Bullous Pemphigoid: A 10-Year Study of Discordant Results on Direct Immunofluorescence

Background: Bullous pemphigoid (BP) is the most common subepidermal autoimmune disorder characterized by tense bullae. It is associated with circulating autoantibodies against BP antigen-1 and BP antigen-2. Diagnosis is based upon clinical, histopathologic, and immunopathologic examination. Direct immunofluorescence (DIF) of perilesional skin highlights C3 with or without IgG in a linear pattern along the basement membrane. Objectives: We hypothesized that repeat biopsies may be required for a definitive DIF diagnosis of BP, as initial DIF evaluation may result in a false-negative result. Methods: A retrospective chart review was conducted on 1143 specimens collected for evaluation for BP. Cases from 2 Vancouver Coastal Health Authority laboratories from 2006 to 2016 were reviewed. Results were interpreted as positive, negative, or indeterminate based on pathologic description and specimen quality. Results: After meeting the inclusion criteria, 739 specimens were further evaluated. There were 289 cases of BP in the 10-year period. Five patients (1.73%; 95% confidence interval [CI], 1.50-1.96) required a second biopsy to support a BP diagnosis, and within this group, 1.04% of the 289 (95% CI, 0.811-1.27) were true successive negative-to-positive DIF results. Conclusions: DIF is the most reliable test used to diagnose BP; however, a small percentage of patients will initially have a negative result. False-negative or indeterminate results may be due to specimen sampling from lesional skin or due to a subthreshold quantity of immune complexes in the skin. Repeat biopsy is warranted despite an initial negative DIF if BP is clinically suspected.

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Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin

Journal of Translational Medicine ◽

10.1186/s12967-021-03192-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Karim Chouchane ◽

Giovanni Di Zenzo ◽

Dario Pitocco ◽

Laura Calabrese ◽

Clara De Simone

Keyword(s):

Bullous Pemphigoid ◽

Complement C3 ◽

Direct Immunofluorescence ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Drug Induced ◽

Inflammatory Phenotype ◽

Linear Band ◽

Circulating Autoantibodies

AbstractBullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs’ exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal–epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens.

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False-Negative Rate of Direct Immunofluorescence on Lower Extremities in Bullous Pemphigoid

American Journal of Dermatopathology ◽

10.1097/dad.0000000000001710 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

David M. Perry ◽

Ashley Wilson ◽

Sally Self ◽

John C. Maize

Keyword(s):

Bullous Pemphigoid ◽

False Negative ◽

False Negative Rate ◽

Lower Extremities ◽

Direct Immunofluorescence ◽

Negative Rate

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A predominant IgG4 subclass may be responsible for false-negative direct immunofluorescence in bullous pemphigoid

Journal of Cutaneous Pathology ◽

10.1034/j.1600-0560.2002.290504.x ◽

2002 ◽

Vol 29 (5) ◽

pp. 282-286 ◽

Cited By ~ 13

Author(s):

Kerry E. Buschman ◽

Mark Seraly ◽

H. Y. Thong ◽

Jau-Shyong Deng ◽

Rose P. Draviam ◽

...

Keyword(s):

Bullous Pemphigoid ◽

False Negative ◽

Direct Immunofluorescence

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Canine Bullous Pemphigoid (BP): Identification of the 180-kd Canine BP Antigen by Circulating Autoantibodies

Veterinary Pathology ◽

10.1177/030098589503200407 ◽

1995 ◽

Vol 32 (4) ◽

pp. 387-393 ◽

Cited By ~ 28

Author(s):

T. Iwasaki ◽

T. Olivry ◽

J. C. Lapiere ◽

L. S. Chan ◽

C. Peavey ◽

...

Keyword(s):

Bullous Pemphigoid ◽

Human Keratinocytes ◽

Direct Immunofluorescence ◽

Western Immunoblotting ◽

Basal Keratinocytes ◽

Immune Mediated ◽

Skin Protein ◽

Blistering Disease ◽

Parallel Features ◽

Circulating Autoantibodies

Human bullous pemphigoid (BP) is an immune-mediated blistering disease characterized by autoantibodies against BP antigens (230/180 kd), which are constitutive glycoproteins of hemidesmosomes found in basal keratinocytes. Blistering diseases similar to human BP have been reported in dogs. IgG deposits at the basement membrane zone (BMZ) are a common feature of canine BP. Although circulating anti-BMZ IgG autoantibodies have been demonstrated in some cases of canine BP, the specific skin protein targeted by these autoantibodies has not been identified. In this study, we characterized the antigenic target of the autoantibodies in the serum from a 3-year-old castrated male Pit Bull Terrier with BP. Direct immunofluorescence of the patient's skin demonstrated IgG deposits at the dermal-epidermal junction. Indirect immunofluorescence demonstrated autoantibodies in the patient's serum that stained the epidermal roof of salt-split canine skin and left the dermal floor unstained. These serum autoantibodies did not stain normal intact dog skin but labeled intact bovine tongue. Direct immunoelectron microscopy of the dog's skin revealed IgG deposits within the hemidesmosomes of the basal keratinocytes. Western immunoblotting experiments showed that canine keratinocytes express both the 230-kd and 180-kd bullous pemphigoid antigens, and the autoantibodies from the patient's serum recognized the 180-kd bullous pemphigoid antigen in proteins extracted from canine and human keratinocytes. Canine BP has many parallel features with human BP including similar immune deposition of IgG within hemidesmosomes and a hemidesmosome-associated 180-kd glycoprotein target for circulating autoantibodies.

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Biopsy Location for Direct Immunofluorescence in Patients with Suspected Bullous Pemphigoid Impacts Probability of a Positive Test Result

Journal of Cutaneous Medicine and Surgery ◽

10.2310/7750.2014.14004 ◽

2014 ◽

Vol 18 (6) ◽

pp. 392-396 ◽

Cited By ~ 6

Author(s):

Chris Sladden ◽

Mark G. Kirchhof ◽

Richard I. Crawford

Keyword(s):

Skin Biopsy ◽

Bullous Pemphigoid ◽

Chart Review ◽

Normal Skin ◽

Retrospective Chart Review ◽

Direct Immunofluorescence ◽

Positive Test Result ◽

Complement Proteins ◽

Biopsy Site ◽

Test Result

Background: Bullous pemphigoid (BP) is an autoimmune polymorphic skin disease characterized by erythematous papules and plaques and tense bullae. A skin biopsy for direct immunofluorescence (DIF) is used to detect autoantibodies and complement proteins. Objective: We sought to determine which location would provide the highest probability of obtaining a positive DIF result. Method: We undertook a retrospective chart review of 1,423 DIF biopsies. Biopsies with a clinical suspicion of BP were designated as either lesional, perilesional, or indeterminate. Results: Fifty percent of lesional DIF biopsies were positive, whereas 22% of perilesional and 12% of indeterminate biopsies had a positive DIF result. The odds ratio of a positive DIF from a lesional versus perilesional biopsy site was found to be 3.45 (95% CI 1.44–8.29). Conclusion: Clinicians are more likely to obtain a positive DIF result from a lesional nonbullous skin biopsy than from a perilesional or normal skin biopsy.

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Lichen Planus Pemphigoides: A Case Report

Journal of Shaheed Suhrawardy Medical College ◽

10.3329/jssmc.v4i1.12002 ◽

2012 ◽

Vol 4 (1) ◽

pp. 35-37

Author(s):

I Bhuiyan ◽

MS Hossain ◽

MSA Khan ◽

M Alam ◽

MA Haque

Keyword(s):

Bullous Pemphigoid ◽

Lichen Planus ◽

Normal Skin ◽

Topical Steroid ◽

Oral Disease ◽

Linear Pattern ◽

Bullous Lesion ◽

Split Skin ◽

Pemphigoid Nodularis ◽

Chronic Course

Lichen planus pemphigoides describe a rare subset of patients who usually have typical lichen planus then develop blistering on their lichen planus lesions and in normal skin. Less commonly the blistering antedates the lichen planus. They clinically appear to be a combination of lichen planus and bullous pemphigoid. Oral disease may occur and resemble either lichen planus or bullous pemphigoid. Lichen planus pemphigoides has been triggered by medication & PUVA. Pruritus may be severe and lesions may evolve to resemble pemphigoid nodularis. Histopathologically lichen planus lesions show lichen planus and bullous lesion shows the features of bullous pemphigoid. DIF is positive in a linear pattern with IgG and C3 along the basement membrane zone, at the roof of saline split skin. The antigen targeted by the autoantibody in Lichen planus pemphigoides is located in the same region as the bullous pemphigoid antigen (at the basal hemidesmosomes). Lichen planus pemphigoides tends to follow a benign and chronic course, even when compared to bullous pemphigoid. We diagnosed a case of Lichen planus pemphigoides on the basis of history, clinical examination, histopathology & DIF. The patient was treated with systemic & topical steroid, Dapsone. After 2 month of treatment steroid was withdrawn, but Dapsone continue with no relapse.To our knowledge this is the first diagnosed and treated case in this hospital. DOI: http://dx.doi.org/10.3329/jssmc.v4i1.12002 J Shaheed Suhrawardy Med Coll, 2012;4(1):35-37

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P113: Comparison of age-adjusted and clinical probability-adjusted D-dimer for diagnosing pulmonary embolism

CJEM ◽

10.1017/cem.2017.315 ◽

2017 ◽

Vol 19 (S1) ◽

pp. S116

Author(s):

S. Sharif ◽

C. Kearon ◽

M. Li ◽

M. Eventov ◽

R. Jiang ◽

...

Keyword(s):

Pulmonary Embolism ◽

False Negative ◽

False Negative Rate ◽

Retrospective Chart Review ◽

Ct Scanning ◽

Clinical Probability ◽

Negative Rate ◽

Wells Score ◽

Acute Pe ◽

D Dimer

Introduction: Diagnosing pulmonary embolism (PE) in the emergency department can be challenging due to non-specific signs and symptoms; this often results in the over-utilization of CT pulmonary angiography (CT-PA). In 2013, the American College of Chest Physicians identified CT-PA as one of the top five avoidable tests. Age-adjusted D-dimer has been shown to decrease CT utilization rates. Recently, clinical-probability adjusted D-dimer has been promoted as an alternative strategy to reduce CT scanning. The aim of this study is to compare the safety and efficacy of the age-adjusted D-dimer rule and the clinical probability-adjusted D-dimer rule in Canadian ED patients tested for PE. Methods: This was a retrospective chart review of ED patients investigated for PE at two hospitals from April 2013 to March 2015 (24 months). Inclusion criteria were the ED physician ordered CT-PA, Ventilation-Perfusion (VQ) scan or D-dimer for investigation of PE. Patients under the age of 18 were excluded. PE was defined as CT/VQ diagnosis of acute PE or acute PE/DVT in 30-day follow-up. Trained researchers extracted anonymized data. The age-adjusted D-dimer and the clinical probability-adjusted D-dimer rules were applied retrospectively. The rate of CT/VQ imaging and the false negative rates were calculated. Results: In total, 1,189 patients were tested for PE. 1,129 patients had a D-dimer test and a Wells score less than 4.0. 364/1,129 (32.3%, 95%CI 29.6-35.0%) would have undergone imaging for PE if the age-adjusted D-dimer rule was used. 1,120 patients had a D-dimer test and a Wells score less than 6.0. 217/1,120 patients (19.4%, 95%CI 17.2-21.2%) would have undergone imaging for PE if the clinical probability-adjusted D-dimer rule was used. The false-negative rate for the age-adjusted D-dimer rule was 0.3% (95%CI 0.1-0.9%). The false-negative rate of the clinical probability-adjusted D-dimer was 1.0% (95%CI 0.5-1.9%). Conclusion: The false-negative rates for both the age-adjusted D-dimer and clinical probability-adjusted D-dimer are low. The clinical probability-adjusted D-dimer results in a 13% absolute reduction in CT scanning compared to age-adjusted D-dimer.

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Autoimmune bullous disorders

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2006.027 ◽

2006 ◽

Vol 44 (2) ◽

Cited By ~ 12

Author(s):

Rüdiger Eming ◽

Michael Hertl

Keyword(s):

Basement Membrane ◽

Skin Diseases ◽

Immunoblot Analysis ◽

Primary Diagnosis ◽

Basement Membrane Zone ◽

Epidermal Keratinocytes ◽

Direct Immunofluorescence ◽

Organ Specific ◽

Circulating Autoantibodies ◽

Bullous Skin Diseases

AbstractBullous skin diseases represent a group of organ-specific autoimmune disorders characterised by binding of circulating autoantibodies to adhesion molecules of the epidermis and the dermo-epidermal basement membrane zone. Binding of these autoantibodies to their antigenic targets results in loss of adhesion between epidermal keratinocytes and at the level of the basement membrane zone. Chronic blisters and secondary painful erosions are the clinical hallmark of autoimmune bullous disorders. Histopathology reveals the location of blister formation and helps to classify the subtype of the bullous skin disorder. Immunofluorescence is crucial for diagnosing autoimmune bullous skin disorders. Tissue-bound autoantibodies are detected by direct immunofluorescence of perilesional skin. Circulating autoantibodies can be visualised by indirect immunofluorescence using tissue substrates such as monkey oesophagus and sodium chloride-split human skin. Most of the autoantigens are available as recombinant proteins, which allows for autoantibody screening by ELISA or immunoblot analysis to confirm the primary diagnosis and, importantly, for immunoserological follow-up of patients.

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