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.

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.

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.

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.

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.

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.

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.

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.

Cutaneous collagenous vasculopathy with generalized telangiectasia in two female patients.

Cutaneous collagenous vasculopathy is characterized by generalized cutaneous telangiectasia and unique microscopic and ultrastructural vascular changes, consisting of marked collagen deposition within the vascular walls of the post-capillary venules in the superficial dermis. There are only 4 previous cases described in the medical literature, all in males, mostly middle-aged. We have recently seen two female patients with clinical and histopathologic features diagnostic of cutaneous collagenous vasculopathy, indicating that it is not restricted to males. As cutaneous collagenous vasculopathy can be clinically indistinguishable from generalized essential telangiectasia, and histopathologic studies are rarely performed for this condition, it is likely that cutaneous collagenous vasculopathy frequently passes unrecognized, but it may be more common than previously thought.

Epidermal receptor activator of NF-kappaB ligand controls Langerhans cells numbers and proliferation.

Langerhans cells (LC) are the dendritic APC population of the epidermis, where they reside for long periods and are self-replicating. The molecular signals underlying these characteristics are unknown. The TNF superfamily member receptor activator of NF-kappaB ligand (RANKL, TNFSF11) has been shown to sustain viability of blood dendritic cells in addition to its role in promoting proliferation and differentiation of several cell types, notably osteoclasts. In this study, we have studied expression of the RANKL system in skin and have defined a key role for this molecule in LC homeostasis. In vitro and in vivo, human KC expressed RANKL and epidermal LC expressed cell surface RANK. In vitro, RANKL sustained CD34(+) progenitor-derived LC viability following 72-h cultures in cytokine-free medium (79.5 +/- 1% vs 55.2 +/- 5.7% live cells, respectively; n = 4; p < 0.05). In vivo, RANKL-deficient mice displayed a marked reduction in epidermal LC density (507.1 +/- 77.2 vs 873.6 +/- 41.6 LC per mm(2); n = 9; p < 0.05) and their proliferation was impaired without a detectable effect on apoptosis. These data indicate a key role for the RANKL system in the regulation of LC survival within the skin and suggest a regulatory role for KC in the maintenance of epidermal LC homeostasis.

Expert consensus on the management of erlotinib-associated cutaneous toxicity in the u.k.

Rash has been reported in up to 76% of patients with lung cancer who have received the epidermal growth factor receptor inhibitor (EGFRI) erlotinib. It has also been observed in patients treated with other agents that have a similar mode of action. Erlotinib-associated skin toxicity typically presents as a papulopustular, follicular, acneiform rash. In most cases, it is mild, transient, and well tolerated, but in 8%-12% of patients, it may be sufficiently severe and persistent to necessitate intervention. Increasingly strong data suggest that the incidence and severity of skin toxicity may be predictive of response and survival in patients treated with erlotinib. This has prompted some clinicians to consider "treatment to rash" (i.e., increasing the dosage until a rash appears) as a rational management strategy. In 2007, an international consensus was developed for the management of EGFRI-associated skin toxicity. Subsequently, a multidisciplinary group (the U.K. Erlotinib Skin Toxicity Management Consensus Group) met to validate and modify the international recommendations for U.K. use, with specific reference to erlotinib. Although many aspects of the international consensus were approved by the group as being relevant for the U.K., certain parts were modified. The resulting expert opinion is a practical and workable version of the international proposal that considers all applicable national issues regarding the management of erlotinib-associated skin toxicity.

IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis.

Langerhans cells (LC) migrate rapidly from epidermis to lymph node following epicutaneous application of antigen. In this study, we have explored the role of IL-18, a cytokine with structural similarities to IL-1 beta, in murine LC migration and contact hypersensitivity (CHS), which to oxazolone (OX) and 2-4,dinitrofluorobenzene (DNFB) was suppressed significantly in IL-18 knockout (IL-18-/-) mice and could be rescued by local intradermal administration of IL-18 prior to sensitization, suggesting that the defect in these mice was in the afferent phase of CHS. To determine the effect of IL-18 on LC migration, mice were treated topically with OX or DNFB, and remaining LC numbers were assessed. A significant decline in remaining epidermal LC occurred in wild-type (WT) mice but did not occur in IL-18-/- mice. Sodium lauryl sulfate, a nonantigenic LC migratory stimulus, induced equivalent LC migration in IL-18-/- and WT mice. In IL-18-/- mice, IL-1 beta and TNF-alpha were equally able to mobilize LC from epidermis, indicating that migration in response to these cytokines is not dependent on IL-18 and suggesting that IL-18 acts upstream of these cytokines in the initiation of antigen-induced LC migration. Moreover, IL-1 beta but not IL-18 was able to rescue the defective CHS response observed in caspase-1-/- mice, which have no functional IL-1 beta or IL-18. These data indicate that IL-18 is a key proximal mediator of LC migration and CHS, acting upstream of IL-1 beta and TNF-alpha, and may play a central role in regulation of cutaneous immune responses.

Dental fitness classification in the Canadian forces.

The Canadian Forces Dental Services utilizes a dental classification system to identify those military members dentally fit for an overseas deployment where dental resources may be limited. Although the Canadian Forces Dental Services dental classification system is based on NATO standards, it differs slightly from the dental classification systems of other NATO country dental services. Data collected by dental teams on overseas deployments indicate a low rate of emergency dental visits by Canadian Forces members who were screened as dentally fit to deploy.

An individual with Muir-Torre syndrome found to have a pathogenic MSH6 gene mutation.

Mutations reported to cause Muir-Torre syndrome (MTS) have previously been reported in the mismatch repair genes MLH1 and MSH2 and more recently, in MYH [1]. We report siblings, one of whom has a clinical diagnosis of MTS, who have a pathogenic MSH6 gene mutation. This finding demonstrates that MSH6 gene analysis should be considered in MTS families where no MSH2 or MLH1 gene mutations have been found.