Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.

BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

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.

Expression of PD-1 and Tim-3 is increased in skin of patients with bullous pemphigoid and pemphigus vulgaris.

BACKGROUND: Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are common autoimmune bullous dermatoses (AIBD) characterized by blisters and erosions. Treatment options are limited and often insufficient. Immune checkpoint receptors play critical roles in immune homoeostasis and self- tolerance. Targeting checkpoint receptors is highly efficient in treatment of various cancers, but often also associated with autoimmune side effects. OBJECTIVES: We therefore aimed to investigate the expression of immune checkpoint receptors in patients with BP and PV. METHODS: We analysed expression of the checkpoint receptors programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3) and lymphocyte activation gene 3 (Lag-3) in lesional skin of patients with BP and PV compared to healthy control skin as well as the expression patterns of PD-1 and Tim-3 on various infiltrating immune cells in skin sections of AIBD by immunohistochemistry and immunofluorescence. We also measured serum levels of soluble PD-1, Tim-3 and Lag-3 in AIBD patients by ELISA. RESULTS: We report on increased expression of PD-1 and Tim-3, but not Lag-3, in lesional skin of patients with BP and PV. Investigating the expression pattern of PD-1 and Tim-3 on different cutaneous immune cells, we observed significant upregulation of PD-1 predominantly on infiltrating CD8 T cells and upregulation of Tim-3 on CD8 T cells as well as macrophages. CONCLUSIONS: Our results suggest exploring immune checkpoint receptors as novel therapeutic targets using an agonistic approach in autoimmune bullous diseases.

[Anti-p200 pemphigoid]. / Anti-p200-Pemphigoid.

Anti-p200 pemphigoid is a rare autoimmune blistering disease. It belongs to the group of pemphigoid diseases and was first described in 1996. The diagnostic gold standard is the combination of (1) linear deposits of immunoreactants at the dermal epidermal junction by direct immunofluorescence microscopy of a perilesional skin biopsy, (2) detection of circulating autoantibodies binding to the dermal side (blister floor) of human salt split skin by indirect immunofluorescence microscopy, and reactivity with a 200 kDa protein (p200) in extract of human dermis by immunoblotting. In 2009, laminin γ1 was described as an additional target antigen in 90% of anti-p200 pemphigoid patients. Since ex vivo and in vivo studies have shown no direct pathogenic relevance for laminin γ1 antibodies and the preadsorption of patient sera against laminin γ1 does not reduce their reactivity with p200, the molecular identity of p200 still remains to be elucidated. The clinical phenotype of the disease is heterogeneous; in most cases, however, it resembles bullous pemphigoid. Anti-p200 patients are younger and skin lesions more often appear on palms of the hands and soles of the feet than in bullous pemphigoid. Therapy consists of topical and systemic corticosteroids. In addition, the use of daspone and immunosuppressants has been reported.

A sensitive and specific assay for the serological diagnosis of antilaminin 332 mucous membrane pemphigoid.

BACKGROUND: Antilaminin 332 mucous membrane pemphigoid (MMP) is an autoimmune subepidermal blistering disease with predominant mucosal involvement and autoantibodies against laminin 332. Malignancies have been associated with this disease; however, no standardized detection system for antilaminin 332 serum antibodies is widely available. OBJECTIVES: Development of a sensitive and specific assay for the detection of antilaminin 332 antibodies. METHODS: An indirect immunofluorescence (IF) assay using recombinant laminin 332 was developed and probed with a large number of antilaminin 332 MMP patient sera (n = 93), as well as sera from patients with antilaminin 332-negative MMP (n = 153), bullous pemphigoid (n = 20), pemphigus vulgaris (n = 20) and noninflammatory dermatoses (n = 22), and healthy blood donors (n = 100). RESULTS: In the novel IF assay, sensitivities with the laminin 332 heterotrimer and the individual α3, ß3 and γ2 chains were 77%, 43%, 41% and 13%, respectively, with specificities of 100% for each substrate. The sensitivity for the heterotrimer increased when an anti-IgG4 enriched antitotal IgG conjugate was applied. Antilaminin 332 reactivity paralleled disease activity and was associated with malignancies in 25% of patients with antilaminin 332 MMP. CONCLUSIONS: The novel IF-based assay will facilitate the serological diagnosis of antilaminin 332 MMP and may help to identify patients at risk of a malignancy.

Accelerated barrier recovery and enhancement of the barrier integrity and properties by topical application of a pH 4 vs. a pH 5·8 water-in-oil emulsion in aged skin.

BACKGROUND: Increased skin-surface pH is an important host-related factor for deteriorated barrier function in aged skin. OBJECTIVES: We investigated whether restoration of skin pH through topical application of a water-in-oil emulsion with pH 4 improved the barrier homeostasis in aged skin, and compared the effects with an identical galenic formulation with pH 5·8. METHODS: The effects of the test formulations on barrier recovery were investigated by repeated measurements of transepidermal water loss (TEWL) and skin pH 3 h, 6 h and 24 h after acetone-induced impairment of barrier function in aged skin. The long-term effects of the pH 4 and pH 5·8 emulsions were analysed by investigation of the barrier integrity and cohesion, the skin-surface pH and the skin roughness and scaliness before and after a 4-week, controlled application of the formulations. RESULTS: The application of the pH 4 emulsion accelerated barrier recovery in aged skin: 3 h and 6 h after acetone-induced barrier disruption the differences in the TEWL recovery between the pH 4 treated and acetone control fields were significant. Furthermore, long-term application of the pH 4 formulation resulted in significantly decreased skin pH, enhanced barrier integrity and reduced skin-surface roughness and scaliness. At the same time points, the pH 5·8 formulation exerted only minor effects on the barrier function parameters. CONCLUSIONS: Exogenous acidification through topical application of a water-in-oil emulsion with pH 4 leads to improvement of the skin barrier function and maintenance of the barrier homeostasis in aged skin.

Influence of cigarette smoking on pemphigus - a systematic review and pooled analysis of the literature.

Epidemiological evidence suggests that smoking cigarettes may be beneficial in pemphigus, but no systematic evaluation exists to corroborate this assumption. Therefore, a systematic literature review with pooled data analysis of the smoking status in patients with pemphigus was conducted. Electronic searches using PubMed from inception to November 2017 identified 13 reports meeting predetermined inclusion and exclusion criteria. Most were case-control studies partly reporting that pemphigus vulgaris and foliaceus occurred less frequently in current and former smokers. Studies also indicated that duration of smoking and number of cigarettes smoked were lower in patients with pemphigus than controls and that remission may be achieved sooner in those who smoke. However, although a generally low prevalence of smoking was demonstrated in patients with pemphigus, which was lower than in controls by pooled analysis, some investigations found no difference regarding the smoking status compared with non-pemphigus subjects. One study demonstrated more severe mucosal involvement in non-smoking patients with pemphigus, whereas another observed no difference in the rate of cutaneous or mucosal lesions between smokers and non-smokers with pemphigus. This review indicates that smoking may be a possible protective factor in pemphigus, although some compromised study methodologies yet hinder any firm conclusion. Further investigations with a refined quality design are required to resolve the so far partly conflicting results in this area.

[Mucous membrane pemphigoid]. / Schleimhautpemphigoid.

Mucous membrane pemphigoid (MMP) is a pemphigoid disease defined by the presence of autoantibodies against the dermal-epidermal junction and predominant involvement of mucous membranes. Diagnosis is made by the clinical presentation and linear deposits of IgG and/or IgA and/or C3 at the dermal-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy. Circulating autoantibodies can be detected in most patients by indirect immunofluorescence microscopy on salt-split human skin as well as ELISA and immunoblotting with recombinant and cell-derived target antigens. For systemic treatment of MMP, corticosteroids, dapsone, mycophenolates, and azathioprine are applied. In severe cases and in cases with rapid disease progression cyclophosphamide, rituximab, high-dose intravenous immunoglobulins, and immunoadsorption are used. For the successful management of MMP patients, close cooperation with dentists, ophthalmologists, ENT specialists, gynecologists, and gastroenterologists is essential.

[Response of BRAF(L597Q)-mutant melanoma to trametinib : Targeted melanoma therapy beyond BRAF(V600) mutations]. / Ansprechen eines BRAF(L597Q)-mutierten Melanoms auf Trametinib : Zielgerichtete Melanomtherapie jenseits der BRAF(V600)-Mutationen.

Approximately 7 % of melanomas have a BRAF mutation beyond codon 600. These mutations can be BRAF activating without being addressable by an approved BRAF inhibitor. The case of a patient with fulminant metastatic melanoma and a BRAF(L597Q) mutation is presented. It is demonstrated that the tumor shows an excellent response to the MEK inhibitor trametinib. This is an example for possible targeted therapy in a non-V600-mutated melanoma resulting in a 17-month overall survival.

TNFAIP3 and IL12B gene polymorphisms associated with psoriasis vulgaris in an Egyptian cohort.

BACKGROUND: Psoriasis vulgaris is a common chronic inflammatory skin disease. Development of early onset psoriasis is, to some extent, genetically determined and a strong association with the major histocompatibility complex HLA-Cw6 has been demonstrated. The use of genome-wide association studies has highlighted novel genes associated with the development of psoriasis as IL12B, IL23R, TNFAIP3 and IL13 for instance. The majority of these studies were performed on cohorts of European descent. OBJECTIVE: To determine whether inter-ethnic differences exist in the genetic susceptibility to psoriasis, we genotyped single-nucleotide polymorphism variations in the vicinity of candidate genes in 132 Egyptian patients and 175 healthy controls. METHODS: Blood samples of patients and controls were screened for nucleotide polymorphisms in four candidate genes by TaqMan single-nucleotide polymorphisms Genotyping Assays. RESULTS: We found a significant association between psoriasis and the single-nucleotide polymorphism rs610604, within the TNFAIP3 gene. The TNFAIP3 gene is involved in the TNF-α signalling cascade (P-value: 0.004952), a key step in the pathogenesis of psoriasis. Although there was no significant association found between rs610604 (IL12B) and rs11209026 (IL23R) in this population, the interaction of these two genes showed a significant association with psoriasis (P-value: 0.025). Moreover, when selecting the patients with early disease onset (less than 30 years), we also found that the association of IL12B and psoriasis was highly significant (P-value 1.14 × 10(-12)). No association between rs20541 (IL13) and psoriasis was observed in our Egyptian cohort. CONCLUSION: Replicating the association of single-nucleotide polymorphisms in the TNFAIP3, IL12B and IL23R genes with psoriasis vulgaris, in subjects from different ethnic backgrounds, underlines their importance in the pathogenesis of the disease. In contrast, the lack of any association between rs20541 (IL13) and psoriasis in our Egyptian cohort suggests the existence of important inter-ethnic genetic differences in psoriasis susceptibility.

Differential effects of caffeine on hair shaft elongation, matrix and outer root sheath keratinocyte proliferation, and transforming growth factor-ß2/insulin-like growth factor-1-mediated regulation of the hair cycle in male and female human hair follicles in vitro.

BACKGROUND: Caffeine reportedly counteracts the suppression of hair shaft production by testosterone in organ-cultured male human hair follicles (HFs). OBJECTIVES: We aimed to investigate the impact of caffeine (i) on additional key hair growth parameters, (ii) on major hair growth regulatory factors and (iii) on male vs. female HFs in the presence of testosterone. METHODS: Microdissected male and female human scalp HFs were treated in serum-free organ culture for 120 h with testosterone alone (0·5 µg mL(-1)) or in combination with caffeine (0·005-0·0005%). The following effects on hair shaft elongation were evaluated by quantitative (immuno)histomorphometry: HF cycling (anagen-catagen transition); hair matrix keratinocyte proliferation; expression of a key catagen inducer, transforming growth factor (TGF)-ß2; and expression of the anagen-prolonging insulin-like growth factor (IGF)-1. Caffeine effects were further investigated in human outer root sheath keratinocytes (ORSKs). RESULTS: Caffeine enhanced hair shaft elongation, prolonged anagen duration and stimulated hair matrix keratinocyte proliferation. Female HFs showed higher sensitivity to caffeine than male HFs. Caffeine counteracted testosterone-enhanced TGF-ß2 protein expression in male HFs. In female HFs, testosterone failed to induce TGF-ß2 expression, while caffeine reduced it. In male and female HFs, caffeine enhanced IGF-1 protein expression. In ORSKs, caffeine stimulated cell proliferation, inhibited apoptosis/necrosis, and upregulated IGF-1 gene expression and protein secretion, while TGF-ß2 protein secretion was downregulated. CONCLUSIONS: This study reveals new growth-promoting effects of caffeine on human hair follicles in subjects of both sexes at different levels (molecular, cellular and organ).

[Bullous pemphigoid]. / Bullöses Pemphigoid.

Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering and autoantibodies against structural proteins of the dermal-epidermal junction. In bullous pemphigoid, the most common subepidermal blistering autoimmune disease, antibodies are directed against the hemidesmosomal antigens BP180 (collagen type XVII) and BP230. Bullous pemphigoid typically presents with severe pruritus and tense blisters accompanied by erosions and crusts in elderly patients. Diagnostic landmarks are the detection of linear IgG and/or C3 deposits at the dermo-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy and the detection of serum autoantibodies by indirect immunofluorescence microscopy on human salt-split skin and ELISA employing recombinant immunodominant fragments of BP180 and BP230. Treatment options include topical (class IV) and/or systemic corticosteroids, frequently combined with immunomodulatory agents like dapsone and tetracyclines or immunosuppressants such as methotrexate and azathioprine.

[Primary antiphospholipid syndrome: newly developed leg ulcer and history of stroke]. / Diagnose eines primären Antiphospholipidsyndroms bei Ulcus cruris unter Marcumar-Therapie.

Antiphospholipid syndrome features not only deep vessel thrombosis but also may have cutaneous manifestations such as Raynaud phenomenon, acral necrosis, livedo reticularis, subcutaneous nodules, and leg ulcers. A 72-year-old man presented with a rapidly progressing leg ulcer. He was already on anticoagulation with warfarin due to atrial fibrillation and disclosed a history of stroke with temporary paresis of the left leg. Histopathology of a biopsy of the edge of the ulcer revealed occlusive arteriosclerosis of medium-sized arteries. Serology showed autoantibodies against cardiolipin, ß2- glycoprotein I, and phosphatidylserine which led to the diagnosis of antiphospholipid syndrome. Therapy with low molecular weight heparin, dexamethasone, and azathioprine in combination with stage-adjusted wound care led to complete healing of the ulcer within 5 months.

Cicatrising conjunctivitis with anti-basement membrane autoantibodies in ectodermal dysplasia.

AIMS: To report circulating and mucosa-deposited anti-basement membrane zone autoantibodies in a series of six ectodermal dysplasia patients with severe bilateral cicatrising conjunctivitis and blindness due to both corneal disease and intractable surface inflammation. We also report clinical improvement with steroid-sparing systemic immunosuppression combined with clearance of bacterial colonisation. METHODS: Conjunctival and buccal immunohistopathology, and serological analysis using a panel of epithelial basement membrane zone proteins including the bullous pemphigoid antigen 180 (BP180) were carried out as part of an ocular pemphigoid work-up in each patient. The degree of photophobia, conjunctival inflammation and visual acuity were monitored to evaluate the response to immunosuppression. The mean duration of follow-up was 31 (SD 6) months. RESULTS: Four of the six patients showed positive immunopathology: direct immunofluorescence testing of the conjunctiva in one patient demonstrated linear IgA deposition along the basement membrane zone, and IgG and IgM in the buccal mucosa of another patient. Circulating autoantibodies to BP180 were detected in two other patients. Treatment with systemic immunosuppression, combined with clearance of bacterial colonisation, reduced the severity of photophobia and degree of conjunctival inflammation in 5/6 (83%) patients. CONCLUSIONS: Systemic immunosuppression, used as steroid-sparing therapy, combined with clearance of bacterial colonisation can control inflammation and disabling photophobia, and allow improvement in vision, in a subgroup of ectodermal dysplasia patients who have severe cicatrising conjunctivitis which shares clinical and immunopathological features with ocular mucous membrane pemphigoid.