The diagnosis and treatment of dermatitis herpetiformis

Emiliano Antiga, Marzia Caproni Department of Surgery and Translational Medicine, Section of Dermatology, University of Florence, Florence, Italy Abstract: Dermatitis herpetiformis (DH) is an inflammatory cutaneous disease with a chronic relapsing course, pruritic polymorphic lesions, and typical histopathological and immunopathological findings. According to several evidences, DH is considered the specific cutaneous manifestation of celiac disease, and the most recent guidelines of celiac disease have stated that, in celiac patients with a proven DH, a duodenal biopsy is unnecessary for the diagnosis. In this review, the most recent data about the diagnosis and the management of DH have been reported and discussed. In particular, in patients with clinical and/or histopathological findings suggestive for DH, the finding of granular IgA deposits along the dermal–epidermal junction or at the papillary tips by direct immunofluorescence (DIF) assay, together with positive results for anti-tissue transglutaminase antibody testing, allows the diagnosis. Thereafter, a gluten-free diet should be started in association with drugs, such as dapsone, that are able to control the skin manifestations during the first phases of the diet. In conclusion, although DH is a rare autoimmune disease with specific immunopathological alterations at the skin level, its importance goes beyond the skin itself and may have a big impact on the general health status and the quality of life of the patients. Keywords: dermatitis herpetiformis, celiac disease, diagnosis, treatment, autoimmune disease, inflammatory cutaneous disease&nbsp

Celiac Disease and Dermatologic Manifestations: Many Skin Clue to Unfold Gluten-Sensitive Enteropathy

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

15 Management of refractory skin lupus

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

The role of apoptosis in the pathogenesis of dermatitis herpetiformis.

Apoptosis is a form of cell death that is claimed to be involved in a number of chronic inflammatory and malignant skin diseases. The aim of this study was to investigate whether apoptosis may contribute to the pathogenesis of epidermal changes in dermatitis herpetiformis (DH) and, in particular, whether certain apoptosis-related markers such as Bax, Bcl-2, Fas and Fas ligand (FasL) take part in this process. For the detection of apoptotic nuclei, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling technique (TUNEL) was employed on cryostat sections. Skin lesions from six and perilesional skin from four DH patients were stained with monoclonal antibodies to Bax, Bcl-2, Fas and FasL. The same evaluation was also performed on three patients affected by bullous pemphigoid (BP) and in two healthy donors. Using TUNEL technique, a remarkable increase in the apoptotic rate within the epidermal compartment was observed in DH and BP patients in comparison with normal controls. In our immunohistochemical analysis, Bax/Bcl-2 ratio was almost the same in the epidermis of perilesional/lesional DH, BP and healthy skin specimens. In DH and BP specimens both Bax and Bcl-2 proteins were increased in the dermal perivascular compartment. Fas showed a prevalently epidermal staining, both in DH and BP lesions, while FasL was distributed in perivascular and subjunctional dermis; some FasL+ cells infiltrated the DEJ and the basal layer of epidermis. This study allowed us to highlight conspicuous apoptotic phenomena in basal and suprabasal keratinocytes within lesional and perilesional skin of DH. We conclude that in DH, as well as in BP, apoptosis plays a role in the pathogenesis of cutaneous lesions in concert with other pathogenetic mechanisms

systemic contact dermatitis from herbal and homeopathic preparations used for herpes virus treatment

Systemic contact dermatitis may occur in contactsensitized individuals when they are exposed to haptens orally, transcutaneously, intravenously or by inhalation. We report the case of a woman developing a diffuse skin eruption after the topical use of Rhus toxicodendron alcoholic extract and the oral introduction of a homeopathic preparation of the same substance for herpes treatment. An open test, performed with the Rhus toxicodendron tincture, showed an erythematooedematous response at 48 h and vesicular reaction at 96 h that was still present after 7 days. Patch test with 65% ethyl alcohol gave negative results. The open test performed, as control, in eight healthy informed subjects revealed negative responses to Rhus tincture application. The result is interesting because in Italy, allergic contact dermatitis to Rhus is uncommon and this case increases the understanding of the pathogenetic mechanism leading to systemic contact dermatitis development. Key words: homeopathy; plant extracts; mother tincture; Rhus toxicodendron; herpes virus infection

Chronic Idiopathic and Chronic Autoimmune Urticaria: Clinical and Immunopathological Features of 68 Subjects

Skin tests with autologous serum elicit an immediate wheal-and-flare response in about 30 ‐ 50% of chronic idiopathic urticaria subjects, suggesting that an autoimmune mechanism might be involved in the pathogenesis of this disease. The aim of the present work, involving 68 subjects with chronic idiopathic urticaria, was to distinguish between the serum-positive and serum-negative cases and highlight the clinical differences between the two groups on the basis of the Breneman scale score. We also tried to correlate the finding of a positive response to the autologous serum skin test with other autoimmune diatheses or fully developed autoimmune disorders. Our results did not demonstrate any significant differences between the two groups with regard to mean age, sex distribution, angioedema and mucosal/cutaneous atopy. However, all subjects with positive autologous serum skin test presented more severe clinical features than serumnegative subjects. We found no differences between the two groups in the incidence of autoimmune disease. Key words: chronic urticaria; autologous serum skin test; autoimmunity

Environmental factors in autoimmune bullous diseases with focusing on seasonality: new insights

Autoimmune bullous diseases are a heterogeneous group of rare conditions clinically characterized by the presence of blisters and/or erosions on the skin and on the mucous membranes. Practically, they can be divided into two large groups: the pemphigoid group and the pemphigus group, depending on the depth of the autoimmune process on the skin. Family history of autoimmune disease can often be found, and demonstrating that genetic predisposition is crucial in the development of them. Moreover, numerous environmental risk factors, such as solar radiation, drugs and infections, are known. This study aimed to evaluate how seasonality can affect the trend of BP and PV, especially considering the number of hospitalizations recorded over the course of individual months. The total number of hospitalizations in the twelve months of the year was evaluated. Further, blood chemistry assay and, for some patients, enzyme-linked immunosorbent assay were executed in order to evaluate antibodies. Regarding the severity of the disease BPDAI (Bullous Pemphigoid Area Index) and PDAI (Pemphigus Disease Area Index), score systems were used. Results showed a complex interplay between environmental factors such as seasons and autoimmune conditions