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

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

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

Clinical Patterns, Survival, Comorbidities, and Treatment Regimens in 149 Patients With Pemphigus in Tuscany (Italy): A 12-Year Hospital-Based Study.

Introduction: Pemphigus encompasses a group of muco-cutaneous autoimmune bullous diseases characterized by the loss of adhesion between keratinocytes. The disease is associated with increased morbidity and mortality. Materials and Methods: We characterized clinical patterns, survival, comorbidities, and drug prescriptions in patients with pemphigus referred to the Section of Dermatology of the University of Florence from January 2010 to December 2021. Results: A total of 149 patients were identified (female/male sex ratio = 2.0). Median age at diagnosis was 57.7 ± 17.2 years; 108 patients were diagnosed with pemphigus vulgaris (PV) (72.5%) and 35 (23.5%) with pemphigus foliaceus (PF). Paraneoplastic pemphigus (PNP) and IgA-pemphigus accounted for three patients each. The overall survival rate was 86.9%. Accordingly, 14 (9%) patients died during the study period. The average age at death was 77.8 ± 9.3. Age at diagnosis was a risk factor for death in patients with pemphigus. Average concentration of Dsg3-IgG and Dsg1-IgG was 85.6 ± 68.8 and 75.9 ± 68.4, respectively. The most serious comorbid diseases included cerebro- and cardiovascular accidents and malignancies. Regarding the treatment regimen, we found a substantially stable use of systemic steroids in the 2010-2018 period; the prevalence of use of mycophenolic acid increased, whereas that of azathioprine decreased. The use of rituximab showed the highest increase in the 2013-2018 period. Proton-pump inhibitors and antibiotics were the most frequently prescribed non-immunomodulating drugs. Conclusions: In this large series of the patients, patients with pemphigus showed a high incidence of serious comorbid diseases, highlighting the importance of a multidisciplinary approach for a proper management of the patients. Rituximab was the immunomodulating drug showing the highest increase in use over time, reflecting the growing evidence of its efficacy as a first-line treatment in pemphigus.

Overexpression of helper T cell type 2-related molecules in the skin of patients with eosinophilic dermatosis of hematologic malignancy.

BACKGROUND: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare dermatosis associated with blood tumors. OBJECTIVE: To characterize the expression of T-cell and B-cell markers and pruritogenic mediators in EDHM skin. METHODS: Immunohistochemical and immunofluorescence analysis were performed in 12 skin samples of EDHM, 11 samples of bullous pemphigoid (BP), and 5 samples from healthy controls (HC). Serum levels of interleukin (IL) 4 were analyzed in 11 patients with EDHM, 11 BP patients, and 5 HC by enzyme-linked immunosorbent assay. RESULTS: T-cell markers, including clusters of differentiation (CD) 3, CD4, CD8, and CD5 were significantly overexpressed in EDHM and BP skin compared to HC. A predominance of CD4+ over CD8+ cells and GATA3+ (helper T cell type 2 [Th2] marker) over T-bet+ (Th1 marker) cells were observed. FOXP3 expression was increased but the FOXP3/CD4 ratio was low. B-cell markers were under-represented, without significant differences between the 3 groups. IL-4 and IL-31 were significantly overexpressed in EDHM and BP compared to HC and colocalized with the Th2-associated marker GATA3. Eotaxin-1 was significantly overexpressed in EDHM compared to BP and HC. IL-4 serum concentration was significantly increased in EDHM and BP compared to HC. LIMITATIONS: Small sample size; retrospective design. CONCLUSIONS: Targeting Th2-related molecules, in particular IL-4, holds promise for EDHM management.

Myelodysplasia cutis as the presenting sign of chronic myelomonocytic leukaemia.

We describe an unusual case of myelodysplasia cutis in a patient with chronic myelomonocytic leukaemia.

The Role of TRPA1 in Skin Physiology and Pathology.

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, acts as 'polymodal cellular sensor' on primary sensory neurons where it mediates the peripheral and central processing of pain, itch, and thermal sensation. However, the TRPA1 expression extends far beyond the sensory nerves. In recent years, much attention has been paid to its expression and function in non-neuronal cell types including skin cells, such as keratinocytes, melanocytes, mast cells, dendritic cells, and endothelial cells. TRPA1 seems critically involved in a series of physiological skin functions, including formation and maintenance of physico-chemical skin barriers, skin cells, and tissue growth and differentiation. TRPA1 appears to be implicated in mechanistic processes in various immunological inflammatory diseases and cancers of the skin, such as atopic and allergic contact dermatitis, psoriasis, bullous pemphigoid, cutaneous T-cell lymphoma, and melanoma. Here, we report recent findings on the implication of TRPA1 in skin physiology and pathophysiology. The potential use of TRPA1 antagonists in the treatment of inflammatory and immunological skin disorders will be also addressed.

Immune-Mediated Dermatoses in Patients with Haematological Malignancies: A Comprehensive Review.

Haematological malignancies induce important alterations of the immune system, which account for the high frequency of autoimmune complications observed in patients. Cutaneous immune-mediated diseases associated with haematological malignancies encompass a heterogeneous group of dermatoses, including, among others, neutrophilic and eosinophilic dermatoses, autoantibody-mediated skin diseases, vasculitis and granulomatous dermatoses. Some of these diseases, such as paraneoplastic pemphigus, are associated with an increased risk of death; others, such as eosinophilic dermatoses of haematological malignancies, run a benign clinical course but portend a significant negative impairment on a patient's quality of life. In rare cases, the skin eruption reflects immunological alterations associated with an unfavourable prognosis of the associated haematological disorder. Therapeutic management of immune-mediated skin diseases in patients with haematological malignancies is often challenging. Systemic corticosteroids and immunosuppressive drugs are considered frontline therapies but may considerably augment the risk of serious infections. Indeed, developing a specific targeted therapeutic approach is of crucial importance for this particularly fragile patient population. This review provides an up-to-date overview on the immune-mediated skin diseases most frequently encountered by patients with onco-haematological disorders, discussing new pathogenic advances and therapeutic options on the horizon.

Thymoma-Associated Paraneoplastic Autoimmune Multiorgan Syndrome-From Pemphigus to Lichenoid Dermatitis.

Introduction: Paraneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin. PAMS is occasionally associated with thymoma, in which altered immune surveillance eventually leads to multiorgan autoimmunity which often includes variable cutaneous symptoms. This disorder is associated with a profound disturbance of peripheral immune tolerance against human autoantigens. Objectives: We here present a patient with relapsing thymoma who developed PAMS with several cutaneous and extracutaneous autoimmune disorders. Materials: Peripheral blood mononuclear cells (PBMC), sera, and lesional skin biopsies were obtained at different clinical disease stages. Peripheral T cell subsets were characterized phenotypically and the cytokine profile of the peripheral blood T cellular response against distinct epidermal and dermal autoantigens of the skin was analyzed by ELISpot assay. Serological screening was performed by ELISA and immunoblot analysis. Skin biopsies were subjected to immunohistochemical analysis of distinct T cell subsets. Thymoma tissue was analyzed for the presence of T regulatory cells and compared with adult thymus and indolent thymoma. Results and Conclusions: In the present case, thymoma was the cause of the observed multi-organ autoimmune syndromes as its recurrence and surgical removal was associated with the relapse and regression of the cutaneous symptoms, respectively. Initially, the patient presented with two autoimmune disorders with Th2/Th1 imbalance, myasthenia gravis (MG) and pemphigus foliaceus (PF), which regressed upon immunosuppressive treatment. Months later, the patient developed a lichenoid exanthema with a Th1-dominated skin infiltrate. Further clinical evaluation revealed the recurrence of the thymoma and the lichenoid exanthema gradually regressed upon thymectomy. Our contention that T cell recognition against distinct cutaneous autoantigens, such as desmoglein 1 (Dsg1), shifted from a Th2 to a Th1-dominated immune response could not be fully substantiated as the patient was on a stringent immunosuppressive treatment regimen. We could only observe a decrease of the initially present serum IgG autoantibodies against Dsg1. Phenotypic analysis of the associated thymoma showed a lower number of T regulatory cells compared to adult thymus and indolent thymoma, suggesting that impaired thymus-derived immune surveillance had a direct impact on the outcome of the observed cutaneous autoimmune disorders.

Dermatitis Herpetiformis: Novel Perspectives.

Dermatitis herpetiformis (DH) is an inflammatory disease of the skin, considered the specific cutaneous manifestation of celiac disease (CD). Both DH and CD occur in gluten-sensitive individuals, share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8), and improve following the administration of a gluten-free diet. Moreover, almost all DH patients show typical CD alterations at the small bowel biopsy, ranging from villous atrophy to augmented presence of intraepithelial lymphocytes, as well as the generation of circulating autoantibodies against tissue transglutaminase (tTG). Clinically, DH presents with polymorphic lesions, including papules, vesicles, and small blisters, symmetrically distributed in typical anatomical sites including the extensor aspects of the limbs, the elbows, the sacral regions, and the buttocks. Intense pruritus is almost the rule. However, many atypical presentations of DH have also been reported. Moreover, recent evidence suggested that DH is changing. Firstly, some studies reported a reduced incidence of DH, probably due to early recognition of CD, so that there is not enough time for DH to develop. Moreover, data from Japanese literature highlighted the absence of intestinal involvement as well as of the typical serological markers of CD (i.e., anti-tTG antibodies) in Japanese patients with DH. Similar cases may also occur in Caucasian patients, complicating DH diagnosis. The latter relies on the combination of clinical, histopathologic, and immunopathologic findings. Detecting granular IgA deposits at the dermal-epidermal junction by direct immunofluorescence (DIF) from perilesional skin represents the most specific diagnostic tool. Further, assessing serum titers of autoantibodies against epidermal transglutaminase (eTG), the supposed autoantigen of DH, may also serve as a clue for the diagnosis. However, a study from our group has recently demonstrated that granular IgA deposits may also occur in celiac patients with non-DH inflammatory skin diseases, raising questions about the effective role of eTG IgA autoantibodies in DH and suggesting the need of revising diagnostic criteria, conceivably emphasizing clinical aspects of the disease along with DIF. DH usually responds to the gluten-free diet. Topical clobetasol ointment or dapsone may be also applied to favor rapid disease control. Our review will focus on novel pathogenic insights, controversies, and management aspects of DH.