comorbidities, including oral allergy syndrome, anaphylaxis, and gastrointestinal disorders. We conducted an observational pilot study with a longitudinal prospective design, enrolling 20 patients eligible for treatment with dupilumab. Laboratory exams for total serum IgE, specific IgE, and molecular allergen components were performed at baseline and after 16 weeks of therapy. Our results demonstrate a statistically significant decrease in molecular components, specific IgE for trophoallergens, and specific IgE for aeroallergens following treatment with dupilumab. We suggest that modulating type 2 immunity may decrease IgE-mediated responses assessed with laboratory exams and therefore could minimize allergic symptoms in polysensitized patients. Upcoming results of randomized controlled trials investigating dupilumab in food allergy are highly anticipated to confirm its potential effect in the treatment of IgE-mediated food allergies.

Syphilis, the Great Imitator-Clinical and Dermoscopic Features of a Rare Presentation of Secondary Syphilis.

Syphilis is characterized by a wide range of variable clinical symptoms; therefore, it is often referred to as "The Great Imitator". Here, we report the case of a 69-year-old hepatitis-C-positive MSM patient, who was admitted to our clinic due to a solitary firm painless erythematous maculopapular lesion with a central crater-like crust on the upper right thigh that occurred two months prior. The dermoscopy showed an erythematous, copper-colored, oval lesion with diffuse monomorphic dotted and glomerular vessels, central crust, and circular scaling (Biett's sign). The histological findings ruled out neoplasia and described a plasma cell infiltrate and endothelial swelling. Finally, the combination of the dermoscopic image, histological findings and the additionally acquired knowledge about the sexual history of the patient at the second visit led to the diagnosis, which was then confirmed with serological tests. Dermoscopy may become a supportive tool to facilitate the recognition of secondary syphilis; however, the reporting of these atypical cases is crucial to highlight the many faces of the disease so that clinicians consider syphilis as part of the differential diagnosis of non-specific lesions.

Multiple Cutaneous Manifestations in ANCA-Positive Eosinophilic Granulomatosis with Polyangiitis before and after Biologic Therapy: Clinical and Histopathologic Characterization of a Paradigmatic Case.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare immune-mediated vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Having systemic and possibly severe involvement, a prompt recognition of its clinical features is crucial to achieve favorable patient outcomes. Although cutaneous manifestations represent key elements, these still remain poorly characterized. We report a case of ANCA-positive EGPA presenting with palpable purpura, livedo reticularis, and pemphigoid-like lesions that was successfully treated with glucocorticoid therapy and rituximab. This report portrays the evolution of cutaneous lesions in ANCA-positive EGPA and demonstrates how dermatologic signs may represent indicators of active disease, allowing for timely diagnosis and for the monitoring of disease activity during treatment.

Dupilumab facial redness: histologic characterization on a series of four cases.

Dupilumab-related head and neck dermatitis is an increasingly reported clinical manifestation occurring in 4-10% of patients on dupilumab that was apparently not reported in clinical trials. Out of 62 adult patients treated with dupilumab for atopic dermatitis in the authors' center, four cases (6%) of head and neck dermatitis were observed, for which a skin biopsy was obtained. Onset occurred between 8 and 24 weeks after initiation of dupilumab, and the reaction resolved after 8-12 weeks. Histopathology and immunohistochemical findings support the authors' hypothesis that facial redness may be a toxic effect induced by dupilumab, although its pathogenesis still requires further investigation.

Plain language summary Dupilumab is an advanced treatment for atopic dermatitis. The new appearance of a peculiar head and neck dermatitis may be observed in as many as 4­10% of subjects receiving this drug, though it was not reported in the course of the clinical trials that led to the approval of dupilumab. Out of 62 adults treated with dupilumab for atopic dermatitis in the authors' Dermatology Clinic, four subjects (6%) were observed to have head and neck dermatitis. The condition appeared between 8 and 24 weeks after initiation of dupilumab and lasted 8­12 weeks. The four subjects gave permission to perform a skin biopsy. Microscopic analysis of their samples suggested that this peculiar facial redness may be a drug-induced reaction associated with dupilumab, although its causes and mechanisms still require understanding.

Effects of Vaccination against COVID-19 in Chronic Spontaneous and Inducible Urticaria (CSU/CIU) Patients: A Monocentric Study.

BACKGROUND: Patients affected by pre-existing chronic spontaneous/Inducible urticaria (CSU/CIU) still feel unsafe due to the potential risk of an Adverse Event Following Immunization (AEFI) and Cutaneous Adverse Reactions (CARs) of COVID-19 vaccines. The appropriate management in this field remains debated and evidence is still lacking. METHODS: We considered 160 CSU/CIU patients in Omalizumab/antihistamine therapy who received two doses of Comirnaty/Moderna mRNA vaccines; 20 of them also received a booster dose. Urticaria Activity Score-7 (UAS7) was used to assess the severity of the disease. Demographics, medical history, AEFI and CARs outcome after vaccination were collected by administering a web-based questionnaire completed by phone interview. RESULTS: In total, 147 patients did not show urticaria relapse (91.88%). Worsening cutaneous symptoms were experienced by 13 of our patients (8.12%). Exacerbation had a mean duration of 2 days and 11 h and mostly occurred after the first dose (69.23%). Systemic mild side effects were experienced by 9 patients (5.62%). No severe reactions were observed. CONCLUSIONS: Omalizumab can potentially prevent CARs and AEFI; however, major problems were registered during the 2-month stop period scheduled in the treatment. We suggest patients should not undergo vaccination during this period. CSU/CIU exacerbations appear to be transient and can be managed by antihistamines.

The Pathological Culprit of Neuropathic Skin Pain in Long COVID-19 Patients: A Case Series.

Cutaneous neurosensory symptoms have become increasingly reported findings in COVID-19; however, these virus-related manifestations are largely overlooked, and their pathology is poorly understood. Moreover, alterations of skin sensibility currently recognize no clear histopathology substrate. The purpose of this study was to provide pathology evidence of neurosensory skin system involvement in COVID-19 patients complaining of subjective neurological symptoms affecting the skin. Out of 142 patients, six long COVID-19 cases complaining of cutaneous subjective neurological symptoms assessed on an NTSS-6 questionnaire underwent histopathological and immunohistochemical analyses of skin areas affected by paroxysmal diffuse burning and itching sensations. Two patients also performed electroneurography examination. The histology investigation showed hypertrophic glomus vascular bodies with hypertrophic S100+ perineural sheath cells and adjacent hypertrophy of the nerve branches associated with increased basophil polysaccharide matrix. Electroneurography revealed disturbances of A-delta and C dermal neuronal fibers. The main limitation of this study consisted of a limited number of skin biopsy samples, requiring further investigation. Histopathology findings are consistent with hypertrophy of nerve endings, suggesting a condition such as "dermal hyperneury", a recently reported small nerve hypertrophy condition affecting sensory C fibers. Such a neuropathic basis could explain dysesthesia experienced by the patients, as previously described in postherpetic neuralgia.

Cutaneous Reactions to COVID-19 Vaccines in a Monocentric Study: A Case Series.

After coronavirus disease 2019 (COVID-19) caused a global pandemic, vaccines were rapidly developed to control the spread of the virus. Although they were effective in most of the cases at protecting people from becoming seriously ill and being hospitalized, they showed side effects, too. Among other adverse vaccine reactions, cutaneous eruptions following SARS-CoV-2 have been described in the literature, but they are not well-characterized yet. We described the morphology and timing of the spectrum of cutaneous reactions following most of the COVID-19 vaccines available in Italy, which were observed in outpatients referred to our non-invasive diagnostic clinic. Most of these reactions appeared after the second or third COVID-19 vaccine dose (most of them after mRNA COVID-19 vaccines). Our data support that cutaneous reactions to COVID-19 vaccination are generally self-limited; in addition, history of allergic reaction to a specific food, medicine or vaccine should not discourage vaccination in the general population, although patients with immune dysregulation should be accurately selected and monitored. Further research is necessary to better assess the true prevalence and preventive measures of skin reactions to COVID-19 vaccination.

Effects of dupilumab in type 1 neurofibromatosis coexisting with severe atopic dermatitis.

Neurofibromatosis type 1 still lacks established treatment options aimed at controlling the progression of neurofibromas as well as effective therapy for the neurogenic itch associated with the disease. We report the case of a 30-year-old Caucasian woman with type 1 neurofibromatosis coexisting with severe refractory atopic dermatitis. Dupilumab, a novel anti-IL-4 receptor alpha monoclonal antibody, the first biologic agent approved for atopic dermatitis, was the drug of choice in this case. We observed remission of atopic dermatitis and a remarkable reduction in the size and swelling of neurofibromas and in the related pruritus, that became evident after one month of treatment. After 18 months of therapy, no new neurofibromas were detected and preexistent lesions showed no increase in size. These findings are consistent with the hypothesis that dupilumab, a potent anti-inflammatory drug, may have a positive effect on type 1 neurofibromatosis by stopping the progression of preexisting neurofibromas and the onset of new lesions.

Impact of COVID-19 on patients with atopic dermatitis.

Data on the tolerability and response to biologic therapies for type 2 immune disorders in the context of coronavirus disease 2019 (COVID-19) are currently lacking. Our survey aimed at assessing the adherence of patients to dupilumab therapy and the risk of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 80 patients with atopic dermatitis treated with dupilumab completed a web-based survey. Of the 80 patients, 7 discontinued dupilumab owing to concerns and difficulties related to COVID-19. Our sample was highly susceptible to viral infection owing to the frequency of risk factors including living in high SARS-CoV-2 burden areas, such as in Northern Italy; having comorbidities, such as asthma, diabetes, and cardiovascular disease; and being of advanced age. Older patients in our sample are particularly exposed to the risk of COVID-19-related cytokine storm, triggered by excessive interleukin-4 production and type 2 immune response. One patient contracted SARS-CoV-2 infection without the progression of COVID-19 despite continuing scheduled dupilumab treatment. Because evidence on the appropriate management of biologic therapy in the setting of COVID-19 is lacking, the collection of clinical data from patients in treatment with dupilumab is a valuable addition to current clinical practice. Our survey provides a contribution to the understanding of the tolerability and response to dupilumab during COVID-19 and suggests a feasible and effective approach to patients being treated with biologics even when social distancing is required.