Skin Hypopigmentation in Hematology Disorders.

Hypopigmentation disorders pose significant diagnostic challenges in dermatology, sometimes reflecting underlying hematological conditions. This review explores the clinical presentations related to hypopigmentation in hematological disorders, focusing on vitiligo, morphea, and syndromic albinism. Vitiligo, an autoimmune disorder targeting melanocytes, involves interactions between genetic polymorphisms and immune responses, particularly regarding CD8+ T cells and IFN-γ. Drug-induced vitiligo, notably by immune checkpoint inhibitors and small-molecule targeted anticancer therapies, underscores the importance of immune dysregulation. Morphea, an inflammatory skin disorder, may signal hematological involvement, as seen in deep morphea and post-radiotherapy lesions. Syndromic albinism, linked to various genetic mutations affecting melanin production, often presents with hematologic abnormalities. Treatment approaches focus on targeting the immune pathways specific to the condition, and when that is not possible, managing symptoms. Understanding these dermatological manifestations is crucial for the timely diagnosis and management of hematological disorders.

Role of IL-4 and IL-13 in Cutaneous T Cell Lymphoma.

The interleukins IL-4 and IL-13 are increasingly recognized contributors to the pathogenesis of cutaneous T cell lymphomas (CTCLs), and their role in disease-associated pruritus is accepted. The prevailing Th2 profile in advanced CTCL underscores the significance of understanding IL-4/IL-13 expression dynamics from the early stages of disease, as a shift from Th1 to Th2 may explain CTCL progression. Targeted agents blocking key cytokines of type 2 immunity are established therapeutics in atopic disorders and have a promising therapeutic potential in CTCL, given their involvement in cutaneous symptoms and their contribution to the pathogenesis of disease. IL-4, IL-13, and IL-31 are implicated in pruritus, offering therapeutic targets with dupilumab, tralokinumab, lebrikizumab, and nemolizumab. This review analyzes current knowledge on the IL-4/IL-13 axis in mycosis fungoides and Sezary syndrome, the most common types of CTCL, examining existing literature on the pathogenetic implications with a focus on investigational treatments. Clinical trials and case reports are required to shed light on novel uses of medications in various diseases, and ongoing research into the role of IL-4/IL-13 axis blockers in CTCL therapy might not only improve the management of disease-related pruritus but also provide in-depth insights on the pathophysiologic mechanisms of CTCL.

Role of Human Leukocyte Antigen Class II in Antibody-Mediated Skin Disorders.

HLA class II molecules are key factors determining susceptibility to autoimmune disorders, and their role in immune-mediated skin conditions such as psoriasis has been extensively investigated. However, there is currently little understanding of their role in antibody-mediated skin diseases such as autoimmune blistering disorders. We researched the available literature using PubMed to narratively review the current knowledge on HLA associations in antibody-mediated blistering skin pathologies. Our results summarized the risk alleles that are identified in the literature, together with certain known protective alleles: in the pemphigus group, alleles HLA-DQB1*0503 and HLA-DRB1*0402 are most commonly associated with disease; in the pemphigoid group, the most studied allele is HLA-DQB1*0301; in epidermolysis bullosa acquisita, few genetic studies are available; in dermatitis herpetiformis, the association with haplotypes HLA-DQ2 and HLA-DQ8 is strongly established; finally, in linear IgA bullous disease, specific HLA alleles may be responsible for pediatric presentations. Our current pathogenic understanding of this group of disorders assigns a key role to predisposing HLA class II alleles that are able to bind disease autoantigens and therefore stimulate antigen-specific autoreactive T cells. The latter engage B lymphocytes that will produce pathogenic autoantibodies. The distribution of HLA alleles and their disease associations are variable across demographics, and an in-depth pathogenetic understanding is needed to support associations between HLA alleles and disease phenotypes. Additionally, in a personalized medicine approach, the identification of HLA alleles associated with the risk of disease may become clinically relevant in identifying susceptible subjects that should avoid exposure to known triggers, such as medication, when possible.

Analysis of predictive factors influencing dupilumab continuation rate in adult patients with atopic dermatitis: results from an Italian multicenter study.

OBJECTIVES: The purpose of this study was to analyze the drug survival rate of dupilumab up to 2 years in a large real-world cohort of adult patients affected by moderate/severe atopic dermatitis (AD), and to investigate the clinical, demographic and predictive factors influencing the patients' treatment persistence. MATERIAL AND METHODS: This study included adult patients affected by moderate-to-severe AD treated with dupilumab for at least 16 weeks who visited 7 dermatologic outpatient clinics in Lazio, Italy, from January 2019 until August 2021. RESULTS: A total of 659 adult patients (345 male [52.3%], mean age: 42.8 years) with an average treatment duration of 23.3 months were enrolled in the study. Overall, 88.6% and 76.1% of patients were still on treatment after 12 and 24 months, respectively. The drug survival rate for discontinuation due to AEs and dupilumab ineffectiveness was 95.0% at 12 months and 90.0% at 24 months. The main reasons for drug discontinuation included inefficacy (29.6%), failed compliance (17.4%), persistent efficacy (20.4%) and adverse events (7.8%). Adult AD onset (≥18 years) and EASI score severity measured at the last follow-up visit were the only factors significantly associated with lower drug survival. CONCLUSION: This study revealed an increased cumulative probability of dupilumab survival at 2 years, reflected by a sustained effectiveness and a favorable safety profile of the drug.

Cutaneous Lymphoma and Antibody-Directed Therapies.

The introduction of monoclonal antibodies such as rituximab to the treatment of cancer has greatly advanced the treatment scenario in onco-hematology. However, the response to these agents may be limited by insufficient efficacy or resistance. Antibody-drug conjugates are an attractive strategy to deliver payloads of toxicity or radiation with high selectivity toward malignant targets and limited unwanted effects. Primary cutaneous lymphomas are a heterogeneous group of disorders and a current area of unmet need in dermato-oncology due to the limited options available for advanced cases. This review briefly summarizes our current understanding of T and B cell lymphomagenesis, with a focus on recognized molecular alterations that may provide investigative therapeutic targets. The authors reviewed antibody-directed therapies investigated in the setting of lymphoma: this term includes a broad spectrum of approaches, from antibody-drug conjugates such as brentuximab vedotin, to bi-specific antibodies, antibody combinations, antibody-conjugated nanotherapeutics, radioimmunotherapy and, finally, photoimmunotherapy with specific antibody-photoadsorber conjugates, as an attractive strategy in development for the future management of cutaneous lymphoma.

Neoplastic and Autoimmune Comorbidities in Patients with Primary Cutaneous B-Cell Lymphoma.

Primary cutaneous B-cell lymphomas (PCBCLs) constitute a rare subset of non-Hodgkin lymphoma (NHL), with distinctive clinical and biological characteristics. The risk of autoimmune or neoplastic comorbidities in subjects with NHL has been extensively reported in the literature, but the data available are not directly applicable to PCBCLs. The aim of our study was to determine the frequency of relevant medical conditions, with a primary focus on autoimmune and neoplastic disorders, in subjects with PCBCL. We performed a retrospective observational study involving 56 patients diagnosed histologically with PCBCL and 54 sex- and age-matched controls. Our results show a statistically significant association for neoplastic comorbidities in general (41.1% vs. 22.2%, p = 0.034) and hematological malignancies specifically (19.6% vs. 1.9%, p = 0.0041) with PCBCL compared to controls. We did not highlight a statistically significant difference in the frequency of autoimmune comorbidities (21.4% vs. 9.3%, p = 0.1128) and of chronic viral hepatitis (7.1% vs. 0, p = 0.1184). Finally, type 2 diabetes (19.6% vs. 1.9%, p = 0.0041) was significantly associated with PCBCL. Our preliminary data supporting the association between PCBCLs and neoplastic disorders suggest that altered immune surveillance may be a common predisposing mechanism.

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.

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.

Role of Rituximab in the Treatment of Pemphigus Vulgaris: Patient Selection and Acceptability.

Anti-CD20 monoclonal antibody rituximab is an approved adjuvant treatment, in combination with oral corticosteroids, for patients with pemphigus vulgaris, a severe and potentially life-threatening autoimmune blistering skin disorder. Updated approaches to the management of pemphigus vulgaris support rituximab as a first-line adjuvant treatment to induce remission early in the course of disease; however, its feasibility in the clinical setting is often reduced by a series of limitations, including high cost of this biological drug, physician and patient concern for the risk of adverse reactions, and uncertainty regarding the optimum dosing and schedule of administration. The standard approved rituximab dosages, which are derived from lymphoma protocols, have been recognized to exceed the effective dose required for inducing B cell depletion, since the B cell burden in pemphigus vulgaris is much lower than in lymphoproliferative disorders. To overcome these limitations, recent research has investigated alternative regimens of rituximab, using lower doses of the drug. Moreover, differences in patient and disease characteristics that are highlighted in the literature strongly suggest that therapy should be tailored individually on a case-by-case basis: personalized treatment schedules may be necessary to optimize response to treatment and tolerability in different subjects, with the possibility of repeated infusions for severe forms and in case of relapse. Finally, low-dose regimens of rituximab were suggested to be favorable during the COVID-19 pandemic by providing a lesser degree of immune cell depletion while retaining a sufficient response. In conclusion, the current literature suggests that lower-dose regimens of rituximab are not only tolerable and cost-effective but may also be associated with a positive response in pemphigus vulgaris, comparable to that achieved with higher doses especially in early disease. Further evidence from rigorous clinical trials will be required to optimize lower-dose regimens of RTX and establish their position within the treatment scenario of pemphigus vulgaris.

Granulocyte Apheresis: Can It Be Associated with Anti PD-1 Therapy for Melanoma?

In the field of advanced melanoma, there is an urgent need to investigate novel approaches targeting specific components of the cancer-immunity cycle beyond immune checkpoint inhibitors. The authors reviewed the basic understanding of the role of neutrophils in cancer biology, and the latest clinical evidence supporting the correlation between cancer-associated neutrophils and the prognosis and response to the immunotherapy of advanced melanoma. Finally, they propose that granulocyte and monocyte apheresis, an emerging non-pharmacological treatment in current dermatology, could become an investigative treatment targeting melanoma-associated neutrophils which could be potentially used in combination with the usual immune checkpoint inhibitors.

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.

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.

Bullous pemphigoid: An immune disorder related to aging (Review).

Bullous pemphigoid (BP) is the most frequent subepidermal autoimmune blistering disease and is caused by autoantibodies directed against two principal antigens of the hemidesmosome, BP antigen 180 and BP antigen 230. The pathogenesis of BP is dependent upon the interaction between genetic predisposition, physiological skin alterations due to aging and specific triggers. Several triggers have already been reported to induce this disease and include drugs, thermal or electrical burns, surgical procedures, trauma, UV radiation, radiotherapy, chemicals and infections. Data from the current literature support the hypothesis that alterations of the skin barrier associated with aging increase individual susceptibility to these aforementioned triggers. Consequently, this has been reported to lead to the attack of autoantibodies, demonstrating the predilection of BP for the elderly population. The identification of triggering factors and comorbidities may aid in understanding the pathogenesis of BP and improve clinical management by encouraging their prompt recognition and removal. Moreover, the present review has indicated that current management of BP should be aimed at counteracting the detrimental effects of aging on the skin by restoring skin barrier integrity and maintaining cutaneous homeostasis, for example with systematic applications of topical emollients and photoprotection. This strategy could prove even more beneficial in the elderly, in which frequent comorbidities associated with age often narrow available immunosuppressive treatment options. Furthermore, the safety of treatment regimens may significantly affect outcome and prognosis.

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.

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.

Telogen Effluvium after SARS-CoV-2 Infection: A Series of Cases and Possible Pathogenetic Mechanisms.

INTRODUCTION: Physicians have largely studied the cutaneous involvement of coronavirus disease 2019 (COVID-19), but only few reports have focused on telogen effluvium (TE) as a possible sequela of COVID-19. We assessed 14 cases of hair loss occurring after SARS-CoV-2 infection using trichoscopy and trichogram to investigate patterns related to COVID-19. Furthermore, we discussed possible mechanisms involved in COVID-19 TE. CASE PRESENTATION: Fourteen individuals were referred to our post-COVID-19 dermatology office complaining acute hair loss after SARS-CoV-2 infection. Clinical evaluation included pull test, trichoscopy, and trichogram. CO-VID-19 TE occurred after a median of 2 months (range 1-3 months) following SARS-CoV-2 infection. The median duration of hair loss was 5 months (range 1-6 months). Trichoscopy showed variable but typical TE patterns. Trichogram showed different telogen/anagen ratio depending on the interval between onset of hair loss and trichological visit. DISCUSSION/CONCLUSION: Our cases showed TE between 1 and 3 months after the onset of SARS-CoV-2 infection, thus earlier than classic TE. Trichoscopic features and trichogram showed no variations from classic TE. Different pathogenetic mechanisms including pro-inflammatory cytokines and direct viral damage on the hair follicle can be hypothesized; further studies on a larger sample are needed to better understand this condition.

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.