Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: 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. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

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.

S2k guidelines (consensus statement) for diagnosis and therapy of dermatitis herpetiformis initiated by the European Academy of Dermatology and Venereology (EADV).

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.

Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV).

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, 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 United States. 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 organizations.

Precursory worldwide signatures of earthquake occurrences on Swarm satellite data.

The study of the preparation phase of large earthquakes is essential to understand the physical processes involved, and potentially useful also to develop a future reliable short-term warning system. Here we analyse electron density and magnetic field data measured by Swarm three-satellite constellation for 4.7 years, to look for possible in-situ ionospheric precursors of large earthquakes to study the interactions between the lithosphere and the above atmosphere and ionosphere, in what is called the Lithosphere-Atmosphere-Ionosphere Coupling (LAIC). We define these anomalies statistically in the whole space-time interval of interest and use a Worldwide Statistical Correlation (WSC) analysis through a superposed epoch approach to study the possible relation with the earthquakes. We find some clear concentrations of electron density and magnetic anomalies from more than two months to some days before the earthquake occurrences. Such anomaly clustering is, in general, statistically significant with respect to homogeneous random simulations, supporting a LAIC during the preparation phase of earthquakes. By investigating different earthquake magnitude ranges, not only do we confirm the well-known Rikitake empirical law between ionospheric anomaly precursor time and earthquake magnitude, but we also give more reliability to the seismic source origin for many of the identified anomalies.

Burden of disease during quiescent periods in patients with pemphigus.

BACKGROUND: Studies conducted using different tools have invariably observed that physical and mental components of health status are seriously compromised in patients with pemphigus. An improvement in quality of life (QoL) has been commonly observed over the treatment period. OBJECTIVES: The aim of the study is to verify whether the patients' wellbeing is affected by pemphigus also in absence of cutaneous and mucosal lesions. MATERIALS AND METHODS: The clinical records of 203 patients were analysed. A total of 47 patients were without bullae/erosions and reported a score = 0 for both the Patient Global Assessment and the Ikeda index. In order to assess the QoL we used the Skindex-17 and the 12-item General Health Questionnaire (GHQ-12). RESULTS: Patients without bullae/erosions had a better QoL when compared with patients with active lesions. This difference, with a reduction of approximately 30% of the Skindex-17 scores in the patients without lesions, was statistically significant, for both the symptoms and the psychosocial scales. The proportion of patients at risk of anxiety/depression (GHQ-positive cases) was 44% lower in patients without lesions compared with patients with lesions. In a multiple linear regression model the presence of bullae/erosions negatively influences QoL with an average increase of Skindex-17 symptoms and psychosocial scale scores of 11·7 and 10·6 points, respectively. Female patients had a statistically significantly worse QoL than males on the symptoms but not on the psychosocial Skindex-17 scales. CONCLUSIONS: While patients without lesions reported a better QoL than patients with bullae/erosions, their Skindex-17 scores remained elevated. Dermatologists should be aware that a clearing of the skin manifestations does not mean 'perfect health' for the patient.

Treatment of cutaneous lichen planus: an evidence based analysis of efficacy by the Italian Group for Cutaneous Immunopathology.

Cutaneous lichen planus (LP) is an inflammatory papulo-squamous disorder presenting with violaceous, polygonal, flat-topped papules and plaques on the skin that shows a chronic-relapsing course. However, in most cases, the disease spontaneously regresses 1 month to 7 years after onset; for this reason, it is very difficult to evaluate the effectiveness of the therapeutic strategies for cutaneous LP. This study reviewed the more recent status of systemic therapies for cutaneous LP. No level A trials on the medical or physical treatment of cutaneous LP were found in the literature. Moreover, only three trials were found with acceptable methods including more than 20 patients (one on the use of acitretin, one on the use of phototherapy and the other one on the use of sulfasalazine, respectively). Among the new drugs, although few evidences could be provided, alitretinoin may represent a novel effective and well-tolerated treatment option for refractory cutaneous LP. By contrast, no trials were found about the treatment of specific LP variants (including inverse, hypertrophic or ulcerative LP), but only treatment reports of single cases. Finally, basing on the careful revision of the whole Literature and on the personal experience of the Authors, the therapeutic recommendations for cutaneous LP proposed by the Italian Group for Cutaneous Immunopathology were reported.

Quality of life in patients with pemphigus receiving adjuvant therapy.

BACKGROUND: Pemphigus has a strong effect on patients' quality of life (QOL). AIM: To analyze QOL and psychological well-being within patient groups, subdivided according to their different adjuvant treatments. METHODS: All adult patients with pemphigus enrolled in the study were assessed using the Short Form (SF)-36, the Skindex-29, and the General Health Questionnaire (GHQ)-12 for health status, effect of dermatology-specific aspects, and the presence of psychological comorbidity, respectively. The study population was subdivided into the following treatment groups: (i) those who were untreated or were treated only with corticosteroids (CS) at a dose of ≤ 5 mg/day (no adjuvant treatment, NAT); and patients receiving or not receiving CS ≤ 5 mg/day who also received either (ii) azathioprine (AZ), (iii) cyclophosphamide (CY), (iv) mycophenolate mofetil (MM) or (v) rituximab (RTX). RESULTS: In total, 113 patients were recruited. There were no significant differences between the treatment subgroups in either the SF-36 or Skindex-29 results. However, for the GHQ, there were large differences in QOL scores between patients scoring > 4 points (GHQ+) and those scoring < 4 points (GHQ-), especially for the more 'physical' components of QOL. The overall observed proportion of GHQ+ patients was 33.6%. CONCLUSIONS: We found no significant differences in QOL impairment between the treatment subgroups; however, we observed a strong association between psychiatric morbidity and poorer QOL within each of the treatment groups. This should be of concern for dermatologists, as psychiatric morbidity is associated with poor treatment adherence and dissatisfaction with care.

Psychological distress and investment in one's appearance in patients with pemphigus.

BACKGROUND: Pemphigus vulgaris is a chronic disease not currently curable. Physical involvement and the impact of chronic therapies can lead patients to changes in psychological and relational areas. OBJECTIVES: To provide a measure of psychological distress, dysfunctional investment in one's appearance, and their relationship. METHODS: Self-administered questionnaires (ASI, HADS) were given to 74 pemphigus inpatients. RESULTS: Strong associations between psychological distress and dysfunctional investment in one's appearance were observed [adjusted odds ratio (OR)=7.36, 95% confidence intervals (CI) 1.20-45.11; OR 5.38, 95% CI 0.81-35.87, respectively, for appearance stereotyping and body-image vulnerability], together with a perceived high disease severity (OR 6.03, 95% CI 1.90-23.46). CONCLUSIONS: Our results are compatible with the idea that some forms of psychological distress could be in part due to one's perception of his/her own body image.

The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the Medical Outcomes Study 36-item short form health survey questionnaire.

BACKGROUND: Pemphigus vulgaris and pemphigus foliaceus are rare, potentially life-threatening, autoimmune disorders characterized by antibodies to epidermal adhesion molecules. Clinical characteristics are painful chronic erosions of mucous membranes and of the skin. There are only few published studies on the impact of the disease on the health status (HS) of patients with these conditions. OBJECTIVES: To assess the impact of disease on the HS of patients with pemphigus. METHODS: Fifty-eight patients enrolled at the Bullous Skin Diseases Unit of IDI-IRCCS in the period January-June 2006 were assessed for their HS using the Medical Outcomes Study 36-item short form health survey (SF-36) questionnaire and for anxiety and depression using the Institute for Personality and Ability Testing questionnaires. RESULTS: A compromised HS on both the physical and the psychosocial scales was observed, similar to other chronic dermatological diseases such as psoriasis. Patients with anxiety had severe disease as measured by the Physician's Global Assessment and the degree of mucocutaneous involvement, as well as those with a more recent disease onset. A better HS was observed in patients whose clinical condition was rated as nonsevere, and also in patients with pemphigus foliaceus. In pemphigus vulgaris, antidesmoglein 3 antibody levels directly correlated with clinical severity and with lower SF-36 scores. CONCLUSIONS: HS evaluated with the SF-36 can be a very useful additional outcome criterion in clinical studies with pemphigus. The management of the disease must take into account its impact on various aspects of life of the patient.

Interleukin-16 expression and release in bullous pemphigoid.

Cutaneous infiltration of activated CD4(+) T cells and eosinophils is an early event in blister formation during bullous pemphigoid (BP), suggesting that the trafficking of circulating leucocytes through the sites of inflammation, their activation and cytokine release is crucial in the pathogenesis of the disease. IL-16 is a major chemotactic factor able to recruit CD4(+) cells in the skin during inflammation and to induce the expression of functional high-affinity interleukin (IL)-2 receptors, thus contributing to cellular activation and proliferation. We performed a study in order to evaluate the presence of IL-16 in skin samples and sera and blister fluids of patients affected with BP in active phase of the disease (n = 39), compared with healthy donors studied as control group. Ten patients were also evaluated before and after steroid therapy. Our results demonstrated that IL-16 was expressed strongly by keratinocytes and by dermal infiltrating CD4(+) T lymphocytes in lesional skin of BP patients. High levels of IL-16 were detected in sera and blisters of BP, significantly higher in respect to healthy donors. When patients were investigated for the presence of eosinophil cationic protein (ECP) and soluble CD30 (sCD30) to reveal signs of eosinophils and Th2-cells activation, we found a positive correlation between IL-16 serum levels and both ECP and sCD30, suggesting that IL-16 is involved in Th2 lymphocytes and eosinophils recruitment during BP.

Association of piebaldism and neurofibromatosis type 1 in a girl.

We report an 11-year-old girl with both piebaldism and neurofibromatosis type 1 (NF1). The patient had large depigmented patches on her lower limbs and a white forelock since birth. In addition, some café au lait spots were present on her trunk at birth and had increased in number and size during childhood in concomitance with the appearance of axillary and inguinal freckling. Neither neurofibromas nor Lisch nodules were detected and the patient was otherwise healthy. Pedigree analysis revealed inheritance for piebaldism on the paternal side. To our knowledge, the association of piebaldism and NF1 has been described previously in only three patients. Awareness of this rare association is relevant to ensure early diagnosis and adequate follow-up for NF1.

Pigmented purpura-like eruption as cutaneous sign of mycosis fungoides with autoimmune purpura.

We describe the clinical and laboratory findings of a young man with mycosis fungoides. The disease was associated, since the early stages, with autoimmune purpura. Interferon alfa (IFN-alpha) administration improved this patient's condition, both the purpuric eruption and patchy cutaneous lesions, thus suggesting T-cell abnormalities may be responsible for the development of the disease.