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Pemphigus vulgaris (PV) is an autoimmune disease in which the body’s immune system develops antibodies to two of its own proteins, the desmogleins DSG1 and DSG3 that help maintain the integrity of the skin. The immune attack causes painful blisters on the skin and mucus membranes that can lead to infections. Current therapies are geared towards suppressing the entire immune system, but this is problematic as it causes many side effects and leaves the patient vulnerable to infection.

To identify better therapeutic targets, researchers at the Institute for Research in Biomedicine in Bellinzona, Switzerland, identified the portions of DSG1 and DSG3 that are targeted by antibodies. In the study, published this month in the Journal of Clinical Investigation, Antonio Lanzavecchia and colleagues collected immune cells from PV patients and isolated the antibodies to determine which ones were involved in PV. By studying the antibodies, they were able to identify regions of DSG3 that are the primary target of the immune sysm. These findings could help with new ways to diagnose and treat PV.

Full article available at: http://www.medicalnewstoday.com/releases/249883.php

We evaluated the effectiveness of mizoribine, a newly developed immunosuppressive agent, as an adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus. Eleven pemphigus patients (eight pemphigus vulgaris and three pemphigus foliaceus) received the combination therapy of prednisolone and mizoribine. Complete remission was observed in three of the eight patients with pemphigus vulgaris and in one of the three patients with pemphigus foliaceus. The four patients with complete remission had a rapid clinical response and achieved remission at a median of 11.8 months. Partial remission was achieved in two of the three patients with pemphigus foliaceus. The median time to achieve partial remission was 16.0 months. Six (55.6%) of the 11 patients with pemphigus had complete or partial remission and were able to taper their prednisolone. The cumulative probability of having a complete remission was 64.3% at 19 months of follow-up using Kaplan–Meier analysis. The effectiveness of the additional mizoribine therapy could be attributed to its corticosteroid-sparing properties as well as its immunosuppressive effects. The serum concentration titer of mizoribine was around 1.0 μg/mL 2 hours after administration. Patients who were not improved by the additional mizoribine might require a continuously higher dose of mizoribine to achieve effective therapy.

Full Article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1529-8019.2012.01469.x/abstract

Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease of skin and mucous membranes caused by autoantibodies that bind to the cadherin-type cell-cell adhesion molecules desmoglein 3 (DSG3) and DSG1, the main constituents of desmosomes, and cause the loss of keratinocyte cell adhesion. The critical role of autoantibodies in PV pathogenesis is supported by the observations that the disease activity correlates with anti-DSG3 antibody titers , that newborns of mothers with active PV exhibit blisters caused by the placental transfer of maternal antibodies, and that pemphigus-like lesions are induced in neonatal mice by passive transfer of anti-DSG3 IgG from PV patients.

In the skin, DSG3 is mainly expressed in the basal and suprabasal layers, while DSG1 is predominantly expressed in the upper epidermal layers. In contrast, in noncornified stratified epithelia, such as the oral mucosa, DSG3 is highly expressed throughout the epithelium, while DSG1 is expressed at a much lower level. The differential expression pattern of DSG1 and DSG3 is responsible for clinical variants of pemphigus: antibodies to DSG3 are present in the mucosal form, while antibodies to both DSG3 and DSG1 are associated with mucocutaneous lesions.

DSG3 is a calcium-binding membrane glycoprotein with an extracellular domain comprising 5 distinct subdomains (EC1–EC5), and it is synthesized as proprotein, which is processed in the Golgi apparatus by removal of a propeptide before transporting to the cell surface. The cleavage of the propeptide occurs upstream of a conserved tryptophan residue in the EC1 subdomain, unmasking residues critical for the formation of homophilic interactions with DSG3 on opposing cells. Several studies have shown that polyclonal antibodies in PV serum react primarily with the aminoterminus of DSG3 in the EC1 and EC2 subdomains (amino acids 1–161).

The isolation of pathogenic mAbs is instrumental for addressing questions as to the mechanism that induces the autoreactive response and drives blister formation in PV patients. Amagai and coworkers isolated from an active mouse model of PV a pathogenic antibody, AK23, which causes loss of cell adhesion by binding to the EC1 subdomain of DSG3 that is involved in the formation of the trans-adhesive interface. A number of human anti-DSG pathogenic and nonpathogenic mAbs were isolated as single-chain variable-region fragments (scFvs) from a PV patient . Similarly to the AK23 mAb, the pathogenic activity of these human antibodies was mapped to the aminoterminal region of EC1, which is masked by the propeptide . Taken together, the human and mouse data suggest that pathogenic antibodies bind primarily to EC1 and disrupt the keratinocyte adhesion by interfering with the trans-adhesive interface of DSG3.

In this study, we isolated from 2 PV patients several IgG autoantibodies that bind DSG3. These antibodies carried high levels of somatic mutations that were required for binding to DSG3. The epitopes recognized by 3 pathogenic antibodies were mapped to the EC1 and EC2 subdomains in regions that are expected to be involved in cis-adhesive interactions. This region was found to be the primary target of serum autoantibodies in PV patients. These results identify the cis-adhesive interface as the immunodominant region targeted by pathogenic antibodies in PV and suggest that autoreactivity relies on somatic mutations triggered by an unrelated antigen.

Full article Available at: http://www.jci.org/articles/view/64413

We report a case of neutropenic ulceration in a 42-year-old woman receiving azathioprine for pemphigus vulgaris. She developed multiple indolent ulcers involving the nose, neck, and back, after about 6-8 weeks following commencement of azathioprine 50 mg daily. The ulcers were large, disfiguring, dry, and with basal necrotic slough. They were painless and did not discharge pus. The absolute neutrophil count was severely depressed initially, but normalized following azathioprine withdrawal. Swab culture revealed colonization with Klebsiella pneumoniae and the ulcers healed with local debridement, treatment with imipenem, and topical application of mupirocin. However, nasal disfigurement persisted. Neutropenic ulceration is known to be associated with azathioprine therapy but we report this case because of the unusual presentation-indolent cutaneous ulcers. Early recognition of the problem and drug withdrawal can prevent complications like disfigurement.

Neutropenia is characterized by an abnormally low number of neutrophils in the blood. Neutrophils normally comprise 45-75% of circulating white blood cells, and neutropenia is diagnosed when the absolute neutrophil count falls to <1500/ μL. Slowly developing neutropenia often goes undetected and is generally discovered when the patient develops sepsis or localized infections.

There are many causes of neutropenia, and immunosuppressants are a common iatrogenic cause. Azathioprine is an immunosuppressant drug that is being used for nearly 50 years now in organ transplantation and in diseases with suspected autoimmune etiology. Dermatologists use azathioprine as a steroid-sparing agent in various dermatoses such as psoriasis, immunobullous diseases, photodermatoses, and eczematous disorders. [1] The drug has been used in ulcerative autoimmune disorders such as Crohn’s disease and pyoderma gangrenosum. On the other hand, it has also been implicated as a cause of ulceration associated with neutropenia. [2] Most reports of neutropenic ulceration document involvement of the buccal mucosa and oral cavity.  We report a case of multiple severe cutaneous ulcers associated with long-term azathioprine use in a patient with pemphigus vulgaris.

Full article available at: http://www.ijp-online.com/article.asp?issn=0253-7613;year=2012;volume=44;issue=5;spage=646;epage=648;aulast=Laha

Pemphigus vulgaris (PV) is a rare immunobullous dermatosis with worldwide distribution. The core manifestation of the condition is mucosal erosions and easily ruptured bullae that emerge on an apparently normal skin and mucous membranes or on an erythematous base. It is perhaps the most formidable dermatologic emergency which requires prompt treatment without which it may prove to be fatal. Though, new treatment modalities have decreased the mortality, nevertheless complications of the treatment are the main hazards presented by various clinical manifestations, and among them fever represents one of the most important presentations.

To characterize pyrexia, seventy two febrile pemphigus cases admitted to dermatology ward of a University Teaching Hospital, Tabriz University of Medical Sciences, Tabriz, Iran, were enrolled in this study, during March 2010 to February, 2011. The patients received oral therapy (oral prednisolone 1-2 mg/kg/day) and cytotoxics including azathioprine and cyclophosphamide or pulse therapy (with methyl prednisolone 500-1000 mg daily for three days and cyclophosphamide 500 mg with MESNA [2 Mercapto Ethane Sulfonate Sodium] rescue). Investigations for the management of fever included blood, cerebrospinal fluid (CSF), urine, cutaneous lesions and synovial fluid culture, gram’s and AFB (Acid Fast Bacilli) staining of sputum, complete blood count (CBC), erythrocyte sedimentation rate (ESR), chest X-ray and stool examination for ova or cyst of parasites. Statistical analysis was performed using SPSS software version 16.

Among 72 febrile pemphigus patients admitted, majority (97.2%) of them were classified as pemphigus vulgaris, with suprabasal acantholysis, while only 2.8% cases presented with pemphigus foliaceous, with more superficial (subcorneal) acantholysis. Though not significant, 56.9% of patients were females. Mean age of cases was 45.31 ± 16.75. Mean interval since diagnosis of pemphigus (and initiation of treatment) to the presence of fever was 5.72 ± 4.97 days. Oral therapy was prescribed to 91.7% of patients, while 8.3% received pulse therapy. The prime etiology of pyrexia was the presence of infection at various sites including: cutaneous lesions (19.4%), pulmonary infections (15.27%), urinary tract infections (11.1%) and gastroenteritis (5.5%). No patient was found positive for the presence of mycobacterium morphology on AFB smear of sputum. Staphylococcus aureus infection was revealed in 82.9% of cases with cutaneous erosions.

Full article can be found here: http://www.ijdvl.com/article.asp?issn=0378-6323;year=2012;volume=78;issue=6;spage=774;epage=774;aulast=Qadim

Paraneoplastic pemphigus (PNP) is a rare, life-threatening, autoimmune, mucocutaneous blistering disease associated with neoplasia. Both humoral and cellular immunity are involved in the pathogenesis of PNP. Characteristically, PNP has a diverse spectrum of clinical and immunopathological features. We retrospectively analyzed 12 Korean patients with PNP who were diagnosed between 1993 and 2011. We performed analysis of the

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clinical features, clinical outcomes, underlying neoplasia, histological features and laboratory findings. All of the patients except one had severe mucosal involvement. Two patients had only mucosal lesions but no cutaneous involvement was observed. Erythema multiforme or lichen planus-like eruptions rather than bullous lesions were more commonly observed skin rashes. The most common histological features were interface dermatitis and apoptotic keratinocytes. There were associated hematological-related neoplasms in 11 patients, with Castleman’s disease (n = 4) as the most frequent. Twelve patients were followed for 5–148 months (mean, 43.0). The prognosis depended on the nature of the underlying neoplasm. Six patients died due to respiratory failure (n = 3), postoperative septicemia (n = 1), lymphoma (n = 1) and sarcomatosis (n = 1). The 2-year survival rate was 50.0%, and the median survival period after diagnosis was 21.0 months. Immunoblotting was performed in 12 patients and autoantibodies to plakins were detected in 11 patients. The results of this study demonstrated the clinical, histological and immunological diversity of PNP. Widely accepted diagnostic criteria that account for the diversity of PNP are needed.

Full Article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1346-8138.2012.01655.x/abstract

MADAM, Autoantibodies in pemphigus target preferentially desmoglein 1 (Dsg1) and Dsg3, and rarely desmocollins 1-3 (Dsc1-3). Pemphigus herpetiformis (PH) is one of pemphigus subtypes and characterized by pruritic annular erythemas with vesicles in the periphery, rarity of mucosal involvement and histopathological change of eosinophilic spongiosis. Recently, IgG anti-Dsc3 autoantibodies were suggested to cause skin lesion in a case of pemphigus vulgaris. In this study, we report the first case of concurrent bullous pemphigoid (BP) and PH with IgG antibodies to both Dsgs and Dscs.

from: http://onlinelibrary.wiley.com/doi/10.1111/bjd.12019/abstract

Background  Promoter polymorphisms of the macrophage migration inhibitory factor gene are associated with increased production of macrophage migration inhibitory factor. Elevated levels of macrophage migration inhibitory factor have been observed in the sera of patients with pemphigus vulgaris. More than this, macrophage migration inhibitory factor promoter gene polymorphism has been found to confer increased risk of susceptibility to chronic inflammatory diseases.

Objective  We investigated whether there is an association between promoter polymorphism of the macrophage migration inhibitory factor gene and pemphigus vulgaris.

Methods  One hundred and six patients with pemphigus vulgaris, and a control panel of one hundred healthy volunteers were genotyped for a single nucleotide polymorphism identified in the 5′-flanking region at the position −173 of the gene, using polymerase chain reaction–restriction fragment length analysis.

Results  We found a notably high prevalence of C/C genotype in our nation but no significant difference was observed between patients and controls.

Conclusion  The result of this study using a large and well documented trial of patients showed that macrophage migration inhibitory factor −173G-C polymorphism is not associated with pemphigus vulgaris; but as the role of macrophage migration inhibitory factor in the inflammatory process has not been delineated in detail and the prevalence of C/C genotype is notably higher in our nation, this finding merits more consideration.

full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-3083.2012.04676.x/abstract

Background

Various antigen-specific immunoassays are available for the serological diagnosis of autoimmune bullous diseases. However, a spectrum of different tissue-based and monovalent antigen-specific assays is required to establish the diagnosis. BIOCHIP mosaics consisting of different antigen substrates allow polyvalent immunofluorescence (IF) tests and provide antibody profiles in a single incubation.

Methods

Slides for indirect IF were prepared, containing BIOCHIPS with the following test substrates in each reaction field: monkey esophagus, primate salt-split skin, antigen dots of tetrameric BP180-NC16A as well as desmoglein 1-, desmoglein 3-, and BP230gC-expressing human HEK293 cells. This BIOCHIP mosaic was probed using a large panel of sera from patients with pemphigus vulgaris (PV, n equals 65), pemphigus foliaceus (PF, n equals 50), bullous pemphigoid (BP, n equals 42), and non-inflammatory skin diseases (n equals 97) as well as from healthy blood donors (n equals 100). Furthermore, to evaluate the usability in routine diagnostics, 454 consecutive sera from patients with suspected immunobullous disorders were prospectively analyzed in parallel using a) the IF BIOCHIP mosaic and b) a panel of single antibody assays as commonly used by specialized centers.

Results

Using the BIOCHIP mosaic, sensitivities of the desmoglein 1-, desmoglein 3-, and NC16A-specific substrates were 90 percent, 98.5 percent and 100 percent, respectively. BP230 was recognized by 54 percent of the BP sera. Specificities ranged from 98.2 percent to 100 percent for all substrates. In the prospective study, a high agreement was found between the results obtained by the BIOCHIP mosaic and the single test panel for the diagnosis of BP, PV, PF, and sera without serum autoantibodies (Cohen’s kappa between 0.88 and 0.97).

Conclusions

The BIOCHIP mosaic contains sensitive and specific substrates for the indirect IF diagnosis of BP, PF, and PV. Its diagnostic accuracy is comparable with the conventional multi-step approach. The highly standardized and practical BIOCHIP mosaic will facilitate the serological diagnosis of autoimmune blistering diseases.

Full article available at: http://www.medworm.com/index.php?rid=6328120&cid=c_297_49_f&fid=36647&url=http%3A%2F%2Fwww.ojrd.com%2Fcontent%2F7%2F1%2F49

Pemphigus is a potentially fatal autoimmune epidermal bullous disorder. Rituximab is a novel therapy for the treatment of refractory pemphigus. However, there is limited clinical data on safety and efficacy of rituximab in pediatric age group. Herein, we report an 11-year-old boy of childhood pemphigus vulgaris who failed to respond to dexamethasone pulse therapy and was subsequently treated with rituximab and achieved complete remission.

http://www.ijdvl.com/article.asp?issn=0378-6323;year=2012;volume=78;issue=5;spage=632;epage=634;aulast=Kanwar