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.

A training programme for medical students in providing spiritual care to people with advanced diseases and their loved ones: A case study from the Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland.

Purpose: This article presents the first programme on spiritual care particularly for people with advanced life-limiting illness including heart failure, lung disease or cancer for medical students in Poland implemented at the Collegium Medicum in Bydgoszcz of the Nicolaus Copernicus University in Torun. Methods and materials: Several steps were identified for the development of the first programme on spirituality for medical students at the Collegium Medicum in Bydgoszcz including preliminary work on the content of the programme, agreement on key concepts, terms, and definitions; consultations with teachers and review of the literature. Results: The first Polish spiritual curriculum for medical students was implemented. The spirituality curriculum will potentially contribute to better care for the people with advanced illnesses such as heart failure, chronic lung disease or cancer and improve the quality of relationships between professionals and patients. Conclusion: The article presents the content of the program, the expected learning objectives and ascribed teaching methods, along with the preliminary evaluation made by students.

Epidermolysis bullosa aquisita following immune-checkpoint inhibitor treatment for metastatic melanoma.

A case of epidermolysis bullosa aquisita following immunotherapy for melanoma. This adds to the repertoire of subepidermal blistering disorders documented following immune checkpoint therapy.

Epidermolysis bullosa acquisita: a case series of three paediatric patients.

Epidermolysis bullosa acquisita is a highly uncommon condition in the paediatric population. This article describes three children with this disease, different clinical presentation and management. It also reviews the most relevant articles on this topic.

Human marginal zone B cell development from early T2 progenitors.

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4ß7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.

Autoantibody Detection for Diagnosis in Direct Immunofluorescence-Negative Mucous Membrane Pemphigoid: Ocular and Other Sites Compared.

PURPOSE: To assess whether a panel of serum pemphigoid autoantibody tests could be used to confirm an immunopathologic diagnosis of mucous membrane pemphigoid (MMP) in direct immunofluorescent negative (DIF-) MMP patients. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Seventy-six patients with multisite MMP with 45 matched control participants. METHODS: Enzyme-linked immunosorbent assays (ELISAs) for BP180 and BP230 (MBL International), immunoglobulin A (IgA) A and immunoglobulin G indirect immunofluorescence (IIF) on human salt-split skin and the keratinocyte footprint assay for anti-laminin 332 antibodies. MAIN OUTCOME MEASURES: Sensitivity and specificity of autoantibody detection and significant differences for individual tests and test combinations for MMP involving different sites. RESULTS: All DIF- patients (24/73 [31.8%]) had either ocular-only disease or ocular involvement in multisite disease. Serum pemphigoid autoantibodies were detected in 29 of 76 MMP patients (38.2%) compared with 3 of 45 control participants (6.7%). Autoantibody reactivity detected by any 1 or more of the tests was present in 6 of 24 DIF- patients (25%) compared with 22 of 49 DIF positive (DIF+) patients (44.9%). Ocular-only MMP serum reactivity was not significantly different for any test or test combination compared with control participants, whereas DIF- multisite ocular MMP differed for 1 ELISA and 3 of 7 test combinations. By contrast, for DIF+ nonocular MMP patients, all the individual tests, apart from IgA IIF, and all test combinations were significantly different compared with those for control participants. For the entire MMP cohort, the sensitivity of all individual tests was low, having a maximum of 21.05% for BP180 reactivity but increasing to 38.16% for an optimal test combination. Disease activity was associated strongly with positive serologic findings. CONCLUSIONS: Pemphigoid serum autoantibody tests did not provide immunopathologic evidence of MMP in ocular-only MMP patients but showed limited value in DIF- multisite ocular MMP patients. The requirement for immunopathologic confirmation of MMP by autoantibody detection is inappropriate for DIF- ocular-only MMP patients, resulting in missed diagnoses, delayed therapy, and poor outcomes. Alternative diagnostic criteria for ocular-only MMP are required to exclude the other causes of scarring conjunctivitis until more sensitive and specific immunopathologic tests become available.

Epidermolysis Bullosa Acquisita (Brunsting-Perry Pemphigoid Variant) Localized to the Face and Diagnosed With Antigen Identification Using Skin Deficient in Type VII Collagen.

Brunsting-Perry pemphigoid is defined as an autoimmune vesiculobullous eruption typically localized on the head and neck region with minimal or no mucosal involvement. The disease tends to run a chronic and recurrent course with residual scarring. Histological features are characterized by subepidermal bullae and linear IgG deposits at the dermo-epidermal junction. We report a case of a 46-year-old lady who presented with typical features of Brunsting-Perry pemphigoid. Autoantibodies to type VII collagen were identified by using recessive dystrophic epidermolysis bullosa skin which lacks type VII collagen in an indirect immunofluorescence assay. As a result, we diagnosed our patient as having the Brunsting-Perry pemphigoid variant of epidermolysis bullosa acquisita (EBA). This finding led us to review the literature on target antigens in Brunsting-Perry pemphigoid. Only 11 out of the 58 cases reported to date had target antigens identified. Interestingly, type VII collagen was the second most common target antigen/autoantibody (4 cases) detected after BP180 (5 cases). However, 2 further cases of EBA localized to the face with typical features of Brunsting-Perry pemphigoid were found in the literature. Although the target antigens are heterogeneous in Brunsting-Perry pemphigoid, a significant number of cases represent a clinical presentation of localized EBA.

Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease of the skin and mucous membranes, characterized by autoantibodies against type VII collagen (COL7), a major component of anchoring fibrils. Different clinical EBA phenotypes are described, including mechanobullous and inflammatory variants. Most EBA patients' sera react with epitopes located within the non-collagenous 1 (NC1) domain of human COL7. However, it has remained unclear whether antibody binding to these different epitopes is pathogenically relevant. To address this issue, we generated recombinant proteins covering the entire NC1 domain. IgG reactivity with these proteins was analyzed in sera of 69 EBA patients. Most recognized clusters of epitopes throughout the NC1 domain. No correlation was detected between antibody specificity and clinical phenotype. To study the pathogenicity of antibodies specific to different NC1 subdomains, rabbit antibodies were generated. All these antibodies caused dermal-epidermal separation ex vivo. Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters. We here document that autoantibodies to COL7, independent of the targeted epitopes, induce blisters both ex vivo and in vivo. In addition, using COL7-humanized mice, we provide in vivo evidence of pathogenicity of autoantibodies binding to human COL7.

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

The current state of play in the histopathologic assessment of alopecia: two for one or one for two?

The histopathologic assessment of a scalp biopsy for alopecia relies largely on the quality of the specimen provided for evaluation. There are a number of different protocols in the literature which have been proposed over the years, but no consensus has yet been reached as to the appropriate number of biopsies to be taken, or to which sectioning technique is the gold standard for achieving the best diagnostic yield. We herein review the pros and cons of the various protocols and share the experience with our St John's protocol.

Sensitive and specific assays for routine serological diagnosis of epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a severe autoimmune subepidermal blistering disease characterized by autoantibodies against the N-terminal collagenous domain (NC1) of type VII collagen (Col VII). OBJECTIVE: Development of reliable assays for the detection of anti-Col VII-NC1 antibodies. METHODS: NC1 was expressed in human HEK293 cells and used as target antigen in an enzyme-linked immunosorbent assay (ELISA) and in an immunofluorescence assay (IFA). These two assays were probed in a large cohort of patients with EBA (n = 73), bullous pemphigoid (BP, n = 72), anti-p200 pemphigoid (n = 24), anti-laminin 332 mucous membrane pemphigoid (MMP, n = 15), pemphigus vulgaris (PV, n = 24), and healthy control subjects (n = 254). RESULTS: The cut-off for the ELISA was optimized for accuracy by receiver-operating characteristics (area under the curve [AUC] = 0.9952). IgG reactivity against NC1 was detected in 69 of 73 EBA (94.5%) and 5 control sera (2 healthy controls and 3 BP patients), resulting in a specificity of 98.7%. The IFA showed a sensitivity of 91.8% and specificity of 99.8%. Reproducibility of the ELISA was demonstrated by an intra-class correlation coefficient of 0.97. IgG subclass analyses by ELISA revealed IgG1, IgG2, IgG3, and IgG4 anti-NC1 reactivity in 83.6%, 85.3%, 37.7%, and 83.6% of EBA sera, respectively. LIMITATIONS: The novel assays were not evaluated prospectively and their use in monitoring serum levels during the disease course was not tested. CONCLUSION: The two assays are highly specific and sensitive to diagnose EBA. Their diagnostic competence was demonstrated in a large cohort of well-characterized EBA sera.

Immunofluorescence antigen mapping for hereditary epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of inherited, mechanobullous disorders that are caused by mutations in the structural proteins in the epidermis or dermoepidermal junction. Characteristic clinical picture is the presence of blisters at trauma prone areas of the body, which develops at or soon after birth. Availability of specific monoclonal antibodies against the target proteins together with advances in the molecular genetics have led to the revision in the classification of EB. Now four major types of EB are recognized depending upon the level of blister and the location of target protein: EB simplex (epidermolytic), junctional EB (lucidolytic), dystrophic EB (dermolytic) and Kindler's syndrome (mixed cleavage plane). The laboratory tests not only help to confirm the diagnosis of EB but are also an important tool to classify (and subtype) EB. These include immunofluorescence antigen mapping (IFM), transmission electron microscopy (TEM) and mutation analysis. IFM is the most preferred method for final diagnosis of EB worldwide. It is relatively easy to perform and results can be obtained rapidly. This article describes the technicalities and significance of IFM in various types of EB.

Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study.

Pyoderma gangrenosum (PG) is an important disease with significant complications. The objectives of this study were to determine incidence and mortality of PG and strength of reported associations. A retrospective cohort study was completed using computerized medical records from the General Practice Research Database, a large representative UK database. Patients with PG and three groups of age-, sex-, and practice-matched controls--general population, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) controls--were included in the study. Incidence and mortality were determined and validation undertaken to inform diagnostic accuracy. In all there were 313 people with the median age of 59 (interquartile range 41-72) years, and of them 185 (59%) were female. The adjusted incidence rate standardized to European standard population was 0.63 (95% confidence interval (CI) 0.57-0.71) per 100,000 person-years. The risk of death was three times higher than that for general controls (adjusted hazard ratio=3.03, 95% CI 1.84-4.73, P<0.001), 72% higher than that for IBD controls (adjusted hazard ratio=1.72, 95% CI 1.17-2.59, P=0.013), with a borderline increase compared with RA controls (adjusted hazard ratio=1.55, 95% CI 1.01-2.37, P=0.045). Disease associations were present in 110 (33%) participants: IBD, n=67 (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%). To our knowledge, there are no previous population-based studies of the epidemiology of PG, an important disease with significantly increased mortality.

Receptor activator of NF-kappaB (RANK) stimulates the proliferation of epithelial cells of the epidermo-pilosebaceous unit.

Receptor activator of NF-κB (RANK), known for controlling bone mass, has been recognized for its role in epithelial cell activation of the mammary gland. Because bone and the epidermo-pilosebaceous unit of the skin share a lifelong renewal activity where similar molecular players operate, and because mammary glands and hair follicles are both skin appendages, we have addressed the function of RANK in the hair follicle and the epidermis. Here, we show that mice deficient in RANK ligand (RANKL) are unable to initiate a new growth phase of the hair cycle and display arrested epidermal homeostasis. However, transgenic mice overexpressing RANK in the hair follicle or administration of recombinant RANKL both activate the hair cycle and epidermal growth. RANK is expressed by the hair follicle germ and bulge stem cells and the epidermal basal cells, cell types implicated in the renewal of the epidermo-pilosebaceous unit. RANK signaling is dispensable for the formation of the stem cell compartment and the inductive hair follicle mesenchyme, and the hair cycle can be rescued by Rankl knockout skin transplantation onto nude mice. RANKL is actively transcribed by the hair follicle at initiation of its growth phase, providing a mechanism for stem cell RANK engagement and hair-cycle entry. Thus, RANK-RANKL regulates hair renewal and epidermal homeostasis and provides a link between these two activities.

The relationship between neurological disease and bullous pemphigoid: a population-based case-control study.

Previous small studies and case reports have suggested that neurological disorders may be associated with bullous pemphigoid (BP). The objective of this study was to assess BP risk in patients with neurological diseases. Computerized medical records from the Health Improvement Network, a large population-based UK general practice database, were used to conduct a matched case-control analysis. Conditional logistic regression was used to calculate odds ratios for specified neurological disorders. Comparing cases (n=868) to controls (n=3,453), stroke was seen in 8 vs. 5%, odds ratio (OR) 1.8 (1.3-2.5); dementia in 7 vs. 2%, OR 3.4 (2.4-4.8); Parkinson's disease in 3 vs. 1%, OR 3.0 (1.8-5.0); epilepsy in 2 vs. 1%, OR 1.7 (1.0-3.0); and multiple sclerosis in 1 vs 0.1% (OR 10.7 (2.8-40.2). Estimates were not altered greatly when diagnoses up to 3 years before BP were excluded, except the association with epilepsy was no longer significant. Significant associations were only observed where neurological disease was diagnosed before the onset of pemphigoid. Study findings, except the association with epilepsy, were robust to sensitivity analysis. Strong associations were observed between specific neurological diseases and the later development of BP, supporting possible causal associations. Mechanisms for disease occurrence based on these findings include immobility or age-related autoimmunity.