S2k guidelines on diagnosis and treatment of linear IgA dermatosis initiated by the European Academy of Dermatology and Venereology.

INTRODUCTION: Linear IgA dermatosis (LAD) is a rare subepidermal autoimmune bullous disease (AIBD) defined by predominant or exclusive immune deposits of immunoglobulin A at the basement membrane zone of skin or mucous membranes. This disorder is a rare, clinically and immunologically heterogeneous disease occurring both in children and in adults. The aim of this project is to present the main clinical features of LAD, to propose a diagnostic algorithm and provide management guidelines based primarily on experts' opinion because of the lack of large methodologically sound clinical studies. METHODS: These guidelines were initiated by the European Academy of Dermatology and Venereology (EADV) Task Force Autoimmune Bullous Diseases (AIBD). To achieve a broad consensus for these S2k consensus-based guidelines, a total of 29 experts from different countries, both European and non-European, including dermatologists, paediatric dermatologists and paediatricians were invited. All members of the guidelines committee agreed to develop consensus-based (S2k) guidelines. Prior to a first virtual consensus meeting, each of the invited authors elaborated a section of the present guidelines focusing on a selected topic, based on the relevant literature. All drafts were circulated among members of the writing group, and recommendations were discussed and voted during two hybrid consensus meetings. RESULTS: The guidelines summarizes evidence-based and expert opinion-based recommendations (S2 level) on the diagnosis and treatment of LAD. CONCLUSION: These guidelines will support dermatologists to improve their knowledge on the diagnosis and management of LAD.

Serum reactivity in dermatitis herpetiformis: an international multicentre study.

BACKGROUND: Dermatitis herpetiformis (DH) is a rare gluten-induced skin disorder characterized predominantly by IgA autoantibodies against endomysium, tissue transglutaminase (TG2/tTG), epidermal transglutaminase (TG3/eTG) and deamidated gliadin. To date, circulating autoantibody reactivity has not been systematically described. OBJECTIVES: Characterization of serum reactivities in DH. METHODS: This multicentre international study analysed sera from 242 patients with DH taken at the time of initial diagnosis. DH-specific IgA and IgG serum autoantibodies were analysed by indirect immunofluorescence (IF) on monkey oesophagus, and by enzyme-linked immunosorbent assay (ELISA) based on recombinant TG2/tTG, TG3/eTG and deamidated gliadin (GAF3X). RESULTS: IgA indirect IF microscopy on monkey oesophagus revealed the highest reactivity (84.3%; specificity 100%) followed by IgA TG2/tTG ELISA (78.5%, specificity 99.0%), IgA TG3/eTG ELISA (72.7%, specificity 95.0%) and IgA GAF3X ELISA (69.0%, specificity 98.5%). CONCLUSIONS: Serum IgA and IgG autoantibodies against endomysium, TG2/tTG, TG3/eTG and deamidated gliadin are highly prevalent in DH. Indirect IF microscopy on monkey oesophagus (IgA) provides the highest diagnostic accuracy that can be further enhanced by 4.5% when combined with IgA TG2/tTG ELISA.

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.

Gliptin-associated bullous pemphigoid shows peculiar features of anti-BP180 and -BP230 humoral response: Results of a multicenter study.

BACKGROUND: Recently, several case-control studies demonstrated an association between gliptins and bullous pemphigoid (BP) occurrence. However, data on the clinical and immunologic features of gliptin-associated bullous pemphigoid (GABP) are controversial. OBJECTIVE: This study aimed to clinically and immunologically characterize a large cohort of GABP patients to get an insight into the pathophysiology of this emerging drug-induced variant of BP. METHODS: Seventy-four GABP patients were prospectively enrolled and characterized from 9 different Italian dermatology units between 2013 and 2020. RESULTS: Our findings demonstrated the following in the GABP patients: (1) a noninflammatory phenotype, which is characterized by low amounts of circulating and skin-infiltrating eosinophils, is frequently found; (2) immunoglobulin (Ig)G, IgE, and IgA humoral responses to BP180 and BP230 antigens are reduced in frequency and titers compared with those in patients with idiopathic BP; (3) IgG reactivity targets multiple BP180 epitopes other than noncollagenous region 16A. LIMITATIONS: A limitation of the study is that the control group did not comprise only type 2 diabetes mellitus patients with BP. CONCLUSION: GABP patients show peculiar features of anti-BP180 and -BP230 humoral responses, laying the foundation for diagnostic improvements and getting novel insights into understanding the mechanism of BP onset.

Neutrophil Gelatinase-Associated Lipocalin as Potential Predictive Biomarker of Melanoma and Non-Melanoma Skin Cancers in Psoriatic Patients: A Pilot Study.

Background: Studies have demonstrated a higher risk of nonmelanoma skin cancers (NMSC) and a modestly increased melanoma risk in patients with psoriasis. To date, no biomarkers predictive of evolution have been identified yet. Methods: The aim of this prospective case-control study was to investigate the potential role of neutrophil gelatinase-associated lipocalin (NGAL) as a predictive biomarker of skin cancers in psoriatic patients. Patients with a diagnosis of psoriasis were enrolled, as well as healthy subjects and patients with skin cancers as controls. Plasma protein expression of NGAL, metalloproteinases (MMP)-2, and MMP-9 was performed by an enzyme-linked immunosorbent assay (ELISA). In all the patients who developed skin cancer at follow-up, NGAL, MMP-2, and MMP-9 serum levels were dosed again. Results: Plasma NGAL levels were significantly higher in psoriatic patients with NMSC than without (182.3 ± 36.6 ng/mL vs. 139.9 ± 39.3 ng/mL) (p < 0.001). Plasma NGAL levels were significantly higher (p < 0.00001) in patients with psoriasis and NMSC than in patients with skin tumors without psoriasis (182.3 vs. 122.9). Patients with psoriasis who developed NMSC at follow-up showed increased plasma MMP-9 levels. Conclusion: NGAL seems to play a role in the pathogenesis of NMSC but not melanoma in patients with psoriasis.

Clinical characteristics of itch in cutaneous lupus erythematosus: A prospective, multicenter, multinational, cross-sectional study.

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.

The clinical spectrum of COVID-19-associated cutaneous manifestations: An Italian multicenter study of 200 adult patients.

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 among the 6 main cutaneous phenotypes and systemic findings. METHODS: Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical, and histopathologic 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 was significantly associated with a younger age (P < .0001) and, after adjusting for age, significantly associated with less severe COVID-19 (P = .0009). However, the median duration of chilblain-like lesions was significantly longer than that of the other cutaneous manifestations taken together (P < .0001). Patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among the patients with cutaneous manifestations other than chilblain-like lesions, but only the confluent erythematous/maculo-papular/morbilliform phenotype was significantly associated with more severe COVID-19 (P = .015), and this significance disappeared after adjustment for age. LIMITATIONS: Laboratory confirmation of COVID-19 was not possible in all cases. CONCLUSIONS: After adjustment for age, there was no clear-cut spectrum of COVID-19 severity in patients with COVID-19-related skin manifestations, although chilblain-like acral lesions were more frequent in younger patients with asymptomatic/pauci-symptomatic COVID-19.

Granular Deposits of IgA in the Skin of Coeliac Patients Without Dermatitis Herpetiformis: A Prospective Multicentric Analysis.

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.

Autoantibody Profile of a Cohort of 54 Italian Patients with Linear IgA Bullous Dermatosis: LAD-1 Denoted as a Major Auto-antigen of the Lamina Lucida Subtype.

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.

An update on the nomenclature for cutaneous vasculitis.

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.

Granular IgA Deposits in the Skin of Patients with Coeliac Disease: Is it Always Dermatitis Herpetiformis?

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.

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus.

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real-life-based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real-life setting.