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We read with interest the study by Koga H et al1 and we believe that in light of recent observations including our data (Table 1) the “desmoglein compensation theory” as a explanation for localization of blisters should be revisited 2,3,4. Although the disruption of desmoglein-dependent cell adhesion by autoantibodies is the basic pathophysiology underlying blister formation in pemphigus 2−4, the clinical spectrum does not always mirror this pathogenic process. Three clinical types of pemphigus have been described, the mucosal dominant, cutaneous and mucocutaneous type 2,,3,4 .
http://onlinelibrary.wiley.com/doi/10.1111/bjd.12012/abstract

Background:  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein adhesion proteins. Previous studies have shown an IgG4>IgG1 predominance of anti-desmoglein antibodies in pemphigus; however, no studies have examined total serum IgG4 levels in pemphigus. IgG4 is induced by chronic antigen stimulation, which could occur with persistent skin blistering and potentially elevate the total serum IgG4 relative to other IgG subclasses in pemphigus patients. Objectives:  The primary aim of the study was to quantitate total and desmoglein-specific IgG subclasses in pemphigus patients. Methods:  IgG subclasses and desmoglein-specific IgG1 and IgG4 were quantitated in PV, PF, and age-matched normal sera using a subclass ELISA. The effectiveness of IgG4 depletion in blocking PV IgG pathogenicity was determined using a keratinocyte dissociation assay. Results:  Desmoglein-specific antibodies comprised a median of 7.1% and 4.2% of total IgG4 in PV and PF patients, with 8-fold and 4-fold enrichment in IgG4 versus IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in PV and PF patients compared to age-matched controls (p=0.004 and p=0.005, respectively). IgG4 depletion of PV sera reduced pathogenicity in a keratinocyte dissociation assay and showed that affinity-purified IgG4 is more pathogenic than other serum IgG fractions. Conclusions:  Desmoglein-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some pemphigus patients. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.
http://www.ncbi.nlm.nih.gov/pubmed/22803659?dopt=Abstract
Authors: Asahina A, Koga H, Suzuki Y, Hashimoto T Abstract IgA pemphigus includes subcorneal pustular dermatosis (SPD)-type and intraepidermal neutrophilic IgA dermatosis (IEN)-type. Cases of IgG/IgA pemphigus have recently been documented(1) . Nonetheless, individual reports of IgA pemphigus indicate considerable heterogeneity. PMID: 22757612 [PubMed – as supplied by publisher] (Source: The British Journal of Dermatology)
http://www.ncbi.nlm.nih.gov/pubmed/22757612?dopt=Abstract
Background:  Pemphigus vulgaris (PV) is an autoimmune blistering skin disorder characterized by the presence of suprabasal acantholysis and autoantibodies against desmoglein 3. There are two different clinical forms: mucocutaneous (MCPV) or mucosal (MPV). However, it is not clear how PV lesions in oral, ear, nose and throat (OENT) areas produced by the very dynamic of the anatomical structures involved in the functions of the aerodigestive tract. Objectives:  To investigate the pattern of OENT manifestations in PV, and their relationship with physiological traumatic mechanisms in stratified squamous epithelium structures. Patients:  A prospective analysis of 40 patients diagnosed with MCPV (22 patients) or MPV (18 patients) was carried out in the University Clinic of Navarra. OENT manifestations were evaluated in all patients endoscopically. OENT involvement was divided into anatomical areas. Results:  The most frequent symptom was pain, mainly on oral mucosa (87,5%). Buccal mucosa (90%), posterior wall of pharynx (67.5%), upper edge of epiglottis (85%) and nasal vestibule (70%) were the areas most frequently affected in the OENT mucosa. These localizations were related to physiological traumatic mechanisms in polystratified squamous epithelium structures. Conclusions:  OENT endoscopy should be included in the examination of all PV patients. To know the most frequent localizations of active lesions on OENT mucosa in PV will help us to interpreter more efficiently the findings from OENT endoscopy. Also, information related to traumatic physiological mechanisms on OENT areas must be offered to patients in order to avoid the appearance of new active PV lesions.
PMID: 22716123 [PubMed – as supplied by publisher] (Source: The British Journal of Dermatology)
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Bullous pemphigoid (BP) is an autoimmune blistering skin disease. Autoantibodies to BP180 and BP230 can be detected by indirect immunofluorescence (IIF) on different substrates (oesophagus, salt-split-skin, BP180-antigen dots, BP230-transfected cells) and ELISA. Here, we compared test characteristics of these test systems. We analysed sera from BP patients (n=60) in whom the clinical diagnosis had been confirmed histopathologically. The control cohort comprised sera from patients with other autoimmune-associated (n=22) or inflammatory (n=35) skin diseases. All samples were tested by IIF (EUROIMMUN™ Dermatology Mosaic) and ELISA (EUROIMMUN and MBL). Anti-BP180 is best detected with BP180-antigen dots by IIF (sensitivity: 88%; specificity: 97%). As

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compared to IIF, the differences with both BP180 ELISA techniques are small though. Likelihood ratios (LRs) for positive and negative test results are >10 and between 0.1 and 0.2, respectively, for all test systems. Detection of anti-BP230 is highly variable (sensitivity range 38-60%; specificity range 83-98%). Only the IIF test reveals a LR for positive test results >10. Since the LRs for a negative test are all ~0.5, negative test results for anti-BP230 antibodies do not help to exclude BP. In conclusion, the multi-parameter IIF test reveals a good diagnostic performance in BP. Since this test simultaneously allows for the detection of anti-Dsg1 and anti-Dsg3 antibodies, involved in pemphigus foliaceus and vulgaris, a single test-incubation may be sufficient to differentiate between the most frequent autoimmune blistering diseases.

In conclusion, the multi-parameter IIF test reveals a good diagnostic performance in BP. Since this test simultaneously allows for the detection of anti-Dsg1 and anti-Dsg3 antibodies, involved in pemphigus foliaceus and vulgaris, a single test-incubation may be sufficient to differentiate between the most frequent autoimmune blistering diseases. PMID: 22580378 [PubMed – in process] (Source: Journal of Immunological Methods)
from MedWorm: Pemphigus http://www.medworm.com/index.php?rid=6304089&cid=c_297_3_f&fid=33859&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2FPubMed%2F22580378%3Fdopt%3DAbstract

Abstract

BACKGROUND:

Systematic reviews and meta-analysis are essential tools to accurately and reliably summarize evidence, and can be used as a starting point for developing practice guidelines for the diagnosis and treatment of patients.

AIM:

To estimate the diagnostic accuracy of enzyme-linked immunosorbent assays (ELISA) to detect anti-BP180 and anti-desmoglein 3 (Dsg3) autoantibodies in the diagnosis of autoimmune blistering skin diseases.

METHODS:

A Medline search of English written articles, published between 1994 and 2011, reporting data on the sensitivity and specificity of diagnostic tests was conducted using the following search terms: “BP180 autoantibodies”, “Dsg3 autoantibodies”, and “enzyme linked immunosorbent assay”. The selected articles have been evaluated according to the quality of the statistical methods used to calculate diagnostic accuracy (definition of cutoff value, use of ROC curves, and selection of control cases). The meta-analysis was performed using a summary ROC (SROC) curve and a random-effect model to independently combine sensitivity and specificity across studies.

RESULTS:

The search yielded 69 publications on BP180 autoantibodies and 178 on Dsg3 autoantibodies. A total of 30 studies met the inclusion criteria: 17 provided data on the assays to detect autoantibodies to BP180 in a sample of 583 patients with bullous pemphigoid (BP), while 13 studies provided data on the assays to search for anti-Dsg3 autoantibodies in a sample of 1058 patients with pemphigus vulgaris (PV). The 17 studies on BP180 autoantibodies yielded a pooled sensitivity of 0.87 (95% confidence interval (CI) 0.85 to 0.89) and a pooled specificity of 0.98 (CI, 0.98 to 0.99). The area under the curve (AUC) for the SROC curve was 0.988, and the summary diagnostic odds ratio was 374.91 (CI, 249.97 to 562.30). The 13 studies on Dsg3 autoantibodies which met the inclusion criteria, yielded a pooled sensitivity of 0.97 (CI, 0.95 to 0.98), and a pooled specificity of 0.98 (CI, 0.98 to 0.99). The AUC for the SROC curve was 0.995 and the summary diagnostic odds ratio was 1466.11 (95% CI, 750.36 to 2864.61).

CONCLUSIONS:

Results of the meta-analysis demonstrated that ELISA tests for anti-BP180 and anti-Dsg3 autoantibodies have high sensitivity and specificity for BP and PV, respectively, and can be used in daily laboratory practice for the initial diagnosis of autoimmune blistering skin diseases.
PMID: 22781589 [PubMed – as supplied by publisher] (Source: Autoimmunity Reviews)

from MedWorm: Pemphigus http://www.medworm.com/index.php?rid=6303276&cid=c_297_3_f&fid=34528&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2FPubMed%2F22781589%3Fdopt%3DAbstract

Fogo Selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeterminate Chagas disease was identified in a Brazilian Amerindian population of high risk for FS. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. The profile of anti-Dsg1 antibodies showed positive results in 15 of 40 FS sera and in 33 of 150 sera from healthy individuals from endemic FS sites, and no cross-reactivity between Chagas disease and FS was observed.

Authors: Sousa JX, Diaz LA, Eaton DP, Hans-Filho G, Lanzani de Freitas E, Delgado L, Ichimura LM, Cristaldi F, Orlandi R, Kesper N, Umezawa ES, Rivitti EA, Aoki V, The Cooperative Group on Fogo Selvagem Research Abstract Fogo Selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeterminate Cha…

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Background -  Glucocorticoids as sole therapy for pemphigus foliaceus (PF) in cats are not always successful, and it is common to need additional immunomodulating agents to manage the disease. Hypothesis/Objectives -  This retrospective study evaluated the use of modified ciclosporin as an adjuvant or sole immunomodulating drug in cats with PF and compared their response to PF cats managed with chlorambucil. Animals -  Fifteen client-owned cats diagnosed with PF that received ciclosporin and/or chlorambucil as part of their treatment and had adequate follow-up to assess treatment response were evaluated. Methods -  Records were reviewed from feline PF patients presented between the years of 1999 and 2009. Cats were divided into two treatment groups: those treated with ciclosporin and those treated with chlorambucil. Most cats in both groups also received concurrent systemic glucocorticoids. Each group contained six patients. Three cats were treated with both medications and are discussed separately. Time to disease remission, remission-inducing glucocorticoid dose, maintenance or final glucocorticoid dose, disease response and adverse effects were assessed. Results -  There was no significant difference in remission times or disease response between groups. All six patients maintained with ciclosporin for PF management were weaned off systemic glucocorticoids, while glucocorticoid therapy was stopped in only one of the six cats receiving chlorambucil. Conclusions and clinical importance -  Modified ciclosporin is effective in the management of feline pemphigus foliaceus and is glucocorticoid sparing. PMID: 22731616 [PubMed – as supplied by publisher] (Source: Veterinary Dermatology)
http://www.ncbi.nlm.nih.gov/pubmed/22731616?dopt=Abstract

Background  Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering disease that is characterized by superficial blistering of the skin, and according to the current perspective is caused by autoantibodies directed against desmoglein 1 (Dsg1).

Objectives  To examine early acantholysis in skin of PF patients at an ultrastructural level.

Methods  Two Nikolsky negative (N-), five Nikolsky positive (N+) and two lesional skin biopsies of immunoserological defined PF patients were studied by light and electron microscopy.

Results  We found no abnormalities in N- PF skin, whereas all N+ skin biopsies displayed intercellular widening between desmosomes, a decreased number of desmosomes, and hypoplastic desmosomes in the lower epidermal layers. Acantholysis was present in two of five N+ biopsies, but only in the upper epidermal layers. The lesional skin biopsies displayed acantholysis in the higher epidermal layers. Hypoplastic desmosomes were partially (pseudo-half-desmosomes) or completely torn off from the opposing cell.

Conclusion  We propose the following mechanism for acantholysis in PF: initially PF IgG causes a depletion of non-junctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of non-junctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic and a decreased number of desmosomes. In addition antibodies might promote disassembly of desmosomes. In the upper layers of the epidermis, where Dsg3 is not expressed and cannot compensate for Dsg1 loss, ongoing depletion of Dsg1 will finally result in a total disappearance of desmosomes and subsequent acantholysis.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2012.11173.x/abstract

Background:  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein adhesion proteins. Previous studies have shown an IgG4>IgG1 predominance of anti-desmoglein antibodies in pemphigus; however, no studies have examined total serum IgG4 levels in pemphigus. IgG4 is induced by chronic antigen stimulation, which could occur with persistent skin blistering and potentially elevate the total serum IgG4 relative to other IgG subclasses in pemphigus patients.

Objectives:  The primary aim of the study was to quantitate total and desmoglein-specific IgG subclasses in pemphigus patients.

Methods:  IgG subclasses and desmoglein-specific IgG1 and IgG4 were quantitated in PV, PF, and age-matched normal sera using a subclass ELISA. The effectiveness of IgG4 depletion in blocking PV IgG pathogenicity was determined using a keratinocyte dissociation assay.

Results:  Desmoglein-specific antibodies comprised a median of 7.1% and 4.2% of total IgG4 in PV and PF patients, with 8-fold and 4-fold enrichment in IgG4 versus IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in PV and PF patients compared to age-matched controls (p=0.004 and p=0.005, respectively). IgG4 depletion of PV sera reduced pathogenicity in a keratinocyte dissociation assay and showed that affinity-purified IgG4 is more pathogenic than other serum IgG fractions.

Conclusions:  Desmoglein-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some pemphigus patients. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2012.11144.x/abstract