Materiały źródłowe

• #1 Bullous Pemphigoid – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535374/

  Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder, representing 80% of subepidermal immunobullous cases. […] This activity reviews the etiology, presentation, evaluation, and management of bullous pemphigoid and the interprofessional team’s role in evaluating, diagnosing, and managing the condition. […] A biopsy for hematoxylin and eosin staining will show a subepidermal split with eosinophils, and direct immunofluorescence will highlight the autoantibodies against the basement membrane zone. ELISA testing is also useful in diagnosing bullous pemphigoid. […] The diagnosis of bullous pemphigoid relies on the clinical scenario and laboratory tests. Histology with direct and indirect immunofluorescence studies aids in diagnosis. […] Direct immunofluorescence involves directly detecting tissue-bound autoantibodies and is the gold standard of evaluation in autoimmune blistering diseases.

• #2

  https://link.springer.com/article/10.1007/s40257-017-0264-2

  Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease in Western countries, and typically affects the elderly. […] The diagnosis of BP relies on immunopathologic findings, especially based on both direct and indirect immunofluorescence microscopy observations, as well as on anti-BP180/BP230 enzyme-linked immunosorbent assays (ELISAs). […] Evaluation of clinical criteria for diagnosis of bullous pemphigoid. […] Clinical criteria for the diagnosis of bullous pemphigoid: a reevaluation according to immunoblot analysis of patient sera. […] Direct immunofluorescence studies of sodium chloride-separated skin in the differential diagnosis of bullous pemphigoid and epidermolysis bullosa acquisita. […] Comparative study of direct and indirect immunofluorescence and of bullous pemphigoid 180 and 230 enzyme-linked immunosorbent assays for diagnosis of bullous pemphigoid.

• #3 Bullous Pemphigoid: Clinical Practice Guidelines | Actas Dermo-Sifiliográficas

  https://actasdermo.org/es-bullous-pemphigoid-clinical-practice-guidelines-articulo-S1578219014000778

  Bullous pemphigoid (BP) is diagnosed on the basis of clinical, histologic, and immunologic findings. There are no fixed diagnostic criteria, unlike in other bullous disorders, although one group of French authors proposed that the following clinical predictors of BP should be evaluated in a patient with a bullous eruption: absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and age greater than 70 years. Based on the authors calculations, the presence of 3 of these 4 diagnostic criteria for BP had a sensitivity of 90%, a specificity of 83%, and a positive predictive value of 95%. […] Two skin biopsies should be taken when BP is suspected. […] For the standard histologic study, a sample should be taken from a recent vesicular lesion (to avoid reepithelialization phenomena) and fixed in formaldehyde. Typical findings include a subepidermal blister with a mixed superficial perivascular inflammatory infiltrate with abundant eosinophils. […] For the direct immunofluorescence (DIF) study, a second biopsy sample should be taken from healthy perilesional skin or from inflamed skin without vesicles or blisters (to avoid the false negatives that can occur in such cases). Biopsies should be fresh-frozen immediately or placed in saline solution or Michel’s transport medium. The best results have been found with biopsies stored in saline for 12 to 24 hours. Characteristic DIF findings are linear deposits of IgG and C3 along the basement membrane, although there may also be less intense deposits of other immunoglobulins, such as IgA and IgM.

• #4 Bullous Pemphigoid – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535374/

  At least 2 punch biopsies should be obtained during evaluation: 1 for hematoxylin and eosin staining and another using perilesional, uninvolved skin for direct immunofluorescence. […] A salt-split skin immunofluorescence study is an option, where the patient serum is applied on salt-split skin, which splits the skin at the level of the lamina lucida. […] ELISA testing to detect antibodies to the NC16A domain of BP180, also known as BPAG2, is available and has a sensitivity of 89% and specificity of 98%. […] The clinical predictors of bullous pemphigoid were described in a report from the French Bullous Study Group in 1998. […] Their reports stated 3 out of 4 diagnostic criteria have a sensitivity of 90% and specificity of 83%.

• #5 Bullous Pemphigoid & Pemphigus Vulgaris- Dermatology Advisor

  https://www.dermatologyadvisor.com/ddi/bullous-pemphigoid-pemphigus-vulgaris/

  A 55-year-old man presents to the clinic with multiple tense bullae diffusely involving his trunk and extremities that overlie urticarial plaques. […] Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease. […] The gold standard in establishing a diagnosis of BP is by lesional fixed tissue histopathology and perilesional direct immunofluorescence (DIF) analysis. […] Light microscopy usually shows subepidermal blister formation with a superficial dermal eosinophilic infiltrate. […] DIF analysis shows linear IgG and/or complement C3 deposition at the epithelial basement membrane zone. […] At present, there are no generally accepted criteria for the diagnosis of BP; however, according to Vaillant et al, diagnosis of BP can be made when 3 of the 4 clinical criteria are present: (1) age 70 years, (2) absence of atrophic scars, (3) absence of mucosal involvement, and (4) absence of predominant bullous lesions on the neck and head.

• #6 Strategies to improve outcomes of bullous pemphigoid | CCID

  https://www.dovepress.com/strategies-to-improve-outcomes-of-bullous-pemphigoid-a-comprehensive-r-peer-reviewed-fulltext-article-CCID

  BP should be suspected in older individuals who have generalized pruritus with or without prominent bullae. […] A French analysis showed that the diagnosis of BP may be confirmed with high sensitivity (90% and specificity (83%), in patients with a subepidermal blistering disease and linear epidermal basement membrane deposits of IgG or C3 if these criteria are present: i) no head and neck involvement; ii) no mucosal involvement; iii) age over 70 years. […] These clinical criteria, however, need an history of recent blisters, which are reported to be absent in about 20% of patients at the time of diagnosis. […] Hence, in patients with non-bullous manifestations, such as in those presenting urticarial, erosive, or eczematous lesions, a prominent role to reach BP diagnosis is played by direct IF microscopy evaluation and the detection of typical serum antibodies (anti-BP180, and anti-BP-230).

• #7 Strategies to improve outcomes of bullous pemphigoid | CCID

  https://www.dovepress.com/strategies-to-improve-outcomes-of-bullous-pemphigoid-a-comprehensive-r-peer-reviewed-fulltext-article-CCID

  BP should be suspected in older individuals who have generalized pruritus with or without prominent bullae. […] A French analysis showed that the diagnosis of BP may be confirmed with high sensitivity (90% and specificity (83%), in patients with a subepidermal blistering disease and linear epidermal basement membrane deposits of IgG or C3 if these criteria are present: i) no head and neck involvement; ii) no mucosal involvement; iii) age over 70 years. […] These clinical criteria, however, need an history of recent blisters, which are reported to be absent in about 20% of patients at the time of diagnosis. […] Hence, in patients with non-bullous manifestations, such as in those presenting urticarial, erosive, or eczematous lesions, a prominent role to reach BP diagnosis is played by direct IF microscopy evaluation and the detection of typical serum antibodies (anti-BP180, and anti-BP-230).

• #8 Bullous pemphigoid: Diagnosis and treatment

  https://www.aad.org/public/diseases/a-z/bullous-pemphigoid-treatment

  Bullous pemphigoid is a disease that can cause widespread blisters, itching, and rash on your skin, and sometimes even inside your mouth and other areas. […] If you are worried that you have bullous pemphigoid, seeing a board-certified dermatologist can help you get an accurate diagnosis and treatment. […] Different types of diseases can cause blisters, and specialized testing may be necessary to find out what type of blistering disease you have. This specialized testing is usually performed by dermatologists. […] To find out if you have bullous pemphigoid, your dermatologist will: Ask questions, Examine your blisters and rashes, Perform one or more skin biopsies (can be done during an office visit), Order blood tests, as needed. […] If the medical tests confirm that you have bullous pemphigoid, your dermatologist will create a personalized treatment plan.

• #9 Bullous pemphigoid – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/453

  Bullous pemphigoid typically occurs in older people and has a distinctive clinical appearance. […] In the bullous stage, characteristic, tense vesicles or bullae develop on apparently normal or erythematous skin of the pre-existing eczematous or urticarial eruption. […] The treatment goal is to decrease or stop blister formation, to promote healing of existing blisters and erosions, and to control the associated pruritus. […] Bullous pemphigoid is a chronic, acquired autoimmune blistering disease characterized by autoantibodies against hemidesmosomal antigens, resulting in the formation of a subepidermal blister. […] Key diagnostic factors include pruritus and tense blisters on normal or erythematous skin. […] Other diagnostic factors include erythematous or urticarial plaques and oral lesions.

• #10 Bullous Pemphigoid Workup: Laboratory Studies, Other Tests, Histologic Findings

  https://emedicine.medscape.com/article/1062391-workup

  To establish a diagnosis of bullous pemphigoid, the following tests should be performed: Histopathologic analysis from the edge of a blister […] Direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed with the patient’s serum. The preferred substrate for IDIF is salt-split normal human skin substrate. DIF demonstrates in-vivo deposits of antibodies and other immunoreactants (eg, complement). Usually, immunoglobulin G (IgG; 70-90% of patients) and complement C3 deposition (90-100% of patients) can be seen in a linear band at the dermoepidermal junction. This pattern of immunoreactants is not specific for bullous pemphigoid and may also be seen in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Bullous pemphigoid can be differentiated from CP and EBA by incubating the patient’s skin biopsy sample in 1 mol/L salt before performing DIF. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals immunoglobulin G (IgG) on the blister roof (epidermal side of split skin) in patients with bullous pemphigoid, whereas in CP and EBA, IgG localizes to the blister floor (dermal side of split skin). The optimal location for DIF testing is normal-appearing perilesional skin; false-positive results may occur when it is performed on lesional skin. There is a significant false-negative rate if the skin biopsy specimen is taken from skin of the legs. Rarely, skin biopsy samples placed in transport media may yield false-negative results. Thus, fresh tissue is the preferred substrate for DIF studies. IDIF studies document the presence of IgG circulating autoantibodies in the patient’s serum that target the skin basement membrane component. About 70% of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course. IDIF studies can be used to detect the patient’s IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate. Tests available in research laboratories include direct and indirect immunoelectron microscopy (immunoEM), immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin. Sensitivity varies: In 75% of patients, a reaction occurs with the BP230 antigen, whereas in 50%, a reaction occurs with the BP180 antigen. Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, however, immunoprecipitation is performed with native rather than denatured protein; consequently, it is more sensitive. Immunoprecipitation is more difficult to perform than immunoblotting and is generally less available. In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180. ELISA analyzes the bullous pemphigoid antigen (BPAg)-specific IgG autoantibodies in the patients’ sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. It has been demonstrated to be highly sensitive and specific. ELISA kits for testing BPAg-specific IgG autoantibodies are available commercially; however, relatively few centers offer this service. ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed; though not commercially available, these assays are promising as investigational tools. ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients who have bullous pemphigoid. If freshly frozen tissue is not available for DIF microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone for confirmation of the diagnosis. The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor bullous pemphigoid).

• #11 Bullous pemphigoid pathology

  https://dermnetnz.org/topics/bullous-pemphigoid-pathology

  Bullous pemphigoid is the most common autoimmune dermatosis presenting with crops of tense pruritic blisters, often in older adults. […] Autoantibodies are directed to components of the basement membrane, particularly the BP antigens BP180 and BP230. […] Immunofluorescence is very helpful in this early phase. […] Direct immunofluorescence shows linear deposition of IgG (most often IgG4 subtype) and C3 along the basement membrane. […] Split skin indirect immunofluorescence studies are generally not needed, but may be useful in rare cases when epidermolysis bullosa aquisita is suspected. […] Epidermolysis bullosa aquisita shows subepidermal bullae with linear IgG/C3 deposition however indirect immunofluorescence in these condition reveals positivity on the floor of split skin whereas bullous pemphigoid has positivity on the epidermal side.

• #12 Bullous Pemphigoid – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535374/

  Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder, representing 80% of subepidermal immunobullous cases. […] This activity reviews the etiology, presentation, evaluation, and management of bullous pemphigoid and the interprofessional team’s role in evaluating, diagnosing, and managing the condition. […] A biopsy for hematoxylin and eosin staining will show a subepidermal split with eosinophils, and direct immunofluorescence will highlight the autoantibodies against the basement membrane zone. ELISA testing is also useful in diagnosing bullous pemphigoid. […] The diagnosis of bullous pemphigoid relies on the clinical scenario and laboratory tests. Histology with direct and indirect immunofluorescence studies aids in diagnosis. […] Direct immunofluorescence involves directly detecting tissue-bound autoantibodies and is the gold standard of evaluation in autoimmune blistering diseases.

• #13 Diagnosis and clinical severity markers of bullous pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2920699/

  The use of a broad spectrum of novel detection systems for autoantibodies to the basement membrane proteins BP180 and BP230 has greatly facilitated the diagnosis of bullous pemphigoid, which most likely explains its increasing incidence in central Europe. […] Direct immunofluorescence (IF) microscopy of a perilesional skin biopsy that typically reveals linear deposits of complement component 3 (C3) and/or immunoglobulin G (IgG) at the basal membrane zone (BMZ) is still the diagnostic gold standard. […] For more than a decade, B-cell epitopes have been known to be unequally distributed on BP180 in BP. […] The novel diagnostic assays have greatly facilitated the diagnosis of BP, which may explain the increased incidence of BP that was recently observed in a prospective study with patients from a well-defined region, Lower Franconia in Germany.

• #14 Bullous Pemphigoid Workup: Laboratory Studies, Other Tests, Histologic Findings

  https://emedicine.medscape.com/article/1062391-workup

  To establish a diagnosis of bullous pemphigoid, the following tests should be performed: Histopathologic analysis from the edge of a blister […] Direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed with the patient’s serum. The preferred substrate for IDIF is salt-split normal human skin substrate. DIF demonstrates in-vivo deposits of antibodies and other immunoreactants (eg, complement). Usually, immunoglobulin G (IgG; 70-90% of patients) and complement C3 deposition (90-100% of patients) can be seen in a linear band at the dermoepidermal junction. This pattern of immunoreactants is not specific for bullous pemphigoid and may also be seen in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Bullous pemphigoid can be differentiated from CP and EBA by incubating the patient’s skin biopsy sample in 1 mol/L salt before performing DIF. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals immunoglobulin G (IgG) on the blister roof (epidermal side of split skin) in patients with bullous pemphigoid, whereas in CP and EBA, IgG localizes to the blister floor (dermal side of split skin). The optimal location for DIF testing is normal-appearing perilesional skin; false-positive results may occur when it is performed on lesional skin. There is a significant false-negative rate if the skin biopsy specimen is taken from skin of the legs. Rarely, skin biopsy samples placed in transport media may yield false-negative results. Thus, fresh tissue is the preferred substrate for DIF studies. IDIF studies document the presence of IgG circulating autoantibodies in the patient’s serum that target the skin basement membrane component. About 70% of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course. IDIF studies can be used to detect the patient’s IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate. Tests available in research laboratories include direct and indirect immunoelectron microscopy (immunoEM), immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin. Sensitivity varies: In 75% of patients, a reaction occurs with the BP230 antigen, whereas in 50%, a reaction occurs with the BP180 antigen. Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, however, immunoprecipitation is performed with native rather than denatured protein; consequently, it is more sensitive. Immunoprecipitation is more difficult to perform than immunoblotting and is generally less available. In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180. ELISA analyzes the bullous pemphigoid antigen (BPAg)-specific IgG autoantibodies in the patients’ sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. It has been demonstrated to be highly sensitive and specific. ELISA kits for testing BPAg-specific IgG autoantibodies are available commercially; however, relatively few centers offer this service. ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed; though not commercially available, these assays are promising as investigational tools. ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients who have bullous pemphigoid. If freshly frozen tissue is not available for DIF microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone for confirmation of the diagnosis. The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor bullous pemphigoid).

• #15 Bullous pemphigoid – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/bullous-pemphigoid/

  Bullous pemphigoid (BP) is a relatively common autoimmune vesicobullous disease encountered in India. […] The diagnosis can be confirmed by histology, direct and indirect immunofluorescence. […] The diagnosis of BP is confirmed by histologic and immunopathologic investigations. Histopathology from lesional skin demonstrates a subepidermal blister. […] DIF studies on normal appearing perilesional skin within 2 cm of a lesion demonstrate in vivo deposits of IgG antibodies in 90-95% of cases and C3 in 100% cases at the basement membrane zone. […] BP can be differentiated from these conditions by the salt-split technique in which patients skin biopsy sample is incubated in 1 mol/l salt solution prior to performing DIF. […] IIF studies document IgG (subclass IgG4) circulating autoantibodies in the patients serum that target the skin basement membrane component.

• #16 Bullous Pemphigoid Workup: Laboratory Studies, Other Tests, Histologic Findings

  https://emedicine.medscape.com/article/1062391-workup

  To establish a diagnosis of bullous pemphigoid, the following tests should be performed: Histopathologic analysis from the edge of a blister […] Direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed with the patient’s serum. The preferred substrate for IDIF is salt-split normal human skin substrate. DIF demonstrates in-vivo deposits of antibodies and other immunoreactants (eg, complement). Usually, immunoglobulin G (IgG; 70-90% of patients) and complement C3 deposition (90-100% of patients) can be seen in a linear band at the dermoepidermal junction. This pattern of immunoreactants is not specific for bullous pemphigoid and may also be seen in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Bullous pemphigoid can be differentiated from CP and EBA by incubating the patient’s skin biopsy sample in 1 mol/L salt before performing DIF. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals immunoglobulin G (IgG) on the blister roof (epidermal side of split skin) in patients with bullous pemphigoid, whereas in CP and EBA, IgG localizes to the blister floor (dermal side of split skin). The optimal location for DIF testing is normal-appearing perilesional skin; false-positive results may occur when it is performed on lesional skin. There is a significant false-negative rate if the skin biopsy specimen is taken from skin of the legs. Rarely, skin biopsy samples placed in transport media may yield false-negative results. Thus, fresh tissue is the preferred substrate for DIF studies. IDIF studies document the presence of IgG circulating autoantibodies in the patient’s serum that target the skin basement membrane component. About 70% of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course. IDIF studies can be used to detect the patient’s IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate. Tests available in research laboratories include direct and indirect immunoelectron microscopy (immunoEM), immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin. Sensitivity varies: In 75% of patients, a reaction occurs with the BP230 antigen, whereas in 50%, a reaction occurs with the BP180 antigen. Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, however, immunoprecipitation is performed with native rather than denatured protein; consequently, it is more sensitive. Immunoprecipitation is more difficult to perform than immunoblotting and is generally less available. In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180. ELISA analyzes the bullous pemphigoid antigen (BPAg)-specific IgG autoantibodies in the patients’ sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. It has been demonstrated to be highly sensitive and specific. ELISA kits for testing BPAg-specific IgG autoantibodies are available commercially; however, relatively few centers offer this service. ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed; though not commercially available, these assays are promising as investigational tools. ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients who have bullous pemphigoid. If freshly frozen tissue is not available for DIF microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone for confirmation of the diagnosis. The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor bullous pemphigoid).

• #17 Bullous Pemphigoid: Clinical Practice Guidelines | Actas Dermo-Sifiliográficas

  https://actasdermo.org/es-bullous-pemphigoid-clinical-practice-guidelines-articulo-S1578219014000778

  Bullous pemphigoid (BP) is diagnosed on the basis of clinical, histologic, and immunologic findings. There are no fixed diagnostic criteria, unlike in other bullous disorders, although one group of French authors proposed that the following clinical predictors of BP should be evaluated in a patient with a bullous eruption: absence of atrophic scars, absence of head and neck involvement, absence of mucosal involvement, and age greater than 70 years. Based on the authors calculations, the presence of 3 of these 4 diagnostic criteria for BP had a sensitivity of 90%, a specificity of 83%, and a positive predictive value of 95%. […] Two skin biopsies should be taken when BP is suspected. […] For the standard histologic study, a sample should be taken from a recent vesicular lesion (to avoid reepithelialization phenomena) and fixed in formaldehyde. Typical findings include a subepidermal blister with a mixed superficial perivascular inflammatory infiltrate with abundant eosinophils. […] For the direct immunofluorescence (DIF) study, a second biopsy sample should be taken from healthy perilesional skin or from inflamed skin without vesicles or blisters (to avoid the false negatives that can occur in such cases). Biopsies should be fresh-frozen immediately or placed in saline solution or Michel’s transport medium. The best results have been found with biopsies stored in saline for 12 to 24 hours. Characteristic DIF findings are linear deposits of IgG and C3 along the basement membrane, although there may also be less intense deposits of other immunoglobulins, such as IgA and IgM.

• #18 Bullous Pemphigoid (BP) Laboratory Testing | Beutner Labs

  https://www.beutnerlabs.com/bullous-pemphigoid-bp-laboratory-testing

  Bullous pemphigoid was described as a subepidermal blistering disease with distinctive clinical and histologic features by Walter Lever in 1953. […] Diagnosis of Bullous Pemphigoid is based on clinical, histological and immunopathological findings. […] DIF of perilesional biopsies remains the gold standard and rst step in diagnosing BP. This reveals linear deposits of IgG (predominantly IgG4 and IgG1) in the basement membrane zone area of the dermal-epidermal junction. […] Indirect immunofluorescence (IIF) on monkey esophagus (Test#013) and on Salt Split human skin (SSS, Test#014) helps to detect circulating BMZ antibodies and confirm the diagnosis of BP. […] The use of normal and salt split skin substrates improves the sensitivity of the test and helps to differentiate BP from EBA, bullous lupus, Laminin 332 pemphigoid and laminin gamma 1 pemphigoid. […] Antibodies to BP180 (NC16a) and BP230 can be detected by ELISA. A review of the literature reveals a sensitivity of 53% to 95% and specicity of 89.8% to 100% for anti-BP180 ELISA.

• #19 Bullous Pemphigoid: Clinical Practice Guidelines | Actas Dermo-Sifiliográficas

  https://actasdermo.org/es-bullous-pemphigoid-clinical-practice-guidelines-articulo-S1578219014000778

  Indirect immunofluorescence (IDIF) is used to test for circulating anti-basement membrane zone antibodies in peripheral blood or blister fluid. The test can be performed with monkey esophagus substrate, or better still with human skin treated with 1 M sodium chloride solution (the salt-split technique), which separates the basement membrane from the lamina lucida. The salt-split technique is more sensitive and also permits BP antibodies (deposited primarily at the epidermal side of the induced blister) to be distinguished from antibodies encountered in other diseases such as epidermolysis bullosa acquisita. […] Finally, several tests exist to determine the antigenic specificity of autoantibodies. Some of these, such as the immunoblot assay, reveal the presence of antibodies against proteins with a molecular weight of 180 and/or 230 kD corresponding to the antigens BP180 and BP230 (when epidermal extracts are used) or of antibodies against the NC16A portion of the BP180 antigen (when recombinant proteins are used). These techniques, however, are reserved for investigational purposes in highly specialized laboratories. Currently, the most widely used technique is the enzyme-linked immunosorbent assay (ELISA), which detects circulating antibodies against the 2 BP antigens BP180 and BP230 in a large proportion of patients. Quantitative detection of antibodies is useful for monitoring patients, as anti-BP180 antibody levels have been found to correlate with disease activity.

• #20 Bullous Pemphigoid Workup: Laboratory Studies, Other Tests, Histologic Findings

  https://emedicine.medscape.com/article/1062391-workup

  To establish a diagnosis of bullous pemphigoid, the following tests should be performed: Histopathologic analysis from the edge of a blister […] Direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed with the patient’s serum. The preferred substrate for IDIF is salt-split normal human skin substrate. DIF demonstrates in-vivo deposits of antibodies and other immunoreactants (eg, complement). Usually, immunoglobulin G (IgG; 70-90% of patients) and complement C3 deposition (90-100% of patients) can be seen in a linear band at the dermoepidermal junction. This pattern of immunoreactants is not specific for bullous pemphigoid and may also be seen in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Bullous pemphigoid can be differentiated from CP and EBA by incubating the patient’s skin biopsy sample in 1 mol/L salt before performing DIF. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals immunoglobulin G (IgG) on the blister roof (epidermal side of split skin) in patients with bullous pemphigoid, whereas in CP and EBA, IgG localizes to the blister floor (dermal side of split skin). The optimal location for DIF testing is normal-appearing perilesional skin; false-positive results may occur when it is performed on lesional skin. There is a significant false-negative rate if the skin biopsy specimen is taken from skin of the legs. Rarely, skin biopsy samples placed in transport media may yield false-negative results. Thus, fresh tissue is the preferred substrate for DIF studies. IDIF studies document the presence of IgG circulating autoantibodies in the patient’s serum that target the skin basement membrane component. About 70% of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course. IDIF studies can be used to detect the patient’s IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate. Tests available in research laboratories include direct and indirect immunoelectron microscopy (immunoEM), immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin. Sensitivity varies: In 75% of patients, a reaction occurs with the BP230 antigen, whereas in 50%, a reaction occurs with the BP180 antigen. Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, however, immunoprecipitation is performed with native rather than denatured protein; consequently, it is more sensitive. Immunoprecipitation is more difficult to perform than immunoblotting and is generally less available. In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180. ELISA analyzes the bullous pemphigoid antigen (BPAg)-specific IgG autoantibodies in the patients’ sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. It has been demonstrated to be highly sensitive and specific. ELISA kits for testing BPAg-specific IgG autoantibodies are available commercially; however, relatively few centers offer this service. ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed; though not commercially available, these assays are promising as investigational tools. ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients who have bullous pemphigoid. If freshly frozen tissue is not available for DIF microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone for confirmation of the diagnosis. The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor bullous pemphigoid).

• #21 Bullous pemphigoid pathology

  https://dermnetnz.org/topics/bullous-pemphigoid-pathology

  Bullous pemphigoid is the most common autoimmune dermatosis presenting with crops of tense pruritic blisters, often in older adults. […] Autoantibodies are directed to components of the basement membrane, particularly the BP antigens BP180 and BP230. […] Immunofluorescence is very helpful in this early phase. […] Direct immunofluorescence shows linear deposition of IgG (most often IgG4 subtype) and C3 along the basement membrane. […] Split skin indirect immunofluorescence studies are generally not needed, but may be useful in rare cases when epidermolysis bullosa aquisita is suspected. […] Epidermolysis bullosa aquisita shows subepidermal bullae with linear IgG/C3 deposition however indirect immunofluorescence in these condition reveals positivity on the floor of split skin whereas bullous pemphigoid has positivity on the epidermal side.

• #22 Bullous Pemphigoid – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535374/

  At least 2 punch biopsies should be obtained during evaluation: 1 for hematoxylin and eosin staining and another using perilesional, uninvolved skin for direct immunofluorescence. […] A salt-split skin immunofluorescence study is an option, where the patient serum is applied on salt-split skin, which splits the skin at the level of the lamina lucida. […] ELISA testing to detect antibodies to the NC16A domain of BP180, also known as BPAG2, is available and has a sensitivity of 89% and specificity of 98%. […] The clinical predictors of bullous pemphigoid were described in a report from the French Bullous Study Group in 1998. […] Their reports stated 3 out of 4 diagnostic criteria have a sensitivity of 90% and specificity of 83%.

• #23 BPAB – Overview: Bullous Pemphigoid, BP180 and BP230, IgG Antibodies, Serum

  https://www.mayocliniclabs.com/test-catalog/overview/606816

  Initial screening test in the diagnosis of bullous pemphigoid and its variants […] Complementing the standard serum test of indirect immunofluorescence utilizing primate esophagus substrate and primate salt-split skin substrate (CIFS / Cutaneous Immunofluorescence Antibodies [IgG], Serum) […] Antibodies to bullous pemphigoid (BP) BP180 and BP230 have been shown to be present in most patients with pemphigoid. Adequate sensitivities and specificity for disease are documented and Mayo Clinic’s experience demonstrates a very good correlation between BP180 and BP230 results and the presence of pemphigoid (see Supportive Data). However, in those patients strongly suspected to have pemphigoid, either by clinical findings or by routine biopsy or direct immunofluorescence, and in whom the BP180/BP230 assay is negative, follow-up testing by CIFS / Cutaneous Immunofluorescence Antibodies (IgG), Serum is recommended. […] As with other diagnostic test procedures, the results obtained with bullous pemphigoid (BP) BP180 and BP230 enzyme-linked immunosorbent assay kit serve only as an aid to diagnosis and should not be interpreted as diagnostic in themselves.

• #24 Bullous Pemphigoid (BP) Laboratory Testing | Beutner Labs

  https://www.beutnerlabs.com/bullous-pemphigoid-bp-laboratory-testing

  Bullous pemphigoid was described as a subepidermal blistering disease with distinctive clinical and histologic features by Walter Lever in 1953. […] Diagnosis of Bullous Pemphigoid is based on clinical, histological and immunopathological findings. […] DIF of perilesional biopsies remains the gold standard and rst step in diagnosing BP. This reveals linear deposits of IgG (predominantly IgG4 and IgG1) in the basement membrane zone area of the dermal-epidermal junction. […] Indirect immunofluorescence (IIF) on monkey esophagus (Test#013) and on Salt Split human skin (SSS, Test#014) helps to detect circulating BMZ antibodies and confirm the diagnosis of BP. […] The use of normal and salt split skin substrates improves the sensitivity of the test and helps to differentiate BP from EBA, bullous lupus, Laminin 332 pemphigoid and laminin gamma 1 pemphigoid. […] Antibodies to BP180 (NC16a) and BP230 can be detected by ELISA. A review of the literature reveals a sensitivity of 53% to 95% and specicity of 89.8% to 100% for anti-BP180 ELISA.

• #25 Bullous pemphigoid as a diagnostic and therapeutic challenge with a wide spectrum of dermatological symptoms

  https://www.termedia.pl/Bullous-pemphigoid-as-a-diagnostic-and-therapeutic-challenge-with-a-wide-spectrum-of-dermatological-symptoms,56,55448,1,1.html

  Bullous pemphigoid (BP) is considered the most common autoimmune blistering dermatosis in Europe and in the USA. Diagnosis is based on histopathological examination of a biopsy from the lesion. A subsequent biopsy with direct immunofluorescence confirmed a definitive diagnosis of BP, revealing IgG deposits (+++), IgA deposits (+++), and C3 complement component deposits (+++) at the basement membrane zone (BMZ). Serological diagnosis of BP is based on the enzyme-linked immunosorbent assay (ELISA), which detects circulating antibodies directed against the NC16a domain of the BP180 antigen and the BP230 antigen, with a sensitivity of 84% and a specificity of 90%. However, false-positive results in ELISA testing can occur. Therefore, during the diagnostic process for BP, the ELISA test should be used as one of the examinations but not as the sole determinant of diagnosis. Throughout the diagnostic process, the patients clinical presentation should be considered, and specific antibodies should be determined using recommended techniques such as ELISA, direct immunofluorescence (DIF), and indirect immunofluorescence (IIF) which were performed in our case. The initial symptoms of the disease usually manifest within a year, although they can occur even several years after exposure to the physical factor. A combination of antibody lab results, biopsy results, and clinical presentation remains the best method to confirm the diagnosis.

• #26 Bullous pemphigoid – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/bullous-pemphigoid/

  Direct and indirect immunoelectron microscopy ultrastructurally localizes in vivo-bound IgG autoantibodies to the binding site at the basement membrane. […] Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of BP patients, with proteins extracted from healthy human skin. […] Enzyme-linked immunosorbent assay (ELISA) analyzes the BP antigen-specific IgG autoantibodies in the patients sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. […] Immunohistochemistry on formalin-fixed skin sections in BP has been used to examine C3 deposition along the epidermal basement membrane zone. […] In India, histopathology and immunofluorescence (DIF and IIF) studies are routinely used for the diagnosis of BP.

• #27 Pemphigoid | Choose the Right Test

  https://arupconsult.com/content/pemphigoid

  How is pemphigoid diagnosed? […] Recently proposed criteria require that two of the following three conditions be met for a diagnosis of pemphigoid: pruritus and/or predominant cutaneous blisters; linear deposition of immunoglobulin G (IgG) or complement 3 (C3) along the basement membrane zone (BMZ), as determined by direct immunofluorescence (DIF); and/or IgG on epidermal side staining of split-skin substrate, as ascertained by indirect immunofluorescence (also known as indirect immunofluorescence [IIF]) testing. […] Performing both DIF on a perilesional biopsy and IIF serum testing on human split-skin substrate provides the greatest sensitivity and specificity for pemphigoid diagnosis. […] A characteristic feature of pemphigoid is the presence of IgG antibodies against BP180 and BP230, structural proteins of the BMZ. Therefore, testing for BMZ antibodies and IgG antibodies to BP180 and BP230 antigens is sensitive and specific for pemphigoid, and can help to differentiate between pemphigoid, linear IgA disease, and EBA. […] Detection of IgG antibodies to both BP180 and BP230 antigens increases the sensitivity and specificity for diagnosis of pemphigoid. […] Unless pemphigoid is specifically suspected, broad screening is recommended because of the overlap in clinical presentations of immunobullous diseases.

• #28 Bullous Pemphigoid Workup: Laboratory Studies, Other Tests, Histologic Findings

  https://emedicine.medscape.com/article/1062391-workup

  To establish a diagnosis of bullous pemphigoid, the following tests should be performed: Histopathologic analysis from the edge of a blister […] Direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed with the patient’s serum. The preferred substrate for IDIF is salt-split normal human skin substrate. DIF demonstrates in-vivo deposits of antibodies and other immunoreactants (eg, complement). Usually, immunoglobulin G (IgG; 70-90% of patients) and complement C3 deposition (90-100% of patients) can be seen in a linear band at the dermoepidermal junction. This pattern of immunoreactants is not specific for bullous pemphigoid and may also be seen in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Bullous pemphigoid can be differentiated from CP and EBA by incubating the patient’s skin biopsy sample in 1 mol/L salt before performing DIF. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals immunoglobulin G (IgG) on the blister roof (epidermal side of split skin) in patients with bullous pemphigoid, whereas in CP and EBA, IgG localizes to the blister floor (dermal side of split skin). The optimal location for DIF testing is normal-appearing perilesional skin; false-positive results may occur when it is performed on lesional skin. There is a significant false-negative rate if the skin biopsy specimen is taken from skin of the legs. Rarely, skin biopsy samples placed in transport media may yield false-negative results. Thus, fresh tissue is the preferred substrate for DIF studies. IDIF studies document the presence of IgG circulating autoantibodies in the patient’s serum that target the skin basement membrane component. About 70% of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course. IDIF studies can be used to detect the patient’s IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate. Tests available in research laboratories include direct and indirect immunoelectron microscopy (immunoEM), immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin. Sensitivity varies: In 75% of patients, a reaction occurs with the BP230 antigen, whereas in 50%, a reaction occurs with the BP180 antigen. Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, however, immunoprecipitation is performed with native rather than denatured protein; consequently, it is more sensitive. Immunoprecipitation is more difficult to perform than immunoblotting and is generally less available. In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180. ELISA analyzes the bullous pemphigoid antigen (BPAg)-specific IgG autoantibodies in the patients’ sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. It has been demonstrated to be highly sensitive and specific. ELISA kits for testing BPAg-specific IgG autoantibodies are available commercially; however, relatively few centers offer this service. ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed; though not commercially available, these assays are promising as investigational tools. ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients who have bullous pemphigoid. If freshly frozen tissue is not available for DIF microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone for confirmation of the diagnosis. The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor bullous pemphigoid).

• #29 Bullous pemphigoid – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/bullous-pemphigoid/

  Direct and indirect immunoelectron microscopy ultrastructurally localizes in vivo-bound IgG autoantibodies to the binding site at the basement membrane. […] Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of BP patients, with proteins extracted from healthy human skin. […] Enzyme-linked immunosorbent assay (ELISA) analyzes the BP antigen-specific IgG autoantibodies in the patients sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. […] Immunohistochemistry on formalin-fixed skin sections in BP has been used to examine C3 deposition along the epidermal basement membrane zone. […] In India, histopathology and immunofluorescence (DIF and IIF) studies are routinely used for the diagnosis of BP.

• #30 Bullous pemphigoid diagnosis: the role of routine formalin-fixed paraffin-embedded skin tissue immunochemistry | Scientific Reports

  https://www.nature.com/articles/s41598-022-14950-z

  However, because of false-negative DIF results, Fudge et al. recommended repeat biopsy in clinically suspected BP cases with negative DIF findings. […] The diagnostic potential of IHC analysis of C3d and C4d using formalin-fixed paraffin-embedded (FFPE) tissue specimens for autoimmune bullous skin disease has been suggested in previous studies. […] We hypothesized that IgG-stained DEJ might have diagnostic value for BP. […] IHC staining is widely used clinically for FFPE tissues and may be an alternative to DIF. […] We determined that 86% of BP cases diagnosed by DIF could also be diagnosed via the detection of C3d, C4d, or IgG deposition by IHC staining as the diagnostic criterion. […] Thus, IHC staining may be a useful method for diagnosing BP, although DIF remains the gold standard. […] We suggest that performing IHC staining using FFPE tissue before conducting a second biopsy may be helpful in clinicopathologically suspected BP cases with negative DIF results.

• #31 Utility of C3d and C4d immunohistochemical staining in formalin-fixed skin or mucosal biopsy specimens in diagnosis of bullous pemphigoid and mucous membrane pemphigoid | Scientific Reports

  https://www.nature.com/articles/s41598-023-38193-8

  C3d IHC can be employed in diagnosing BP when a second biopsy for direct immunofluorescence (DIF) is not possible or where a facility for IF microscopy does not exist. […] In this study, we aimed to assess the utility of C3d and C4d IHC staining in the diagnosis of BP and MMP and in differentiating between them, when the diagnosis of these two entities were made by a combination of clinical and direct immunofluorescence features as benchmark. […] The sensitivity of C3d and C4d IHC in the diagnosis of BP and MMP was observed to be higher in the Blister+ analysis as compared to Blister and so was the negative predictive value. […] Comparing the usefulness of C3d and C4d IHC in BP and MMP, both C3d and C4d have a higher sensitivity as well as negative predictive value in diagnosing BP as compared to MMP. […] Overall, C3d is significantly more useful than C4d in diagnosis of BP.

• #32 Bullous Pemphigoid Challenge: Analysis of Clinical Presentation and Diagnostic Approach

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Dermatology-and-Clinical-Research/Bullous-Pemphigoid-Challenge:–Analysis-of-Clinical-Presentation–and-Diagnostic-Approach-8472?

  In an attempt to define predictors for the diagnosis of bullous pemphigoid four clinical criteria have been demonstrated. […] The first step in the diagnostic approach in order to confirm a clinical suspicion is the histopathology. […] Immunofluorescence microscopy plays a key role in the diagnostic analysis of bullous autoimmune diseases including BP. […] The direct immunofluorescence (DIF) is the gold standard in the diagnosis of BP which has a great sensitivity in the range of 82 91 %. […] DIF in BP demonstrates a deposition of IgG (70-90% of patients) and C3 (90-100% of patients) or both of them along the basement membrane zone of the patient. […] A salt-split skin technique is a useful diagnostical tool and helps differentiate BP from these conditions. […] The characterization of circulating autoantibodies has an important diagnostic power and can be made by performing IIF or ELISA.

• #33 Bullous Pemphigoid and Other Pemphigoid Dermatoses

  https://www.mdpi.com/1648-9144/57/10/1061

  Diagnosis of pemphigoid dermatoses is made by clinical correlation with histopathologic, immunopathologic, and serologic features. […] In the evaluation of suspected BP, MMP, and EBA, two 4 mm punch biopsies should be taken, as shown in Figure 2. One biopsy is from the lesion itself and is used for routine staining and processing with hematoxylin and eosin (H&E). The other biopsy is taken from perilesional, intact skin near the blister and is sent for direct immunofluorescence (DIF) using Michel’s medium. […] Although subepidermal clefting, separation, or splitting is classically observed, dermatopathologists should avoid the pitfall of solely relying on this feature for diagnosis. […] Common histopathologic features include the presence of a primarily eosinophilic infiltrate in the dermis and/or eosinophilic spongiosis.

• #34 Bullous pemphigoid – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/453

  1st tests to order include skin biopsy for histopathologic evaluation with light microscopy, skin biopsy for direct immunofluorescence testing, and indirect immunofluorescence test on serum. […] Tests to consider include the ELISA test. […] Emerging tests include immunoblotting, immunoprecipitation, and fluorescence overlay antigen mapping (FOAM) technique.

• #35 Bullous Pemphigoid Challenge: Analysis of Clinical Presentation and Diagnostic Approach

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Dermatology-and-Clinical-Research/Bullous-Pemphigoid-Challenge:–Analysis-of-Clinical-Presentation–and-Diagnostic-Approach-8472?

  Therefore, we consider that DIF and IIF should be the first immunological tests performed in the initial diagnosis of BP followed by ELISA assays when the latter one has been negative or in order to exclude other bullous autoimmune diseases with roof-pattern in IIF such as mucous membrane pemphigoid. […] Taken all this into consideration we conclude that a combination of clinical, histopathological and immunological tests in a right diagnostic order is required in order to establish an early and precise diagnosis which may have important therapeutical outcomes as well.

• #36 Bullous pemphigoid – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/453

  1st tests to order include skin biopsy for histopathologic evaluation with light microscopy, skin biopsy for direct immunofluorescence testing, and indirect immunofluorescence test on serum. […] Tests to consider include the ELISA test. […] Emerging tests include immunoblotting, immunoprecipitation, and fluorescence overlay antigen mapping (FOAM) technique.

• #37 Bullous Pemphigoid – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/bullous-pemphigoid

  Diagnosis is by skin biopsy and immunofluorescence testing of skin and serum. […] If bullous pemphigoid is suspected, skin biopsy is done for histology and direct immunofluorescence testing. […] Serum is tested for IgG antibodies to BPAg1 and BPAg2 using an enzyme-linked immunosorbent assay (ELISA). Circulating IgG autoantibodies are present in about three fourths of patients. […] Test results help differentiate bullous pemphigoid from pemphigus vulgaris, linear IgA disease, erythema multiforme, drug-induced eruptions, mucous membrane pemphigoid, paraneoplastic pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita. […] Biopsy the skin for histology and immunofluorescence testing and measure circulating autoantibodies.

• #38 Bullous Pemphigoid Workup: Laboratory Studies, Other Tests, Histologic Findings

  https://emedicine.medscape.com/article/1062391-workup

  To establish a diagnosis of bullous pemphigoid, the following tests should be performed: Histopathologic analysis from the edge of a blister […] Direct immunofluorescence (DIF) studies on normal-appearing perilesional skin. If the DIF result is positive, indirect immunofluorescence (IDIF) is performed with the patient’s serum. The preferred substrate for IDIF is salt-split normal human skin substrate. DIF demonstrates in-vivo deposits of antibodies and other immunoreactants (eg, complement). Usually, immunoglobulin G (IgG; 70-90% of patients) and complement C3 deposition (90-100% of patients) can be seen in a linear band at the dermoepidermal junction. This pattern of immunoreactants is not specific for bullous pemphigoid and may also be seen in cicatricial pemphigoid (CP) and epidermolysis bullosa acquisita (EBA). Bullous pemphigoid can be differentiated from CP and EBA by incubating the patient’s skin biopsy sample in 1 mol/L salt before performing DIF. This process induces cleavage through the lamina lucida. DIF on salt-split skin reveals immunoglobulin G (IgG) on the blister roof (epidermal side of split skin) in patients with bullous pemphigoid, whereas in CP and EBA, IgG localizes to the blister floor (dermal side of split skin). The optimal location for DIF testing is normal-appearing perilesional skin; false-positive results may occur when it is performed on lesional skin. There is a significant false-negative rate if the skin biopsy specimen is taken from skin of the legs. Rarely, skin biopsy samples placed in transport media may yield false-negative results. Thus, fresh tissue is the preferred substrate for DIF studies. IDIF studies document the presence of IgG circulating autoantibodies in the patient’s serum that target the skin basement membrane component. About 70% of patients with bullous pemphigoid have circulating autoantibodies that bind to split skin. The titer of circulating antibody is not correlated with the disease course. IDIF studies can be used to detect the patient’s IgG circulating autoantibodies that bind to the epidermal roof (upper part) of the salt-split skin substrate. Tests available in research laboratories include direct and indirect immunoelectron microscopy (immunoEM), immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Immunoblotting or Western blotting demonstrates reactivity of IgG in the sera of patients with proteins extracted from healthy human skin. Sensitivity varies: In 75% of patients, a reaction occurs with the BP230 antigen, whereas in 50%, a reaction occurs with the BP180 antigen. Like immunoblotting, immunoprecipitation demonstrates reactivity with BP230 and BP180. Unlike immunoblotting, however, immunoprecipitation is performed with native rather than denatured protein; consequently, it is more sensitive. Immunoprecipitation is more difficult to perform than immunoblotting and is generally less available. In most cases, immunoprecipitation detects autoantibodies specific for BP230 and BP180. ELISA analyzes the bullous pemphigoid antigen (BPAg)-specific IgG autoantibodies in the patients’ sera by using various lengths of recombinant proteins of the BPAg1 or BPAg2 antigens. It has been demonstrated to be highly sensitive and specific. ELISA kits for testing BPAg-specific IgG autoantibodies are available commercially; however, relatively few centers offer this service. ELISAs based on recombinant proteins encoded by BP230 and BP180 have been developed; though not commercially available, these assays are promising as investigational tools. ELISA based on BP180 demonstrates sera reactivity with more than 90% of patients who have bullous pemphigoid. If freshly frozen tissue is not available for DIF microscopy, formalin-fixed skin sections from patients with bullous pemphigoid may be used to examine the presence of C3 deposition along the epidermal basement membrane zone for confirmation of the diagnosis. The histopathologic examination demonstrates a subepidermal blister. The inflammatory infiltrate is typically polymorphous, with an eosinophil predominance. Mast cells and basophils may be prominent early in the disease course. Lesional skin biopsy specimens may reveal a predominantly neutrophilic infiltrate or minimal inflammation (pauci-inflammatory or cell-poor bullous pemphigoid).

• #39 Bullous Pemphigoid – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/bullous-pemphigoid

  Diagnosis is by skin biopsy and immunofluorescence testing of skin and serum. […] If bullous pemphigoid is suspected, skin biopsy is done for histology and direct immunofluorescence testing. […] Serum is tested for IgG antibodies to BPAg1 and BPAg2 using an enzyme-linked immunosorbent assay (ELISA). Circulating IgG autoantibodies are present in about three fourths of patients. […] Test results help differentiate bullous pemphigoid from pemphigus vulgaris, linear IgA disease, erythema multiforme, drug-induced eruptions, mucous membrane pemphigoid, paraneoplastic pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita. […] Biopsy the skin for histology and immunofluorescence testing and measure circulating autoantibodies.

• #40 Bullous Pemphigoid & Pemphigus Vulgaris- Dermatology Advisor

  https://www.dermatologyadvisor.com/ddi/bullous-pemphigoid-pemphigus-vulgaris/

  Therefore, a detailed patient history, clinical evaluation, histopathologic examination displaying the characteristic findings of BP, and DIF studies are crucial components necessary to distinguish BP from other similarly presenting disorders. […] Linear IgA dermatosis and BP both present with subepidermal splitting; therefore, DIF must be used to distinguish between these 2 diseases. […] The diagnosis of PV is accomplished through a combination of clinical findings, histopathology, and immunohistochemistry. […] Diagnosis is confirmed by DIF assay, indirect immunofluorescence (IIF) assay, or ELISA to Dsg1 and Dsg3 recombinant fusion proteins. […] Additionally, recent studies looking at the human leukocyte antigen typing of affected individuals have identified pemphigus-prone genes in the patients genotype. […] However, despite the multiple tools available, there are currently no uniformly accepted criteria for the diagnosis of PV.

• #41 Diagnosis and clinical severity markers of bullous pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2920699/

  Direct immunofluorescence (IF) microscopy of a perilesional biopsy is still regarded as the gold standard in the diagnosis of BP. […] Usually, however, in patients with clinical lesions typical for BP, the detection of antibodies to BP180 NC16A suffices to establish the diagnosis of BP, whereas serum antibodies to BP230 require a positive direct IF microscopy to diagnose BP. […] Finally, based on our personal experience, repeated testing for serum anti-BP180 NC16A antibodies during the course of the disease may be a helpful guide for treatment decisions.

• #42

  https://link.springer.com/article/10.1007/s40257-017-0264-2

  The value of BP230 enzyme-linked immunosorbent assay in the diagnosis and immunological follow-up of bullous pemphigoid. […] Positive direct immunofluorescence is of better value than ELISA-BP180 and ELISA-BP230 values for the prediction of relapse after treatment cessation in bullous pemphigoid: a retrospective study of 97 patients.

• #43 Bullous pemphigoid: Diagnosis and treatment

  https://www.aad.org/public/diseases/a-z/bullous-pemphigoid-treatment

  If you have bullous pemphigoid, treatment can reduce the amount of time that it takes for bullous pemphigoid to go into remission. […] Most patients follow a treatment plan for six months to five years before the disease goes into long-term remission. Once the disease is in long-term remission, many patients can stop treatment. However, some patients need to continue treatment. […] Treating bullous pemphigoid can be complicated. Your dermatologist may coordinate with your primary care doctor and other doctors as needed. Keeping all of your medical appointments will help: Determine whether the treatment works for you or needs to be modified, Find side effects early, See if an infection, which can be serious, has developed, Make sure you know what to do, so you can follow your treatment plan.

• #44 Bullous Pemphigoid | Dermatologist In Brevard, NC | Highlands Dermatology

  https://www.highlandsdermatology.com/articles/aad_education_library/920190-bullous-pemphigoid/

  If you have bullous pemphigoid, you must see a dermatologist or other skin specialist for proper diagnosis and treatment. Early diagnosis and treatment are key to preventing serious complications from the disease. […] There is no cure for bullous pemphigoid. However, treatment can help to manage the symptoms and prevent complications. […] Your dermatologist will create a personalized care plan based on the severity of your symptoms. In some cases, bullous pemphigoid may go away on its own without treatment. However, most people will need medication to manage their symptoms.

• #45 Bullous pemphigoid

  https://www.nhs.uk/conditions/bullous-pemphigoid/

  Bullous pemphigoid is a rare skin condition that mainly affects people over the age of 60. […] If a GP thinks you have bullous pemphigoid, they may refer you to a specialist for tests and treatment. […] The main treatments for bullous pemphigoid are: steroid creams, steroid tablets, antibiotics. […] Treatment can help your skin heal, stop new patches or blisters appearing, and lower the chances of your skin getting infected. […] It’s important to go to check-ups with your doctor so problems can be found and treated early.

• #46 Bullous pemphigoid: Diagnosis and treatment

  https://www.aad.org/public/diseases/a-z/bullous-pemphigoid-treatment

  If you have bullous pemphigoid, treatment can reduce the amount of time that it takes for bullous pemphigoid to go into remission. […] Most patients follow a treatment plan for six months to five years before the disease goes into long-term remission. Once the disease is in long-term remission, many patients can stop treatment. However, some patients need to continue treatment. […] Treating bullous pemphigoid can be complicated. Your dermatologist may coordinate with your primary care doctor and other doctors as needed. Keeping all of your medical appointments will help: Determine whether the treatment works for you or needs to be modified, Find side effects early, See if an infection, which can be serious, has developed, Make sure you know what to do, so you can follow your treatment plan.

• #47 Study Highlights Comorbidities Before, After Bullous Pemphigoid Diagnosis

  https://www.hcplive.com/view/study-highlights-comorbidities-before-after-bullous-pemphigoid-diagnosis

  Individuals with bullous pemphigoid have higher odds of psoriasis, pressure ulcers, and neuropsychiatric disorders before diagnosis. […] After diagnosis, patients show increased likelihood of pneumonia, chronic renal disease, sepsis, and cardiac arrest. […] Recognition of comorbidities associated with bullous pemphigoid can provide insights into its pathomechanisms and improve treatment strategies. […] Individuals with bullous pemphigoid prior to diagnosis have greater odds of psoriasis, pressure ulcers, intracerebral hemorrhage, acute renal failure, scabies, drug eruption, and neuropsychiatric disorders, according to recent findings. […] In this same analysis, investigators found that patients had greater odds of pneumonia, chronic renal disease, sepsis, and cardiac arrest after diagnosis.

• #48 Diagnosis and clinical severity markers of bullous pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2920699/

  The use of a broad spectrum of novel detection systems for autoantibodies to the basement membrane proteins BP180 and BP230 has greatly facilitated the diagnosis of bullous pemphigoid, which most likely explains its increasing incidence in central Europe. […] Direct immunofluorescence (IF) microscopy of a perilesional skin biopsy that typically reveals linear deposits of complement component 3 (C3) and/or immunoglobulin G (IgG) at the basal membrane zone (BMZ) is still the diagnostic gold standard. […] For more than a decade, B-cell epitopes have been known to be unequally distributed on BP180 in BP. […] The novel diagnostic assays have greatly facilitated the diagnosis of BP, which may explain the increased incidence of BP that was recently observed in a prospective study with patients from a well-defined region, Lower Franconia in Germany.

• #49

  https://dpcj.org/index.php/dpc/article/view/dermatol-pract-concept-articleid-dp1003a50

  Autoimmune bullous disorders are a heterogeneous spectrum of skin disorders characterized by the production of autoantibodies against adhesion molecules of the skin. […] Diagnosis is based on clinical manifestations and confirmed with histological, immunofluorescence, and serological testing. […] Recently multivariant enzymelinked immunosorbent assay systems have been developed as practical screening tools for patients with suspected autoimmune bullous dermatoses. […] Treatment of bullous pemphigoid is based on disease extension.

• #50 Strategies to improve outcomes of bullous pemphigoid | CCID

  https://www.dovepress.com/strategies-to-improve-outcomes-of-bullous-pemphigoid-a-comprehensive-r-peer-reviewed-fulltext-article-CCID

  Direct IF microscopy of perilesional, nonbullies skin, represents the gold standard for autoimmune bullous disorders diagnosis. […] The enzyme-linked immunoassay (ELISA) reveals the existence of circulating antibodies targeting NC16A, BP180, and BP230. […] The diagnosis of BP may be a challenge, especially in the non-bullous phase, due to non-specific manifestations which may mimic a variety of diseases, such as contact dermatitis, prurigo, drug reactions, urticaria, scabies, and acquired non-autoimmune blistering disorders. […] In conclusion, the management of BP is still considered a challenge in dermatology, due to the high mortality rates and difficulties in treating elderly patients. However, early recognition of the disease, correct treatment choice, and monitoring during follow-up of both BP and patients comorbidities may certainly improve patients outcomes.

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