Introduction: The major obstacle to develop innovative immune therapies in rare bullous pemphigoid (BP) is the identification of continuous peptide epitopes displaying high affinity binding to autoreactive B-cells receptors in the patient's blood. Using peptide-CAR T-cells, one can deliver more precise immune modulation than Rituximab, which gives largely non-specific B-cell depletion and incomplete remission. Methods: Prospective serum samples of thirty-three BP patients, 16 female 17 male, median age 85 years (range 64-90) having confirmed direct immune fluorescence (DIF) IgG and/or complement C3 deposition clinically associated with blisters, erosion and/or lesions on limbs and trunk were tested in enzyme linked immunoassay (MBL ELISA BP180 IgG and BP230 IgG). Thirteen serum with BP180 IgG >60 U/mL or BP230 IgG > 60 U/mL and two controls were screened for reactivity in a 600 peptide array of 17mer peptides printed in duplicate derived from overlapping sequences of NC16-BP180, BP180C-terminus and BP230 C-terminus and control viruses. Results: Positive BP180 IgG in 24 of 33 (73%) and positive BP230 IgG in 19 of 33 (58%) BP patients gave ELISA reactivity with mean values of 56 U/mL (95% CI 39-74 U/mL) and mean 48 U/mL (95% CI 30-66 U/mL), respectively. The peptide array fluorescent intensities reveal specific reactivity against 13 continuous epitopes (nine BP180, four BP230). The autoantibody profile of a larger BP cohort by ELISA, and binding of fluorescent peptides to patient CD19 B cells by flow cytometry are under evaluation. Conclusions: Preliminary findings underscore the potential of BP180-BP230 peptide ELISA to have greater sensitivity than the recombinant auto-antigen based commercial ELISA. Further studies on BP180 and BP230 peptide epitopes which selectively target autoreactive B cells in BP patients are warranted to develop novel therapeutics; CAR-T cells and auto-monoclonal antibodies (AutoMAbs).

Bullous pemphigoid (BP) 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, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo‐like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life.

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.

Journal of the European Academy of Dermatology and VenereologyVolume 35, Issue 8 p. e501-e503 Letter to the Editor Dupilumab for the treatment of recalcitrant eosinophilic dermatosis of haematologic malignancy R. Maglie, Corresponding Author R. Maglie bobmaglie88@gmail.com orcid.org/0000-0002-5106-4042 Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy *Correspondence: R. Maglie. E-mail: bobmaglie88@gmail.comSearch for more papers by this authorF. Ugolini, F. Ugolini Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Florence, ItalySearch for more papers by this authorF. De Logu, F. De Logu Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, ItalySearch for more papers by this authorS. Simi, S. Simi Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Florence, ItalySearch for more papers by this authorS. Senatore, S. Senatore Department of Health Sciences, Section of Dermatology, University of Florence, Florence, ItalySearch for more papers by this authorF. Montefusco, F. Montefusco Department of Health Sciences, Section of Dermatology, University of Florence, Florence, ItalySearch for more papers by this authorR. Nassini, R. Nassini Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, ItalySearch for more papers by this authorD. Massi, D. Massi Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Florence, ItalySearch for more papers by this authorE. Antiga, E. Antiga orcid.org/0000-0001-7787-4433 Department of Health Sciences, Section of Dermatology, University of Florence, Florence, ItalySearch for more papers by this author R. Maglie, Corresponding Author R. Maglie bobmaglie88@gmail.com orcid.org/0000-0002-5106-4042 Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy *Correspondence: R. Maglie. E-mail: bobmaglie88@gmail.comSearch for more papers by this authorF. Ugolini, F. Ugolini Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Florence, ItalySearch for more papers by this authorF. De Logu, F. De Logu Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, ItalySearch for more papers by this authorS. Simi, S. Simi Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Florence, ItalySearch for more papers by this authorS. Senatore, S. Senatore Department of Health Sciences, Section of Dermatology, University of Florence, Florence, ItalySearch for more papers by this authorF. Montefusco, F. Montefusco Department of Health Sciences, Section of Dermatology, University of Florence, Florence, ItalySearch for more papers by this authorR. Nassini, R. Nassini Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, ItalySearch for more papers by this authorD. Massi, D. Massi Department of Health Sciences, Section of Pathological Anatomy, University of Florence, Florence, ItalySearch for more papers by this authorE. Antiga, E. Antiga orcid.org/0000-0001-7787-4433 Department of Health Sciences, Section of Dermatology, University of Florence, Florence, ItalySearch for more papers by this author First published: 17 March 2021 https://doi.org/10.1111/jdv.17232Citations: 7Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume35, Issue8August 2021Pages e501-e503 RelatedInformation

Anti-nuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE).Specific data based on large case-series on the pathogenetic, diagnostic, and prognostic meaning of such autoantibodies are still lacking. Ouor objective was to characterize the correlations between the clinical variants of CLE as well as LE-non specific skin lesions and their autoantibody pattern.Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE-non specific skin lesions were analyzed.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). Subacute CLE resulted to be strongly 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).LE-nonspecific 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 (p=0.001 and pted with ENA (OR=5.19, p=0.002, respectively).According to our findings, some well known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE-nonspecific skin lesions were highlighted.

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.

Pyoderma gangrenosum (PG) is a rare, immune-mediated skin disease classified into the group of neutrophilic dermatoses. Although a number of studies confirmed the central role of innate immunity, only few studies have investigated the possible contributing role of acquired immunity. In particular, no reports concerning T helper type 1 (Th1) and Th2 cells are available as yet. Therefore, 15 patients with PG, five with Sweet's syndrome (SS) and nine skin specimens from healthy controls (HC) were investigated, evaluating the expression of Th1-related markers interleukin (IL)-12, interferon (IFN)-, C-X-C motif chemokine receptor 3 (CXCR3) and C-C motif chemokine receptor 5 (CCR5), of the Th2-related molecules IL-4, IL-5, IL-13 and CCR3, of the co-stimulatory axis CD40/CD40 ligand, of IL-15 and the natural killer (NK) cell marker CD56 in skin lesions by immunohistochemistry. Patients with PG and SS showed a higher expression of Th1 markers than HC. Conversely, IL-5- and CCR3-expressing cells were less numerous in PG skin lesions compared to SS (P=00157 and <00001, respectively). Both CD40 and CD40L were expressed more in PG than in SS and HC (P<00001 for both). Finally, the number of IL-15(+) and CD56(+) cells was higher in the skin of patients with PG than in those of SS and HC (P<00001 for both). Our results suggest that Th2 cells are down-regulated in PG. At the same time, over-expression of the co-stimulatory axis CD40/CD40L amplifies the impairment of the Th1/Th2 balance. Both these findings might explain the most aggressive behaviour of PG in comparison to SS. Moreover, over-expression of IL-15(+) and CD56(+) cells may suggest a possible role of NK cells in the pathogenesis of the disease.

OBJECTIVES:To determine homocysteine (Hcy) serum levels in patients with cutaneous lupus erythematosus (CLE) and a possible correlation with the disease activity.METHODS:Ninety-three patients with LE and 30 healthy controls were included in the study. For each patient, disease activity was calculated and plasma levels of Hcy was measured by enzymatic colorimetric assay.RESULTS:Forty-six patients had chronic cutaneous LE (CCLE), 14 had LE tumidus (LET), 17 had subacute CLE (SCLE) and 16 had SLE. Median values [25°-75° percentile] were 7[4-9] for CCLE, 3.5[2.3-4.8] for LET, and 8[7-10] for SCLE; for SLE the RCLASI score was 7.5[4.8-13] and the SELENA/SLEDAI score was 10.5[9-13.3]. HHcy was present in 73.9% of patients with CCLE, 35.7% with LET, 82.4% with SCLE, 81.2% with SLE, 20% of healthy controls. Overall, patients with LE showed a higher median serum Hcy level than the control group (15[13-18.2] vs. 11[8.8-12.2], p<0.001). There was a significant correlation between Hcy serum levels and disease activity, both in patients with CLE and SLE.CONCLUSIONS:We demonstrated that Hcy levels were higher in patients with different forms of CLE and correlated with disease activity calculated by CLASI. Therefore, HHcy could be related to LE pathogenesis and might be a triggering factor in predisposed individuals.

A 57-year-old man was diagnosed as having a gastric adenocarcinoma, and underwent chemotherapy with 5-fluorouracil and cisplatin. Docetaxel was added as a second-line therapy 4 months later, because of metastases detected in the lung and liver. At the end of the first cycle of docetaxel, the patient developed asymptomatic, violaceous, infiltrated, partially scaling lesions on the dorsal surface of both hands (Fig. 1a) followed by the occurrence of multiple annular, erythematous plaques on his trunk (Fig. 1b). Skin biopsies were taken from lesions on the trunk and on the left hand, and histological examination identified interface dermatitis in both (Fig. 2a,b). Laboratory investigations revealed mild anaemia together with neutropenia and lymphopenia. Thrombocytopenia was absent. Erythrocyte sedimentation rate was 93 mm/h (normal range 0–20 mm/h), while C-reactive protein, rheumatoid factor and complement factors were normal. Serological analysis was positive for Ro/SS-A [7.4 (antibody index; normal range <1 AI)] La/ SS-B (3.8 AI) and antinuclear (1 : 320) antibodies. Direct immunofluorescence (DIF) of the biopsy from the hand lesion revealed granular deposits of IgG, IgM and C3 at the dermoepidermal junction (Fig. 2c). In agreement with the oncologist, docetaxel was discontinued and replaced by capecitabine. The cutaneous lesions improved in the following weeks but, to obtain complete remission, hydroxychloroquine (200 mg/day) was added. After 3 weeks, the skin lesions had resolved and there was no recurrence in the subsequent 9-month follow-up period (Fig. 1c,d). Given the clinical and histopathological data, the trunk lesions were diagnosed as subacute cutaneous lupus erythematosus (SCLE) induced by docetaxel. This was based on the temporal link between drug exposure and onset of skin lesions, which resolved after drug discontinuation. Serological results were consistent with a drug-induced SCLE (DI-SCLE). Moreover, docetaxel has been recently suggested to induce SCLE in immunogenetically predisposed patients by stabilizing microtubules and affecting Ro/SS-A antigen (Ro52) expression. By contrast, the diagnosis of the hand lesions is more questionable. Their appearance resembled dermatomyositis, especially with regard to the localization and the violaceous colour, but no papules or Gottron sign were seen, and no joint or muscle involvement was found. Both electromyography and serology tests were negative. Moreover, the trunk lesions were not consistent with dermatomyositis. Another possible differential diagnosis could be palmoplantar erythrodysaesthesia (PPE) syndrome, which has been reported as a common side effect of docetaxel. However, we excluded PPE because the hand lesions did not involve the palms or affect the feet, and were asymptomatic. Moreover, although the histopathological examination was compatible with PPE, DIF in PPE is usually negative, whereas in our case we found several immunological deposits. Therefore, our final diagnosis for the hand lesions was of an atypical manifestation of SCLE induced by docetaxel, based on (i) the histopathological examina-

Acne is a chronic inflammatory disease of the sebaceous-pilosebaceous unit. Interestingly, inflammation can be detected by histopathological examination and immuohistochemical analysis even in the apparently non-inflammatory acneic lesions, such as comedones. In the last years, it has been clearly demonstrated that acne development is linked to the combination of predisposing genetic factors and environmental triggers, among which a prominent role is played by the follicular colonization by Propionibacterium acnes (P. acnes). P. acnes displays several activities able to promote the development of acne skin lesions, including the promotion of follicular hyperkeratinisation, the induction of sebogenesis, and the stimulation of an inflammatory response by the secretion of proinflammatory molecules and by the activation of innate immunity, that is followed by a P. acnes-specific adaptive immune response. In addition, P. acnes-independent inflammation mediated by androgens or by a neurogenic activation, followed by the secretion in the skin of pro-inflammatory neuropeptides, can occur in acne lesions. In conclusion, acne can be considered as a model of immune-mediated chronic inflammatory skin disease, characterized by an innate immune response that is not able to control P. acnes followed by a Th1-mediated adaptive immune response, that becomes self-maintaining independently from P. acnes itself.

BACKGROUND:No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG).AIM:To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients.MATERIALS AND METHODS:Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls.RESULTS:PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset.CONCLUSIONS:The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).

The Treg/Th17 cell ratio is reduced in the skin lesions of patients with pyoderma gangrenosum

Cutaneous vasculitides (CV) can be idiopathic or secondary to several triggers, including drugs, which account for up to 30% of all the cases of CV. Several drugs can induce CV, including some medications commonly used in dermatology, including minocycline, and several new drugs, such as anti-TNF agents. Different pathomecanisms are involved in the development of drug-induced CV, including the formation and deposition of immune complexes, the induction of neutrophil apoptosis, the formation of neoantigens between the drugs and proteins from the host, the shift of the immune response, and others. Although the diagnosis is difficult, because the clinical picture of drug-induced CV is in general indistinguishable from that of other forms of CV, it is important to recognize such entities in order to correctly manage the patient. Anamnesis, diagnostic algorithms to assess the likelihood of the association between a drug and a cutaneous reaction, skin biopsy and laboratory testing (including the search for antineutrophil cytoplasmic antibodies) are useful tools to make a diagnosis of drug-induced CV. About the therapy, while in idiopathic vasculitides the treatment is usually more aggressive and long-lasting, very often requiring a maintenance therapy with immunosuppressive drugs, in drug-induced CV the discontinuation of the suspected drug alone is usually enough to achieve complete remission, making the prognosis usually very good.

The definition, diagnostic criteria and classification of systemic vasculitides, of which cutaneous vasculitides (CV) are a part, have long been discussed by the medical scientific world. The most significant contribution is due to the consensus-based criteria specifically derived by the combination of judgments from groups of experts, after accurate literature reviews and developed using consensus techniques. First of them came from the American College of Rheumatology (ACR) in 1990. In 1994 the Chapel Hill International Consensus Conference (CHCC) produced the Consensus-based Criteria essentially providing proper nomenclature for systemic vasculitis, which has been modified in 2012 by the CHCC2012. Moreover, in 2006 European League against Rheumatism and Pediatric Rheumatology European Society produced consensus criteria for the classification of childhood vasculitis. In CHCC2012 CV, affecting small vessels with a predominant skin involvement, have been included in both small vessel vasculitis and single organ vasculitis. The general characteristics of so-called CV have been described (epidemiology, clinical features, histopathology and etiopathogenesis) and, finally, the major characteristics of each clinical type of CV as well as their diagnostic criteria currently available in the literature have been reported.

SummaryPyoderma gangrenosum (PG) and Sweet's syndrome (SS) are two inflammatory skin diseases presenting with painful ulcers and erythematous plaques, respectively; both disorders have a debilitating clinical behaviour and PG is potentially life-threatening. Recently, PG and SS have been included among the autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. However, an autoinflammatory pattern clearly supporting this inclusion has never been demonstrated. We studied 16 patients with PG, six with SS and six controls, evaluating, using a sandwich-based protein antibody array method, the expression profile of inflammatory effector molecules in PG, SS and normal skin. The expressions of interleukin (IL)-1 beta and its receptor I were significantly higher in PG (P = 0·0001 for both) and SS (P = 0·004–0·040) than in controls. In PG, chemokines such as IL-8 (P = 0·0001), chemokine (C-X-C motif) ligand (CXCL) 1/2/3 (P = 0·002), CXCL 16 (P = 0·003) and regulated upon activation normal T cell expressed and secreted (RANTES) (P = 0·005) were over-expressed. In SS, IL-8 (P = 0·018), CXCL 1/2/3 (P = 0·006) and CXCL 16 (P = 0·036) but not RANTES were over-expressed, suggesting that chemokine-mediated signals are lower than in PG. Fas/Fas ligand and CD40/CD40 ligand systems were over-expressed in PG (P = 0·0001 for Fas, P = 0·009 for Fas ligand, P = 0·012 for CD40, P = 0·0001 for CD40 ligand), contributing to tissue damage and inflammation, while their role seems to be less significant in SS. Over-expression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that PG and SS are autoinflammatory diseases. The differences in expression profile of inflammatory effectors between these two disorders may explain the stronger local aggressiveness in PG than SS.