Tag Archives: pemphigus vulgaris

Pemphigus is a rare vesiculobullous autoimmune disease that exhibits blistering of the skin and oral cavity. It is caused by autoantibodies directed against antigens on the surface of keratinocytes. All forms of pemphigus are associated with the presence of circulating and skin-fixed autoantibodies. Pemphigus vegetans is a rare clinical variant of pemphigus vulgaris and comprises up to 5 percent of all pemphigus cases. In the following we present the oral presentation of pemphigus vegetans. We describe a 33-year-old man who was referred to our clinic complaining about mouth sores, tooth pain, and multiple pustules. During clinical exam we were able to recognize multiple pustules, ulcerated areas on the gingiva, and whitish mucosal plaques. Clinical, histopathological, and direct immunofluorescence findings were compatible with pemphigus vegetans.

Full article available at: http://www.ncbi.nlm.nih.gov/pubmed/23122017?dopt=Abstract

The clinical and epidemiological features of pemphigus vulgaris (PV) are well documented but there remain few reports of oesophageal involvement of PV. Although previously considered to be rare, recent reports have suggested that up to 87% of patients with PV may have symptoms, or endoscopic features, of oesophageal disease that may be poorly responsive to conventional corticosteroid-sparing immunosuppression.

The present report details the clinical and immunological features of a 53 year old Asian female who developed symptoms and signs of oesophageal PV during therapy with azathioprine and decreasing prednisolone dosage. Oesophageal involvement occurred during stable oral disease.

Oesophageal involvement can occur without significant oro-cutaneous lesions and immunological evidence of PV. This suggests that immunological targets for oesophageal disease may differ from those of other mucocutaneous areas, and that conventional first-line systemic therapy may not be effective for oesophageal lesions.

Full article available at: http://www.ingentaconnect.com/content/ubpl/wlmj/2012/00000004/00000002/art00001

Background.  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune vesicobullous disorders with IgG autoantibodies directed against desmoglein (Dsg)1 and 3, which lead to intraepidermal acantholysis.

Aim.  To characterize the clinical and immunological profile of patients with PF or PV with umbilical involvement.

Methods.  In total, 10 patients (7 women, 3 men; age range 24–70 years, disease duration 3–16 years) diagnosed with either PV (n = 5) or mucocutaneous PF (n = 5) were assessed according to their clinical features, histopathology and immunological findings .

Results.  Erythema, erosions, crusts and vegetating skin lesions were the main clinical features of the umbilical region. DIF of the umbilical region gave positive results for intercellular epidermal IgG and C3 deposits in eight patients and for IgG alone in the other two. Indirect immunofluorescence with IgG conjugate showing the typical pemphigus pattern was positive in all 10 patients, with titres varying from 1 : 160 to 1 : 2560. ELISA with recombinant Dsg1 gave scores of 24–266 in PF and 0–270 in PV. Reactivity to recombinant Dsg3 was positive in all five patients with PV (ELISA 22–98) and was negative in all PF sera.

Conclusions.  All 10 patients with pemphigus with umbilical presentation had the clinical and immunopathological features of either PF or PV. This peculiar presentation, not yet completely elucidated, has rarely been reported in the literature. A possible explanation for this unique presentation may be the presence of either novel epitopes or an association with embryonic or scar tissue located in the umbilical-cord region.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2230.2012.04468.x/abstract

The molecular basis of disease heterogeneity in autoimmune conditions such as Pemphigus vulgaris is poorly understood. Although desmoglein 3 (Dsg3) has been well established as a primary target of immunoglobulin (Ig) autoantibodies in PV, there remain several questions regarding the overall distribution of anti-Dsg3 Ig subtypes among patient subsets and considerable controversy regarding whether an isotype switch can be observed between phases of disease activity. To systematically address the outstanding questions related to Ig-isotype specificity in PV, we analyzed IgA, IgM, IgG1, 2, 3 and 4 anti-Dsg3 levels by ELISA in 202 serum samples obtained from 92 patients with distinct clinical profiles based on a set of defined variable (activity, morphology, age, duration) and constant (HLA-type, gender, age of onset) clinical parameters, and 47 serum samples from HLA-matched and -unmatched controls. Our findings provide support for earlier studies identifying IgG4 and IgG1 as the predominant antibodies in PV with significantly higher levels in active than remittent patients. We do not see evidence for an isotype switch between phases of disease activity and remission, and both IgG4 and IgG1 subtypes remain elevated in remittent patients relative to controls. We do, however, find IgG4 to be the sole subtype that further distinguishes PV patient subgroups based on different disease morphologies, disease duration, and HLA-types. These data provide further insight into the immune mechanisms responsible for phenotypic expression of disease, and contribute to the broader effort to establish comprehensive immunoprofiles underlying disease heterogeneity to facilitate increasingly specific and individualized therapeutic interventions.

Full article available at: http://www.ncbi.nlm.nih.gov/pubmed/22779708

Pemphigus is a chronic, muco-cutaneous autoimmune blistering disorder; two main variants being pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV is the most common subtype, varying between 75 to 92% of total pemphigus patients. Although no community based studies are undertaken to estimate the incidence of pemphigus in India, it is relatively common. A questionnaire based survey in Thrissur district of south India estimated pemphigus incidence to be 4.4 per million population. Mortality due to pemphigus has decreased remarkably with the aggressive and widespread use of corticosteroids, prior to which it was as high as 90%. High dose corticosteroids were once used in combination with other immunosuppressants with good improvement, but such high doses of corticosteroids were often associated with severe side effects, and were responsible for the death of nearly 10% of the patients. With the aim of reducing the adverse effects of long term, high dose steroid administration dexamethasone cyclophosphamide pulse (DCP) therapy was introduced in 1984. Since then DCP or oral corticosteroids with or without adjuvant immunosuppressants (azathioprine, cyclophosphamide, mycophenolatemofetil, and cyclosporine) have been the corner-stone of therapy for these disorders in India. Despite the benefits associated with DCP therapy compared to high dose oral steroids, it cannot be denied that even DCP therapy with or without adjuvants can lead to numerous adverse events, which account for majority of deaths in pemphigus. Moreover there are few patients who fail to improve with these conventional treatments or have contraindications for their usage. Thus there has been a constant search for newer therapeutic modalities in pemphigus. Rituximab (Reditux. Dr. Reddy’s, Hyderabad, India and MabThera TM , Roche, Basel, Switzerland), a monoclonal chimeric IgG1 antibody targeting the B cell specific cell-surface antigen CD20, is one such newer novel therapy for pemphigus (an off-label indication for its use. It has so far been approved by FDA for use only in CD 20+ B cell non-Hodgkin’s lymphoma, treatment resistant rheumatoid arthritis, Wegener’s granulomatosis and microscopic polyangiitis).

There is currently no consensus on the optimal dosage and schedule of rituximab in treatment of pemphigus. The various treatment protocols followed include:

  1. Lymphoma protocol- Most commonly followed protocol. Rituximab is administered at a dose of 375mg/m 2 body surface area weekly for four weeks.
  2. Rheumatoid arthritis protocol- Two doses of rituximab 1g is administered at an interval of 15 days. Increasingly used by dermatologists and is the protocol currently followed in our institute. Advantage over the lymphoma protocol include less cost and fewer infusions.
  3. Combination therapy- Rituximab has been used in combination with IVIG, immunoadsorption and dexamethasone pulse therapy
  4. Long-term rituximab treatment with regular infusions every 4 or 12 weeks following an induction cycle of infusions every week

Full article can be viewed at: http://www.ijdvl.com/article.asp?issn=0378-6323;year=2012;volume=78;issue=6;spage=671;epage=676;aulast=Kanwar

Background  The classic treatment for pemphigus vulgaris is prednisolone. Immunosuppressive drugs can be used in association.

Objective  To compare the efficacy of Azathioprine in reducing the Disease Activity Index (DAI).

Patients and methods  A double blind randomized controlled study was conducted on 56 new patients, assigned to two therapeutic groups: (i) prednisolone plus placebo; (ii) prednisolone plus Azathioprine. Patients were checked regularly for 1 year. ‘Complete remission’ was defined as healing of all lesions after 12 months, and prednisolone <7.5 mg daily, (DAI ≤ 1). Analysis was done by ‘Intention To Treat’ (ITT) and ‘Treatment Completed Analysis’ (TCA).

Results  Both groups were similar in age, gender, disease duration, and DAI. Primary endpoint: By ITT and TCA, the mean DAI improved in both groups with no significant difference between them. The difference became significant for the last trimester (3 months; ITT:P = 0.033, TCA: P = 0.045). Secondary endpoint: The total steroid dose decreased significantly in both groups, with no significant difference between them, except for the last trimester (ITT: P = 0.011, TCA: P = 0.035). The mean daily steroid dose decreased gradually in both groups becoming statistically significant in favour of azathioprine, in the last trimester, especially at 12th months (ITT: P = 0.002, TCA:P = 0.005). Complete remission was significant at 12 months only for TCA (AZA/Control: 53.6%/39.9%, P = 0.043).

Limitations  Sample size was rather small to demonstrate all differences. Other limitations include the choice of primary and secondary endpoints and the unavailability to measure thiopurine methyltransferase activity.

Conclusion  Azathioprine helps to reduce prednisolone dose in long-run.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-3083.2012.04717.x/abstract;jsessionid=4F8C646E8902BB54AC0026B542EF91FD.d03t01

MedWire News: Researchers have identified the primary target of the autoantibodies found in the serum of patients with the blistering skin disorder pemphigus vulgaris (PV).

PV patients develop antibodies against the proteins desmoglein (DSG)1 and 3, which help epidermal cells stick together and maintain the integrity of the skin, causing painful blistering on the skin and mucus membranes.

Giovanna Zambruno (Istituto Dermopatico dell’Immacolata, Rome, Italy) and colleagues found that the cis-adhesive interface of the DSG3 extracellular domain (EC)1 is the main target of the PV autoantibody (A)224 generated in the serum of patients with PV.

Existing therapies for the condition target the whole immune system, but this can cause problems with side effects and can result in patients being vulnerable to infections.

To pinpoint the trigger of the autoantibody production in PV more specifically, Zambruno and team isolated 15 immunoglobulin (Ig)G antibodies specific for DSG3 from two patients with the disorder.

Of these, three disrupted layers of skin cells in the laboratory and two were pathogenic when expressed in a murine passive transfer model.

The epitopes recognized by the pathogenic PV antibodies were isolated to the DSG3 EC1 and EC2 subdomains and a specific serologic assay was used to pinpoint the target of the PVA224 as being the cis-adhesive interface on EC1.

The researchers suggest that the autoreactivity seen in PV is due to somatic mutations that are generated by an antigen other than DSG3, as binding to DSG3 disappeared when the somatic mutations reverted to the germline sequence.

“The identification of an immunodominant region targeted by pathogenic antibodies has implications for diagnosis of PV and opens new perspectives toward the establishment of therapeutic approaches for treatment of PV patients,” write Zambruno and team in the Journal of Clinical Investigation.

“Finally, the germlined version of the PV autoantibodies may lead to the identification of the antigens that eventually lead to development of this life-threatening disease.”

medwireNews (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

Read at: http://www.medwire-news.md/66/101414/Dermatology/Therapeutic_targets_for_pemphigus_vulgaris_discovered.html

This study aimed to highlight the importance of routine screening for hyperglycemia and to develop a standardized, evidence-based approach for the management of pemphigus patients on prolonged systemic corticosteroid (CS) therapy. A cross-sectional study was conducted in two university-affiliated teaching hospitals using a referred sample of 200 patients with a confirmed diagnosis of pemphigus vulgaris, pemphigus foliaceus, or mucous membrane pemphigoid. All patients were receiving systemic CS therapy. A total of 150 patients responded to the survey. Six participants were excluded and 144 were included. The main outcome measure was blood glucose level to detect hyperglycemia. New-onset hyperglycemia was identified in 40% of patients who received CS therapy. None of the expected variables, including age, body mass index, family history of diabetes, corticosteroid dose, and duration of corticosteroid therapy, were independently associated with new-onset hyperglycemia. These findings indicate that the prevalence of CS-induced hyperglycemia in pemphigus patients is 40% and that in patients with pemphigus or MMP, CS therapy is associated with a markedly increased risk for hyperglycemia (odds ratio = 10.7, 95% confidence interval 1.38–83.50) compared with that of patients with the same diseases who do not receive CS therapy.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-4632.2012.05470.x/abstract

Background  Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein (Dsg) adhesion proteins. Previous studies have shown an IgG4 > IgG1 predominance of anti-Dsg 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 patients with pemphigus.

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

Methods  IgG subclasses and Dsg-specific IgG1 and IgG4 were quantitated in patients with PV and PF, and in sera from age-matched controls using a subclass enzyme-linked immunosorbent assay. The effectiveness of IgG4 depletion in blocking IgG pathogenicity in PV was determined using a keratinocyte dissociation assay.

Results  Dsg-specific antibodies comprised a median of 7·1% and 4·2% of total IgG4 in patients with PV and PF, respectively, with eightfold and fourfold enrichment in IgG4 vs. IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in patients with PV and PF compared with 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  Dsg-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some patients with pemphigus. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.

Full article available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2133.2012.11144.x/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