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BackgroundBullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare autoimmune blistering disorders characterized by autoantibodies (autoAbs) targeting dermo-epidermal junction components such as BP180 and BP230. The differential diagnosis, based on both the time of appearance and the extension of cutaneous and/or mucosal lesions, is crucial to distinguish these diseases for improving therapy outcomes and delineating the correct prognosis; however, in some cases, it can be challenging. In addition, negative results obtained by commercially available enzyme-linked immunosorbent assays (ELISAs) with BP and MMP sera, especially from patients with ocular involvement, often delay diagnosis and treatment, leading to a greater risk of poor outcomes.ObjectivesOur aim was to find potentially different reactivity profiles in BP and MMP and improve available approaches for diagnosis with focus on ocular MMP.MethodsTwo cohorts of 90 BP and 90 MMP, recruited from different Italian clinical centers, were characterized also employing a novel ELISA based on the BP180 extracellular domain (ECD-BP180).ResultsImmunoglobulin G (IgG) reactivity to BP180 and BP230 in MMP sera was significantly reduced in comparison with BP, mostly affecting BP230 and E-1080 (53% and 36% in BP vs. 11% and 3% in MMP, respectively, p < 0.0001). The combined sensitivity of BP180-NC16A and ECD-BP180 ELISAs was greater compared to BP180-NC16A and BP230 ELISAs both in BP (97% and 92%, respectively) and in MMP (42% and 31%, respectively). The present study shows that MMP patients with ocular involvement rarely reacted to BP180 by IgG in contrast with patients with oral and/or cutaneous involvement (p = 0.0245 and p = 0.0377, respectively), suggesting that an oral and/or cutaneous MMP positive to BP180 hardly evolves to ocular MMP. Of note, one-third of ocular MMP showed immunoglobulin A (IgA) reactivity to ECD-BP180 by immunoblotting.ConclusionsThe present study provides several hints to perform a correct and timely diagnosis in BP and MMP, which is crucial for improving therapy outcomes and delineating the correct prognosis.

Lupus erythematosus tumidus (LET) is a subset of cutaneous lupus erythematosus that generally presents with urticaria-like papules and plaques located on sun-exposed areas. Systemic treatment with antimalarials, especially hydroxychloroquine (HCQ), is the first-line systemic therapy for LET. Even if these drugs have a safe profile, side effects such as retinal toxicity, maculopapular rash, gastrointestinal upset, hemolytic anemia and blue-gray discoloration of the skin or the mucous membranes, have been rarely reported in the literature. Herein, we describe a rare case of a 46-year-old smoking woman with LET who developed a generalized myopathy after HCQ treatment.

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.

The term gluten-related disorders (GRD) refer to a spectrum of different clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals, including coeliac disease (CD), wheat allergy and non-celiac gluten sensitivity (NCGS). GRD are characterized by a large variety of clinical presentations with both intestinal and extra-intestinal manifestations. The latter may affect almost every organ of the body, including the skin. Besides the well-known association between CD and dermatitis herpetiformis, considered as the cutaneous specific manifestation of CD, many other muco-cutaneous disorders have been associated to GRD. In this review, we analyzed the main features of dermatological diseases with a proven association with GRD and those that improve after a gluten-free diet, focusing on the newly described cutaneous manifestations associated with NCGS. Our main hypothesis is that a “cutaneous-gluten sensitivity,” as specific cutaneous manifestation of NCGS, may exist and could represent a diagnostic marker of NCGS.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease, characterized by severe pruritus and skin blistering. The loss of tolerance against Collagen XVII, also referred to as BP180, is the main pathogenic event of BP, leading to production of IgG autoantibodies which mainly target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. A complex inflammatory network is activated upon autoantibody binding to the basement membrane zone; this inflammatory loop involves the complement cascade and the release of several inflammatory cytokines, chemokines and proteases from keratinocytes, lymphocytes, mast cells and granulocytes. Collectively, these events disrupt the integrity of the dermal-epidermal junction, leading to subepidermal blistering. Recent advances have led to identify novel therapeutic targets for BP, whose management is mainly based on the long-term use of topical and systemic corticosteroids. As an example, targeting type-2 T-helper cell-associated cytokines, such as Interleukin-4 and interleukin-13 has shown meaningful clinical efficacy in case series and studies; targeting IL-17 and IL-23 has also been tried, owing to an important role of these cytokines in the chronic maintenance phase of BP. In this review article, we discuss the complex cytokine milieu that characterized BP inflammation, highlighting molecules, which are currently investigated as present and future therapeutic targets for this life-threatening disease.

IntroductionPemphigus 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 MethodsWe 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.ResultsA 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.ConclusionsIn 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.

Bullous pemphigoid (BP) represents the most common autoimmune bullous disease and is characterized by IgG autoantibodies targeting collagen XVII (BP180). BP has reportedly been occurred in association with other inflammatory skin diseases. Here, we describe the unusual occurrence of BP in a female patient with a concomitant history of generalized morphea (localized scleroderma, LoS) and cutaneous and genital lichen sclerosus (LiS). The occurrence of BP was associated with elevated serum levels of anti-BP180 IgG autoantibodies, which decreased upon clinical remission. Autoimmune bullous diseases and sclerosing dermatitis are immunologically distinct entities, whose association has been rarely described. In this study, we provide a literature review on cases of BP developed in patients with either LoS or LiS. Further, we discussed immunological mechanisms which may have favored the emergence of BP in our patient.

The skin microbiota is a pivotal contributor to the maintenance of skin homeostasis by protecting it from harmful pathogens and regulating the immune system. An imbalance in the skin microbiota can lead to pathological conditions such as eczema, psoriasis, and acne. The balance of the skin microbiota components can be disrupted by different elements and dynamics such as changes in pH levels, exposure to environmental toxins, and the use of certain skincare products. Some research suggests that certain probiotic strains and their metabolites (postbiotics) may provide benefits such as improving the skin barrier function, reducing inflammation, and improving the appearance of acne-prone or eczema-prone skin. Consequently, in recent years probiotics and postbiotics have become a popular ingredient in skincare products. Moreover, it was demonstrated that skin health can be influenced by the skin–gut axis, and imbalances in the gut microbiome caused by poor diet, stress, or the use of antibiotics can lead to skin conditions. In this way, products that improve gut microbiota balance have been gaining attention from cosmetic and pharmaceutical companies. The present review will focus on the crosstalk between the SM and the host, and its effects on health and diseases.

BackgroundA few studies on vaccination in patients with rheumatic diseases, including arthritis, connective tissue diseases, vasculitis, and psoriatic arthropathy (PsA), demonstrated reduced production of neutralizing antibodies to SARS-CoV-2 Spike RBD (receptor-binding domain contained in the N-terminal of the S1 globular head region) when compared to the general population.ObjectiveThe aim of our study was to observe whether different therapies for PsA [methotrexate, anti-TNF antibodies, soluble TNF receptor (etanercept) or IL-17 inhibitors] have a different impact on SARS-CoV-2 vaccination in a homogeneous population of patients.MethodsWe enrolled 110 PsA patients in remission, assessed with Disease Activity in PSoriatic Arthritis (DAPSA). Of these: 63 were in treatment with anti-TNF-α therapy (26 etanercept, 15 certolizumab, 5 golimumab, 17 adalimumab); 37 with anti-IL17 secukinumab; 10 with methotrexate. All patients underwent vaccination for SARS-CoV-2 with mRNA BNT162b2 vaccine. Assessment of absolute and percentage lymphocyte subsets and anti-SARS-CoV-2 Spike RBD IgG antibody value 3 weeks after the second vaccine dose were performed. In addition, the serum antibody levels of 96 healthy healthcare workers (HCW) were analyzed.ResultsThe mean disease activity assessed with DAPSA score was 2.96 (SD = 0.60) with no significant differences between patients under different medications (p = 0.779). Median levels of neutralizing antibodies to SARS-CoV-2 Spike RBD were 928.00 binding antibody unit (BAU)/mL [IQR 329.25, 1632.0]; 1068.00 BAU/ml [IQR 475.00, 1632.00] in patients taking MTX, 846.00 BAU/ml [IQR 125.00, 1632.00] in patients taking etanercept, 908.00 BAU/mL [IQR 396.00, 1632.00] in patients taking anti-IL17 and 1148.00 BAU/ml [IQR 327.00, 1632.00] in patients taking TNF-α inhibitors, without statistically significant differences between these groups. Mean serum antibody level of HCW group was 1562.00 BAU/ml [IQR 975.00, 1632.00], being significantly higher than in the patient group (p = 0.000816). Absolute and percentage count of lymphocyte subsets were not statistically different between the subgroups under different treatments and when compared with HCW.ConclusionsAs for other rheumatic diseases on immunomodulatory treatment, our data showed a reduced humoral response in PsA patients compared to the control group. However, antibody response did not significantly differ between groups treated with different medications.

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA; in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.

Granular deposits of IgA represent the specific cutaneous marker of dermatitis herpetiformis. The prevalence of IgA deposits in the skin of patients with coeliac disease without dermatitis herpetiformis remains unknown. In this prospective case-control study, skin biopsies from newly diagnosed coeliac patients without dermatitis herpetiformis were analysed by direct immunofluorescence. Controls included healthy volunteers and patients with both bowel symptoms and skin eruptions unrelated to coeliac disease. Clinical data and serum level of anti-tissue transglutaminase and anti-epidermal transglutaminase IgA antibodies were collected from patients and controls. Granular deposits of IgA or IgA1 in the skin were found in 29 out of 45 patients with coeliac disease (64.4%), and in none of the included controls (specificity 100%; sensitivity 64.4%). Positive direct immunofluorescence correlated significantly with an increased serum level of anti-epidermal transglutaminase IgA antibodies (p

Coeliac disease is an immune-mediated enteropathy driven by gluten, which can be associated with dermatitis herpetiformis. The presence of granular IgA deposits, detected by direct immunofluorescence, is the hallmark of dermatitis herpetiformis; nevertheless, IgA deposits have also been demonstrated in healthy skin of patients with coeliac disease. The main objective of this study was to investigate whether IgA deposits could be found in the skin of patients with coeliac disease who have non-dermatitis herpetiformis inflammatory skin diseases. Direct immunofluorescence was performed on perilesional skin biopsies of 6 patients with coeliac disease with non-dermatitis herpetiformis inflammatory skin diseases and, as control, on 12 non-coeliac patients with inflammatory skin diseases. IgA deposits were found in all of the patients with coeliac disease, but were absent in the control group. In conclusion, IgA deposits may be considered an immunopathological marker for coeliac disease; therefore, patients with coeliac disease showing skin manifestations with positive direct immunofluorescence should be investigated carefully in order to make a differential diagnosis between dermatitis herpetiformis and other non-dermatitis herpetiformis inflammatory skin diseases.

Vaccines are today considered one of the most effective means against the Sars-CoV-2 pandemic. The BNT162b2 vaccine by Pfizer/BioNTech has been massively administered throughout the globe; since its approval, a wide spectrum of cutaneous reactions has been reported. Here we report the case of a 52-year-old Caucasian male who presented with an acute febrile eruption that arose 72 h after the first dose of the BNT162b2 vaccine. The clinicopathological findings were consistent with Sweet’s syndrome. The short latency time suggested a possible role of the vaccine in triggering Sweet’s syndrome in this case.

Linear IgA bullous dermatosis (LABD) is characterized by presence of multiple IgA autoantibodies, and a comparatively lesser number of IgG antibodies, directed against different hemidesmosomal antigens. The main autoantigens are LAD-1, LABD-97, BP180 and BP230, type VII collagen and laminin 332. We retrospectively studied the serology of 54 Italian patients with LABD using enzyme-linked immunosorbent assay (ELISA), immunoblotting assay, and indirect immunofluorescence on monkey oesophagus and salt-split skin. Among these, indirect immunofluorescence of salt-split skin elicits the greatest sensitivity. Sixty-three percent of the sera were observed to be positive, with a lamina lucida pattern observed in 48%, a sub-lamina densa pattern in 2% and a mixed pattern in 13% of the cases. IgA reactivity to LAD-1 on immunoblotting was found in 52% of sera, to BP180-NC16A by ELISA in 32% and to BP230 in 26%. Only 17% of patients possessed circulating IgG autoantibodies. LAD-1 was determined to be a major autoantigen of the lamina lucida subtype. Combined serological assays demonstrated a high sensitivity (82%), suggesting that this approach could support diagnosis when a biopsy is not feasible or direct immunofluorescence results are negative.

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.

Dermatitis herpetiformis (DH) is an inflammatory cutaneous disease with typical histopathological and immunopathological findings clinically characterized by intensely pruritic polymorphic lesions with a chronic-relapsing course. In addition to classic clinical manifestations of DH, atypical variants are more and more frequently reported and histological and immunological are added to them, whereas the impact on quality of life of patients with DH is increasingly important to a certain diagnosis. The aim of this paper is to describe all the possible clinical, histological, and immunological variants of DH in order to facilitate the diagnosis of a rare disease and, therefore, little known.

Cutaneous manifestations of intestinal diseases are increasingly reported both in the adult and in the children, and this association cannot longer be considered a simple random. Besides the well-known association between celiac disease (CD) and dermatitis herpetiformis (DH), considered as the cutaneous manifestation of gluten-dependent enteropathy, is more frequently reported also the association with other mucocutaneous diseases. Among these there are both autoimmune, allergic, and inflammatory diseases, but also a more heterogeneous group called miscellaneous. The knowledge about pathogenic, epidemiological, clinical, and diagnostic aspects of CD is increasing in recent years as well as those about DH, but some aspects still remain to be defined, in particular the possible pathogenetic mechanisms involved in the association between both CD and DH and CD and other immunological skin diseases. The aim of this paper is to describe the skin diseases frequently associated with CD, distinguishing them from those which have a relationship probably just coincidental.

Dermatitis herpetiformis (DH) is a rare autoimmune disease linked to gluten sensitivity with a chronic-relapsing course. It is currently considered to be the specific cutaneous manifestation of celiac disease (CD). Both conditions are mediated by the IgA class of autoantibodies, and the diagnosis of DH is dependent on the detection of granular deposits of IgA in the skin. There is an underlying genetic predisposition to the development of DH, but environmental factors are also important. This paper describes these different factors and discusses the known mechanism that lead to the development of skin lesions.