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Mucous membrane pemphigoid (MMP) with anti-laminin 332 autoantibodies may be associated with malignancies, however, current serological assays have considerable limitations. At present, no commercial test for anti-laminin 332 antibodies is available, restricting the diagnosis to specialized laboratories worldwide. Biochip immunofluorescence microscopy has shown promising results in selected cohorts of laminin 332-MMP patients. Objectives: To detect anti-laminin 332 antibodies by biochip immunofluorescence microscopy in a real-life cohort of MMP patients and compare the results with those from traditional immunoblotting. Sera were obtained from 31 patients with MMP, 28 with bullous pemphigoid, five with pemphigus vulgaris, five with paraneoplastic pemphigus, five with linear IgA bullous dermatosis, and 10 controls, and analysed by biochip immunofluorescence using human cells expressing laminin 332. Immunoblotting was performed using purified laminin 332. MMP involved the oral mucosa in 65%, ocular mucosa in 9%, oral and ocular mucosae extensively in 13% as well as other mucosae in 13% of patients. Concomitant cutaneous involvement was reported in 35% of patients. Three MMP patients had an underlying malignancy. Anti-laminin 332 antibodies were detected in 2/31 (6%) cases by both methods. Based on immunoblotting, both laminin 332-positive sera reacted with α3 chain (in one case also with β3 chain). Both patients with anti-laminin 332 antibodies had extensive mucosal involvement and only one had cancer. Anti-laminin 332 antibodies were not detected in control groups. Biochip immunofluorescence is an appropriate technique to detect anti-laminin 332 antibodies which should be tested in patients with MMP.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus‐based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue‐bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10–25% of patients laminin 332 is recognized. In 25–30% of MMP patients with anti‐laminin 332 reactivity, malignancies have been associated. As first‐line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first‐line regimens. Additional recommendations are given, tailored to treatment of single‐site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high‐quality randomized controlled trials.

Background Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions. Results The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6–37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17–2.35), congestive heart failure (HR = 2.76, CI 95% 1.80–4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21–4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06–2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008–2017 period. Conclusions The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.

Background: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the USA.Objectives: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. Results: The guidelines for the management of pemphigus were updated and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organisations.

In spite of the large heterogeneity, limited data exist on hidradenitis suppurativa (HS) phenotypes. To identify the HS phenotypes that best explain the disease heterogeneity, a cross-sectional study using latent class (LC) analysis was conducted on a cohort of patients examined at 17 dermatological centers participating in the Italian Registry of Hidradenitis Suppurativa and being enrolled between January 2015 and January 2020. Overall, 965 patients aged 32.0 ± 12.4 years (mean ± SD) were evaluated. A three-class model in LC analysis best fitted the data. Patients in LC1 (20.1%) were females, mostly obese, with a high probability of axillary‒groin (0.85) and mammary (0.59) lesions and the highest HS severity. Patients in LC2 (29.6%) were nonobese males, with moderate disease severity; with a high probability of gluteal (0.50) and genital (0.17) lesions, besides axillary‒groin involvement; and with acne and pilonidal cysts. Patients in LC3 (50%) were nonobese females with a milder disease mostly limited to axillary (0.52) and groin (0.66) areas. The stratification of patients with HS into a severe axillary‒mammary‒groin phenotype with predominantly anterior body involvement in females, an axillary‒gluteal‒groin phenotype of intermediate severity mainly affecting males in the posterior body areas, and an axillary‒groin phenotype with mildest clinical symptoms and limited skin involvement may help in optimizing HS management.

Background COVID-19 is associated with a wide range of skin manifestations. Objective To describe the clinical characteristics of COVID-19-associated skin manifestations, and explore the relationships between the six main cutaneous phenotypes and systemic findings. Methods Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical and histopathological data of 200 patients with COVID-19-associated skin manifestations. The severity of COVID-19 was classified as asymptomatic, mild, moderate, or severe. Results A chilblain-like acral pattern significantly associated with a younger age (p, There are six main COVID-19-related cutaneous phenotypes, but only the chilblain-like acral pattern significantly associated with younger age. After adjusting for patient age, there was no spectrum of COVID-19 severity in relation to cutaneous phenotypes, although the longer-lasting chilblain-like acral pattern significantly associated with milder disease.

Parkinsonism is one of the most common neurologic disorders in the aging population. Although Parkinson disease (PD) is the most common cause, there is a lengthy differential diagnosis. The diagnosis of PD hinges on recognizing its typical features, including bradykinesia, rest tremor, unilateral onset, cogwheel rigidity, and beneficial and sustained response to levodopa. Equally important is to be familiar with the "red flags," which are features not expected with PD and suggest an alternative diagnosis, usually a parkinsonian syndrome. In general, it is best to have the diagnosis confirmed by a neurologist, especially one with expertise in movement disorders.

Objective Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated that it may be associated with autoimmune connective tissue diseases. The aim of this study was to assess the frequency and clinical presentation of itch in CLE. Methods A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in various subtypes of CLE. A total of 153 patients with active CLE lesions were included. Their age ranged between 17 and 82 years (mean 49.8 ± 15.4 years), and 115 patients (75.2%) were women. The disease activity and damage were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used to measure quality of life. Results Pruritus was present in 116 (76.8%) of patients of whom half had NRS scoring equal or above 4 points indicating moderate or severe pruritus. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Sensations connected with pruritus were most frequently described as burning, tingling and like ants crawling feeling, but 31.9% patients described it as “pure itch”. More than half of patients reported that pruritus was present every day, and it was most frequent during the evenings. The pruritus scoring and the CLASI activity score were significantly correlated (r = 0.42, p = 0.0001), while no correlation was found with the CLASI damage score (p = 0.16). Both the maximum and average itch intensity were correlated with systemic lupus erythematosus (SLE) activity measured with the Systemic Lupus Erythematosus Disease Activity Index. Conclusions Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement indicate that pruritus could be an individual indicator of both SLE and CLE activity.

Granuloma annulare and interstitial granulomatous dermatitis are granulomatous dermatoses with variable clinical appearances. Granuloma annulare is associated with diabetes mellitus, metabolic syndrome, chronic infections and malignancies, while two Japanese reports described unusual cases of interstitial-type Granuloma annulare in setting of Sjogren syndrome. Interstitial granulomatous dermatitis was associated with rheumatoid arthritis, systemic lupus erythematosus and autoantibodies. We report a case-series of six patients with granuloma annulare or interstitial granulomatous dermatitis, in which half of the patients were diagnosed with Sjogren syndrome, while all of them presented ANA-positivity and the majority reported arthralgia. In many cases, granuloma annulare showed interstitial-type histology, arising challenges in differential diagnosis with interstitial granulomatous dermatitis. The overlap of clinical and histological features of granuloma annulare and interstitial granulomatous dermatitis can be explained considering them as a broad disease spectrum, including also the other forms of reactive granulomatous dermatitis. These conditions should be considered as an indicator of possible systemic disorders or other immunological dyscrasias, for which patients must be screened. Sjogren syndrome may be associated with granuloma annulare also in Caucasians.

OBJECTIVES: Several predictors of type 2 diabetes mellitus (T2DM) remission after metabolic surgery have been proposed and used to develop predictive scores. These scores may not be reproducible in diverse geographic regions with different baseline characteristics. This study aimed to identify predictive factors associated with T2DM remission after Roux-en-Y gastric bypass (RYGB) in patients with severe obesity. We hypothesized that the body composition alterations induced by bariatric surgery could also contribute to diabetes remission. METHODS: We retrospectively evaluated 100 patients with severe obesity and T2DM who underwent RYGB between 2014 and 2016 for preoperative factors (age, diabetes duration, insulin use, HbA1c, C-peptide plasma level, and basal insulinemia) to identify predictors of T2DM remission (glycemia3 ng/dL as a positive predictor of 3-year postoperative diabetes remission, which was validated in the prospective phase. There was a significant difference in the postoperative body composition changes between non-diabetic and diabetic patients only in trunk mass. CONCLUSION: Preoperative C-peptide levels can be useful for predicting T2DM remission after RYGB. Trunk mass is the most important difference in postoperative body composition changes between non-diabetic and diabetic patients.

Objective.To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease.Methods.We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 ± 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti-Jo1 and 57 non–anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody–negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 ± 17.6 yrs) for NVC measures.Results.NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p < 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP.Conclusion.NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS.

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 < 0.005). This study shows that granular deposits of IgA represent a low sensitive, but highly specific, cutaneous marker of coeliac disease independent of dermatitis herpetiformis.

Introduction Dermatitis herpetiformis (DH) is a chronic, pruritic, gluten-induced skin disorder characterized by subepidermal granular IgA deposition and a variable degree of enteropathy identical to that seen in coeliac disease. So far, there has been no European consensus about the management of DH. Methods The guidelines were created by small subgroups of a guideline committee consisting of 26 specialists from various medical fields and one patients' representative. The members of the committee then discussed the guidelines and voted for the final version at two consensus meetings. The guidelines were developed under the support of the European Academy of Dermatology and Venereology (EADV) and in collaboration with the European Dermatology Forum (EDF). Results The guidelines summarize evidence-based and expert-based recommendations (S2 level) for the management of DH (see Appendix). Conclusion These guidelines will improve the quality of management of DH and support dermatologists in their diagnostic and therapeutic decisions.

Koebner phenomenon, also known as isomorphic response, is the appearance of active skin lesions in sites of epidermal injury. This manifestation is characteristic of different dermatological diseases, such as lichen planus, vitiligo and psoriasis. We present the case of a psoriatic patient who experienced Koebner phenomenon after Mantoux test, followed by eruption of generalized plaque psoriasis.

Management of refractory skin lesions in patients with lupus erythematosus involves combinations of local measures and systemic agents requiring adjustment to activity and development of the disease. The treatment options are fairly similar for the different cutaneous manifestations; however, no drugs have been licensed specifically for the treatment of skin lesions in this disease. Therefore, the aim of the European guideline was to achieve a broad consensus on treatment strategies for patients with cutaneous lupus erythematosus (CLE) by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). Standard treatment of CLE includes preventive measures such as smoking cessation and photoprotection. Ultraviolet (UV) A and B light is one of the most important risk factors for CLE, clearly documented by photoprovocation studies in large patient cohorts. In the past years, several trials have been performed to investigate the preventive effect of sunscreens in patients with UV-induced CLE. A randomised controlled trial demonstrated that the application of a broad-spectrum sunscreen with a high protection factor prevents UV-induced skin lesions under standardised conditions. First-line treatment options in CLE include topical corticosteroids or calcineurin inhibitors. Currently available topical calcineurin inhibitors (0.03% and 0.1% tacrolimus ointment, 1% pimecrolimus cream) have been licensed for the use in patients with atopic dermatitis. The major advantage of these agents is their better safety profile when compared to topical corticosteroids. A multicentre, randomised, double-blind, vehicle-controlled trial showed significant improvement for oedema and erythema of CLE lesions using 0.1% tacrolimus ointment compared to the vehicle. In patients with disfiguring and widespread disease, systemic agents need to be applied. The first-line systemic treatment is antimalarials, such as hydroxychloroquine, chloroquine or quinacrine, which are particularly recommended in patients with a high risk of scarring and/or the development of systemic disease. In addition, systemic corticosteroids are recommended as first-line treatment in highly active and/or severe CLE. Second- and third-line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy-refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B-cell- or interferon alpha-targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE. In 2011, the monoclonal antibody belimumab, a B lymphocyte stimulator-specific inhibitor, was introduced for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. Currently, a validated skin score is used to confirm the efficacy of belimumab on mucocutaneous manifestations. In summary, there is a high unmet need for new therapeutic strategies, such as B-cell- or interferon-targeted agents, focusing on cutaneous manifestations in lupus erythematosus. Therefore, innovative designs of randomised controlled trials are warranted to develop new therapeutic options for patients with refractory skin manifestations in this disease. Case 1: 40-year-old man with SLE and painful erythemato-violaceous lesions Marzia Caproni A 40-year-old man was diagnosed with systemic lupus erythematosus (SLE) in 2013 based on photosensitivity, Raynaud’s phenomenon, positive direct Coombs test, ANA, anti-dsDNA, Sm, Ro, La, RNP antibodies and low complement, followed by malar rash and discoid lesions on the ears. He started hydroxychloroquine (HCQ) 400 mg/day, nicotinamide 500 mg/day, topical corticosteroids and calcineurin inhibitors with benefit, followed by reactivation of malar rash, worsening of immunological parameters, proteinuria and lupus nephritis two years later. Prednisone 25 mg/day and mycophenolate mofetil (MMF) 640 mg/day were added with good clinical and laboratory control. In March 2018 he was hospitalised because of suspected macrophage activation syndrome triggered by cytomegalovirus and MMF was withdrawn. As lupus reactivated, in May 2018 he restarted MMF 320 mg/day with prednisone 25 mg/day and HCQ 200 mg/day. In August 2018, rituximab was administered because of the development of sensory neuropathy with no improvement, thus he underwent intravenous immune globulin treatment with control. In 2020, he developed painful erythemato-violaceous lesions associated with small bullae and ulcers on the distal phalanges of the fingers and toes and of the tip of the nose. Skin lesions were consistent with chilblain lupus. Topical corticosteroid was added. Systemic treatments were replaced by belimumab. Discussion Points Specific and non-specific skin manifestations during SLE course Cutaneous lupus erythematosus (CLE) guidelines Chilblain lupus: differential diagnosis at the time of Covid-19 Case 2: 35-year-old female with SLE and erythemato-desquamative plaques Marzia Caproni A 35-year-old female was diagnosed with SLE in 2013 on the basis of discoid lesions of the face and head, photosensitivity, ANA positivity, lymphadenopathy, hypocomplementemia, leukopenia, low-grade fever and diffuse arthralgias. Comorbidities included Hashimoto’s thyroiditis and fybromyalgia under L-tyroxine, baclofen and escitalopram treatment. She started HCQ 400 mg/day and prednisone 25 mg/day, tapering to 5 mg/day with initial control. After 2 years of treatment arthralgias worsened as well as skin lesions and laboratory findings. On examination, atrophic painful plaque of the scalp and erythemato-desquamative plaques on the face were revealed. Topical and IV corticosteroids were added without improvement. Patient also underwent methotrexate, cyclosporine, mycophenolate, rituximab and azathioprine treatment without improvement. We introduced mepacrine 100 mg/day with skin lesion improvement. Due to the difficulty in finding the drug, the patient stopped the treatment with reactivation of the skin manifestations and systemic involvement. We started belimumab 660 mg IV with HCQ 400 mg/day, prednisone 5 mg/day, azathioprine 50 mg/day and duloxetine 60 mg/day with control. Discussion Points Discoid lupus erythematosus: clinical and histopathological findings CLE guidelines: topical treatments of discoid lupus erythematosus CLE guidelines: mepacrine in recalcitrant cutaneous lupus erythematosus Belimumab and skin lesions in SLE Learning Objectives Discuss specific and non-specific skin manifestations of SLE Describe optimal clinical management of skin lupus in line with CLE guidelines and the role of biologic therapy Explain the challenges of differential diagnosis in patients with CLE References Fairley JL, Oon S, Saracino AM, Nikpour M. Management of cutaneous manifestations of lupus erythematosus: A systematic review. Semin Arthritis Rheum 2020;50:95–127. Chasset F, Frances C. Current concepts and future approaches in the treatment of cutaneous lupus erythematosus: A comprehensive review. Drugs 2019;79:1199–1215. Kuhn A, Aberer E, Bata-Csorgő Z, Caproni M, Dreher A, Frances C, Glaser R, Klotgen HW, Landmann A, Marinovic B, Nyberg F, Olteanu R, Ranki A, Szepietowski JC, Volc-Platzer B. S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol 2017;31:389–404.

Purpose of review Cutaneous vasculitis reflects a spectrum ranging from skin limited to severe systemic forms. To date, there is still no generally acknowledged nomenclature for cutaneous vasculitis. This review aims to summarize the recent advances in the nomenclature of cutaneous vasculitis. Recent findings The most widely adopted vasculitis classification system is the one of 2012 Revised Chapel Hill Consensus Conference (CHCC) which represent not such a classification but a nomenclature system that name vasculitis on the basis of the size of the vessel affected. The CHCC 2012 did not deal with the special features of cutaneous vasculitis and did not explicitly discuss the presence of skin-limited or skin-dominant forms of vasculitis. Therefore, a consensus group was formed to propose an Addendum to CHCC 2012, focusing on cutaneous vasculitis. The Addendum better clarify the main aspects of some single-organ vasculitis, including IgM/IgG vasculitis, nodular vasculitis, erythema elevatum et diutinum and recurrent macular vasculitis in hypergammaglobulinemia. Moreover, it differentiated normocomplementemic from hypocomplementemic urticarial vasculitis. Finally, it recognized cutaneous polyarteritis nodosa as a distinct subtype of polyarteritis nodosa. Summary Classification criteria are useful tools to standardize names and definitions for cutaneous vasculitis; however, they do not represent diagnostic criteria. Collaborative efforts are still needed to get a shared classification and valid diagnostic criteria for cutaneous vasculitis.

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.

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients blister may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions, and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on the quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. This guideline for the treatment of bullous pemphigoid has been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Dermatology Forum (EDF) in collaboration with the European Academy of Dermatology and Venereology (EADV). It summarizes evidence-based and expert-based recommendations (S2 level).

Pemphigus is a life threatening autoimmune epidermal blistering disease involving skin and mucous membranes. Pemphigus usually affects middle age men and women involving oral mucosa first and then spreading on the skin. It is caused by the presence of autoantibodies (IgG and less frequently by IgA) directed against desmogleins, and/or other glycoproteins that plays a critical role in cell-cell attachment. Upon a predisposing genetic background, different agents have been shown to act as triggers for the pathogenesis of pemphigus. This guideline for the diagnosis and treatment of pemphigus has been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations (S2 level).

Background: Psoriasis (Ps) is a chronic systemic autoimmune disease associated with pruritus in 64–98% of patients. However, few modestly sized studies assess factors associated with psoriatic pruritus. Objective: To investigate factors associated with Ps pruritus intensity. Methods: Psoriasis patients 18years or older seen in one of 155 centres in Italy between September 2005 and 2009 were identified from the Italian PsoCare registry. Patients without cutaneous psoriasis and those with missed information on pruritus were excluded. Results: We identified 10802 patients, with a mean age 48.8±14.3years. Mild itch was present in 33.2% of patients, moderate in 34.4%, severe in 18.7% and very severe in 13.7%. Higher itch intensity was associated with female gender, lower educational attainment compared to university degree, pustular psoriasis, psoriasis on the head, face, palmoplantar areas, folds and genitalia, more severe disease, disease duration

Objective. Our objective was to characterize the demographic information, clinical features, and laboratory data of patients with dermatitis herpetiformis (DH). Methods. In this multicentre cross-sectional study, consecutive patients with a new diagnosis of DH that referred to nine different Italian centers between 2011 and 2016 were characterized assessing demographic, clinical and laboratory findings, and evaluating gender and age differences across selected variables. Results. A total of 151 patients were included. Among them, 81 (53.6%) were males and 70 (46.4%) were females, with a male to female ratio of 1.2 : 1. The median age at the time of diagnosis was 41 years (range 0–85). Males had a significant longer diagnostic delay if compared to females (9 vs. 3 months, respectively; p=0.01). Direct immunofluorescence was positive in 94.7% of the patients, while duodenal biopsy showed partial to total villous atrophy in 70.1% of patients. All the females resulted positive to at least one of the antibodies tested, while a total of 12 male patients (10.5%) tested negative to celiac-specific antibodies. Female patients had a high rate (14.1%) of autoimmune thyroiditis. Conclusions. Our study confirmed some of the most relevant data regarding DH that have been previously reported in the literature. In addition, we found a reduced diagnostic delay in females with respect to males, possibly related to the higher sensitivity of serologic testing in females with DH compared to males. Finally, we demonstrated that intestinal involvement could be severe in patients with DH and that females should be tested for thyroiditis.

Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lübeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases. Considerable advances have been made in describing incidences and prevalences of these diseases and linking comorbidities with autoantibody reactivities and clinical variants, for example, dipeptidyl peptidase-IV inhibitor-associated noninflammatory bullous pemphigoid. Although new entities are still being described, diagnosis of most autoimmune blistering diseases can now be achieved using standardized and widely available serological test systems. Various experimental mouse models of pemphigus and pemphigoid disease are increasingly being used to understand mechanisms of central and peripheral tolerance and to evaluate more specific treatment approaches for these disorders, such as molecules that target autoreactive T and B cells and anti-inflammatory mediators, that is, dimethyl fumarate, phosphodiesterase 4, and leukotriene B4 inhibitors in pemphigoid disorders, and chimeric antigen receptor T cells in pemphigus. Very recent experimental data about the immunopathology and the determinants of autoantibody formation and keratinocyte susceptibility in pemphigus were discussed. With regard to cellular mechanisms leading to the loss of cell-cell adhesion, new ideas were shared in the field of signal transduction. Major steps were taken to put the various partly contradictory and controversial findings about the effects of pemphigus autoantibodies and other inflammatory mediators into perspective and broaden our view of the complex pathophysiology of this disease. Finally, two investigator-initiated multicenter trials highlighted doxycycline and dapsone as valuable medications in the treatment of bullous pemphigoid. © 2017 The Authors

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.

Granuloma annulare (GA) and interstitial granulomatous dermatitis (IGD) are granulomatous dermatoses with variable clinical appearances. GA is associated with diabetes mellitus, metabolic syndrome, chronic infections, and malignancies, while two Japanese reports described unusual cases of interstitial-type GA in setting of Sjogren syndrome. IGD was associated with rheumatoid arthritis, systemic lupus erythematosus, and autoantibodies. We report a case series of six patients with GA or IGD. Half of the patients were diagnosed with Sjogren syndrome, while all of them presented ANA positivity and the majority reported arthralgia. In many cases, GA showed interstitial-type histology, arising challenges in differential diagnosis with IGD. The overlap of clinical and histological features of GA and IGD can be explained considering them as a broad disease spectrum, including also the other forms of reactive granulomatous dermatitis. These conditions should be considered as an indicator of possible systemic disorders or other immunological dyscrasias, for which patients must be screened. Sjogren syndrome may be associated to GA also in Caucasians.

BACKGROUND Studies specifically conducted to assess gender differences in genital lichen sclerosus (GLS) are not available. This multicenter study aimed to identify possible gender-related differences on GLS clinical features, history and course, through collecting data from a large mixed-sex sample of patients. METHODS This was a cross-sectional study on 729 subjects (53.8% females, 46.2% males) affected with GLS, consecutively observed within a network of 15 Italian dermatology units. The following information was specifically collected: clinical features and severity of symptoms related to GLS, extragenital involvement, previous therapies, diagnostic suspicion at referral, type of referring physicians, development of genital squamous-cell carcinoma (SCC). RESULTS Females complained of symptoms more frequent and severe than men; pallor and scarring-sclerosis-atrophy were the most frequent features without gender differences; itching- related signs were more frequent in females than in males as well as extragenital involvement; prior to receiving a definitive diagnosis, females received treatment more frequently than males; 40% of patients were referred with a misdiagnosis; the highest rate of correct suspected diagnosis at referral came from dermatologists than from other physicians; duration of the disease was found to predispose to SCC development. CONCLUSIONS Our findings highlighted several gender differences on clinical presentation and symptom profile of GLS. In spite of some characteristic features, misdiagnosis at referrals was frequent.

Estudo de corte transversal, realizado entre outubro de 2016 a dezembro de 2017. Avaliou-se 147 pacientes de ambos os sexos, com idade entre 70 anos, com diagnóstico de asma brônquica (AB) e que faziam uso de dispositivo inalatório (DI) há no mínimo um (1) ano e regularmente por pelo menos três (3) meses, estando em acompanhamento médico em ambulatórios do Sistema Único de Saúde (SUS). O autoconhecimento foi avaliado através de um questionário individual semiestruturado. Entre os entrevistados, 58% (IC95% 49,8-65,8) eram do sexo masculino e a faixa etária mais frequente foi 0,05). A maioria dos entrevistados apresentou um conhecimento entre “satisfatório” a “bom/ótimo” acerca dos métodos de preservação e limpeza dos DIs, mas boa parte apresentou “desconhecimento parcial” quanto à execução correta da técnica para o uso dos DIs, ID ou IPS.

BACKGROUND: Anti-nuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE), with variable frequency depending on skin subtype. However, specific data based on large case-series on the pathogenetic, diagnostic and prognostic meaning of such autoantibodies are still lacking. OBJECTIVE: To characterize the correlations between CLE subtypes as well as LE-non-specific skin lesions and their autoantibody pattern. METHODS: Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE-non-specific skin lesions were analysed. Differences in age, sex, clinical features and autoantibody profile were evaluated in each LE subgroup. RESULTS: Anti-nuclear antibodies (P < 0.0001), anti-dsDNA (P < 0.0001), ENA (P = 0.001), anti-Sm (P = 0.001), anti-RNP (P = 0.004) and anti-histone (P = 0.005) antibodies were associated with SLE. A strong association between ANA (P < 0.0001) and anti-dsDNA (P < 0.0001) and female gender was also found: positive ANA and positive anti-dsDNA had a higher prevalence among females. Chronic CLE resulted to be negatively associated with ENA (OR = 0.51, P < 0.0001), anti-Ro/SSA (OR = 0.49, P < 0.0001) and anti-dsDNA (OR = 0.37, P < 0.0001). Intermittent CLE resulted to be negatively associated with ENA (OR = 0.50, P = 0.007) and ANA (OR = 0.61, P = 0.025). Subacute CLE resulted to be associated with ENA (OR = 5.19, P < 0.0001), anti-Ro/SSA (OR = 3.83, P < 0.0001), anti-Smith (OR = 2.95, P = 0.004) and anti-RNP (OR = 3.18, P = 0.007). Acute CLE resulted to be strongly associated with anti-dsDNA (OR = 6.0, P < 0.0001) and ANA (OR = 18.1, P < 0.0001). LE-non-specific skin lesions resulted to be significantly associated with systemic involvement. Livedo reticularis was significantly associated with ENA (P = 0.007) and anti-Ro/SSA (P = 0.036). Palpable purpura and periungual telangiectasia were significantly associated with ANA. CONCLUSION: According to our findings, some well-known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE-non-specific skin lesions was highlighted. A strict association between anti-ENA and anti-Ro/SSA antibodies and livedo reticularis, ANA and palpable purpura, and ANA and periungual telangiectasia was evidenced.

Background The impact of adverse events (AEs) of antiepileptic drugs (AEDs) have an impact on compliance and dropouts. We compared tolerability of AEs of AEDs among patients with migraine, epilepsy, or both. Methods Overall, 335 patients (epilepsy (n = 142), migraine (n = 131), and both (n = 62)), were evaluated with the Liverpool Adverse Events Profile (LAEP) to assess the magnitude, profile and occurrence rate of the AEs of valproate, topiramate, and lamotrigine. Results AEs were significantly more common with topiramate treatment (71.0%) and among migraineurs (69.5%), the latter being more prone to discontinue AEDs (46.6%). The profile of AEs with topiramate and valproate differed among groups. Moreover, treatment with both topiramate and valproate was associated, for all groups, with a worse tolerability profile compared to lamotrigine. Conclusion Our data suggest a specific drug and disease AE profile of AEDs. Specifically, migraineurs are the most affected by AEs, even though they receive very low dosages of AEDs. This finding might be considered a clinical implication of central sensitization mechanisms. Both the profile and tolerability of AEs, highly influencing quality of life, depended on the underlying conditions, and deeply impacted on treatment dropout. Therefore, before starting, switching or stopping AED treatment, all options need to be considered.

Objetivo: Avaliar condicoes microbiologicas do preparo de formulas lacteas infantis no lactario do Hospital Escola de Itajuba. Materiais e Metodos: Foram realizadas contagens de microrganismos mesofilos viaveis, bolores e leveduras, Staphylococcus aureus , Bacillus cereus , coliformes totais e de origem fecal e Escherichia coli . Resultados: Todas as amostras de formulas lacteas se encontraram aptas para o consumo humano. O crescimento de microrganismos foi superior ao esperado em algumas amostras da colher e do copo do liquidificador utilizados para o preparo das formulas. Houve a presenca de mesofilos ao primeiro dia, o que indica condicoes insatisfatorias na producao das formulas, como armazenamento e temperatura; nao houve presenca de coliformes fecais, o que indica boa pratica de higiene quanto a manipulacao das mesmas, e de acordo com a literatura, esses podem ser considerados os piores indicadores de condicoes higienico-sanitarias no manuseio de alimentos. O crescimento nos utensilios revela falha na higienizacao dos mesmos, oferecendo riscos aos usuarios dos servicos do lactario. Os resultados mostram que a boa pratica de medidas higienico-sanitarias promove qualidade das formulas. Conclusao: O uso de utensilios plasticos aumenta o risco de contaminacoes e poderia ser substituido por objetos metalicos, garantindo melhor qualidade dos produtos. Palavras-chave: Lactario, Formulas Infantis, Microrganismos, Seguranca Alimentar ABSTRACT Objective: To evaluate microbiological preparation of infant milk formulas in lactary of Hospital Escola de Itajuba. Material and Methods: We performed viable mesophilic counts, molds and yeast, Staphylococcus aureus, Bacillus cereus , total coliforms of fecal origin and Escherichia coli. Results: All samples of infant formula are fit for human consumption in accordance with current legal resolution. It occurred growth of microorganisms higher than expected in some samples from the spoon and from the blender cup used for the preparation. Presence of mesophilic on the first day indicates unsatisfactory conditions in the production of the formulas, like storage and temperature; the analyses of fecal coliforms indicates good hygiene practice in the production and according to the literature, it can be considered the worst indicators of sanitary conditions in food handling. Growth in utensils also reveals failure to sanitize this objects, which offers risk to the users of lactary services. The results are in agreement with the literature, and show that the good practice of hygiene and sanitary measures promote quality in formulas. Conclusion : It can be concluded that the use of plastic utensils increases the risk of contamination and should be replaced by metal objects in order to ensure highest quality products. Keywords: Lactary, Infant Formulas, Microrganisms, Food Safety

ObjectiveWe evaluated the effects of grape juice (Vitis labrusca L.) on dyslipidemia, resistance to insulin, and left ventricular hypertrophy (LVH) in mice homozygous for the absence of the LDL receptor gene (LDLr -/-) under a hyperlipidemic diet.MethodologyWe divided 30 male mice (3 months old) into three groups (n = 10); the HL group was fed a high-fat diet, the HLU group received a high-fat diet and 2 g/kg/day of grape juice, and the HLS group was fed a high-fat diet and simvastatin (20 mg/kg/day). We assessed the blood pressure profile of the mice. We also determined the levels of C-reactive protein (CRP) and lipid profile, glycemic and insulinemic profiles, and calculated the HOMA-IR. Cardiomyocyte hypertrophy, interstitial collagen deposit, and the expression of CD40 ligand (CD40L) and metalloproteinases 2 and 9 were assessed immunohistologically.ResultsAfter 60 days, the mice treated with grape juice showed similar results as those of the group treated with simvastatin. The use of grape fruit attenuated dyslipidemia and insulin resistance and significantly increased the levels of high cholesterol density lipoproteins (HDLc). The antioxidant potential of phenolic compounds associated with the increase in HDLc levels in the mice of the HLU group prevented the development of LVH and arterial hypertension since it inhibited the inflammatory response induced by the CD40 pathway and its ligand CD40L. Consequently, there was a lower expression of MMP-2 and MMP-9 and lower serum levels of CRP.ConclusionGrape juice has a hypolipidemic and cardiac protective potential, presenting a similar effect as that of simvastatin through a direct antioxidant action of phenolic compounds, or indirectly, via antioxidant action and anti-inflammatory activity of the HDLc. These results suggest that grape juice is a functional food possessing a high potential to prevent cardiovascular diseases.

Psoriasis (PSO) is traditionally defined as an immune-mediated, inflammatory dermatological disease characterized by a chronic-relapsing course and associated with multifactorial inheritance (genetic predisposition and influence of various environmental factors). Considered until recently a dermatological disease only, today PSO is correctly known as a systemic one because of the involvement of multiple organs with important impact on social life and relationships. PSO is found in the 0.3-4.6% of the world's population, while its prevalence in the Italian population is estimated at 2.8%. Therefore, if we consider that in Tuscany more than 100,000 people out of 3,672,202 suffer of psoriasis, it is of paramount importance to focus on a shared clinical and therapeutic protocol to manage the disease. With the aim of ensuring diagnostic-therapeutic suitability, high levels of care and standardization of treatment, a unique clinical-therapeutic management model has been developed and validated in Tuscany, involving all accredited regional dermatological centers. Among the possible alternatives to be implemented in the treatment of patients with mild, moderate-severe psoriasis, UVBnb phototherapy is widely used alone or in association with other systemic and non-systemic devices. Despite this, there is still no universally shared therapeutic protocol. In this context the CO.FO.TO working group (Consensus Fototerapia Toscana) is born with the aim of defining and validating the main guidelines in the use of phototherapy with UVBnb in psoriasis; the guidelines are based both on the real-life experience of the different centers of reference in the region and on the revision of the recent literature.

Epilepsy and pain, especially headache disorders, including migraine, can frequently co-occur. Over the last decades, increasing evidences pointed to cortical hyperexcitability, spreading depression, and ion channels abnormalities as common substrates of pain and epilepsy. Nevertheless, several questions remain unanswered, with specific focus on phenotypic-genotypic correlations of several mutations, including those associated with familial hemiplegic migraine, where epilepsy prevalence depends on the region of the ion channel affected by the mutation. In this chapter we present evidences regarding shared mechanisms of epilepsy and pain, highlighting effects of antiepileptic drugs as therapeutic targets for both disorders.

Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59 % females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95 % confidence interval [CI]: 11.1-23.2), 56.7 (95 % CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95 % CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95 % CI: 2.73-5.65), higher during the acute phase (14.86, 95 % CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95 % CI: 1.07-7.04) for ABSIS > 48 vs ABSIS < 28, and 2.56 (95 % CI: 1.00-6.70) in patients with >= 2 concomitant risk factors. In conclusion, BP patients have a 15-fold increased VTE risk during acute phase, proportional to disease severity and heightened by concomitant risk factors. Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59 % females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95 % confidence interval [CI]: 11.1-23.2), 56.7 (95 %CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95 %CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95 %CI: 2.73-5.65), higher during the acute phase (14.86, 95 %CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95 %CI: 1.07-7.04) for ABSIS > 48 vs ABSIS

Specific dermatoses of pregnancy are skin disorders that occur specifically during or immediately after pregnancy and cannot be found in non-pregnant patients. According to the current consensus, they include atopic eruption of pregnancy (AEP), polymorphic eruption of pregnancy (PEP), pemphigoid gestationis (PG), and intrahepatic cholestasis of pregnancy (ICP). The diagnosis of specific dermatoses of pregnancy can be challenging due to their variation in clinical presentation; moreover, the tests currently available do not always provide the clue for the diagnosis. However, some distinctive features may be helpful to differentiate between such entities. Accordingly, the knowledge of specific dermatoses of pregnancy and of their management is critical, since their early recognition may allow to provide care for the mother and prevent potential increased fetal risk. In fact, while AEP and PEP do not affect maternal and fetal prognosis, PG and, mainly, ICP are associated to maternal complications as well as the risk of fetal loss. In this paper, the epidemiology, pathogenesis, clinical features as well as management of AEP and PEP are reviewed in detail, while PG is described in another article of this issue. Moreover, the main features of ICP, which cannot be considered a primarily skin disease but may be managed first by dermatologists, are reported.