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• W2073236410 abstract "Epidermolysis bullosa acquisita (EBA) is a cutaneous subepidermal autoimmune blistering disorder (CSEAIBD) that results from the effects of IgG autoantibodies directed against the 145-kDa noncollagenous amino-terminal (NC-1) domain of collagen VII, a major component of anchoring fibrils (Fig. 1).1–6 Clinical and laboratory features of EBA overlap with those of other bullous dermatoses, making diagnosis challenging. Although EBA first was described over a century ago,7 it was not until the early 1970s that clinical diagnostic criteria were proposed (Table 1).8 These criteria included the proviso that other conditions be excluded before diagnosing EBA. This is difficult to achieve with clinical information alone, particularly as EBA may present with a variety of phenotypes.9,10 Establishing an accurate diagnosis is critical for determination of prognosis and selection of appropriate treatment. Schematic representation of basement membrane zone, with relevant antigen targets for immunobullous disorders depicted at approximate anatomic locations Classic EBA, comprising the majority of cases, is characterized by the appearance of skin fragility and noninflammatory, tense, subepidermal vesicles, and bullae that heal with scarring and milia (Fig. 2). Lesions may appear on any mucocutaneous surface and generally are distributed in anatomic areas subjected to repetitive minor trauma, such as the extensor upper extremities. Classic EBA may resemble porphyria cutanea tarda clinically. Other forms of EBA may present with eruptions reminiscent of bullous pemphigoid (BP),11,12 mucous membrane pemphigoid (MMP),13 Brunsting–Perry pemphigoid,14 bullous systemic lupus erythematosus (BSLE), or linear IgA disease (LAD).15 Moreover, a case of EBA presenting with an erythema gyratum repens-like eruption in a patient with ulcerative colitis was reported recently.16 Clinical photographs of a patient with epidermolysis bullosa acquisita. Erosions of the oral mucosa (a), dorsal tongue (b), dorsal foot (d), and esophagus (e) demonstrated above. Note healing with milia and scarring on the dorsal hand (c) Although the original diagnostic criteria for EBA8 stated that disease onset should be in adulthood, several confirmed cases of EBA in children have been documented.17–19 Therefore, we propose that this criterion be modified (Table 1). As EBA cannot be diagnosed reliably solely by clinical findings, a sequence of diagnostic tests may be employed to arrive at the diagnosis, as outlined below (Fig. 3; Table 2). Proposed diagnostic algorithm for acquired, subepidermal immunobullous disorders. DIF, direct immunofluorescence; IIF, indirect immunofluorescence; BMZ, basement membrane zone A B Histologic evaluation may be used to support or reject the diagnosis of EBA. Standard tissue staining with hematoxylin and eosin demonstrates the presence of subepidermal vesicles and bullae in EBA.20 The degree of associated inflammation on histology correlates closely with the clinical appearance of the lesion selected for biopsy. Classic EBA usually presents with a non- or pauci-inflammatory subepidermal blister, whereas the inflammatory forms of EBA is associated with a neutrophil-rich infiltrate with variable numbers of eosinophils. Because histologic findings of EBA are nonspecific, immunofluorescence and other testing modalities are required for definitive diagnosis. In EBA, DIF from perilesional skin demonstrates linear basement membrane zone (BMZ) deposition of IgG (Fig. 4).21,22 Several findings on DIF may be helpful to either raise the suspicion for, or confirm the diagnosis of, EBA. Linear BMZ deposition of IgG in the absence of C3 is seen more commonly in EBA than in BP, whereas linear IgG and C3 deposition or C3 deposition alone is more characteristic of BP.23 Deposits of multiple conjugates, including IgG, IgM, C3, C4, or properdin, at the BMZ is also more frequently seen in the setting of EBA compared to BP.21 Linear IgA deposition has been correlated with mucous membrane involvement in bullous dermatoses, including EBA.24 Linear IgG deposition on direct immunofluorescence testing, a finding seen in epidermolysis bullosa acquisita Further information can be gained by subclassifying linear BMZ patterns as true linear, n-serrated pattern, or u-serrated patterns, findings that are primarily seen in cutaneous but not mucosal biopsy specimens. A u-serrated pattern is most often seen in EBA and bullous systemic lupus erythematosus, whereas an n-serrated pattern is seen in BP, anti-epiligrin cicatricial pemphigoid (AECP), and linear IgA bullous dermatosis (LABD; Fig. 5).25 These findings are particularly helpful in distinguishing EBA from AECP, two entities with similar direct and indirect immunofluorescence (IIF) findings on salt-split skin. DIF following sodium chloride- or vacuum-induced splitting of the cutaneous biopsy specimen has also been used as a means to differentiate EBA from BP, where cutaneous biopsies of patients with EBA will have a dermal pattern of immunofluorescence, while those of patients with BP will have a predominantly epidermal pattern.26,27 Fluorescence overlay mapping of BP180 antigen (a) and in vivo bound IgA (b) of a patient with IgA epidermolysis bullosa acquisita. BP180 deposits in an n-serrated pattern (red), while IgA in EBA deposits in a u-serrated pattern (green). The overlay image (c) demonstrates that the distributions of the target antigens are distinct anatomically. (Vodegel et al., 2004; Used with permission from Blackwell Publishing) Cases in which DIF has already demonstrated the presence of a subepidermal autoimmune blistering disorder, another technique that uses cutaneous biopsy specimens to help distinguish EBA from BP and AECP is collagen IV immunomapping. This method of epitope mapping uses collagen IV immunoperoxidase staining to delineate the lamina densa of the BMZ.28 The stained region is compared to the location of the split in lesional skin to determine whether the pathogenic autoantibodies are directed against epitopes above or below the lamina densa, of which collagen IV is a major component. Positive collagen IV immunoperoxidase staining in the roof of the blister implicates autoantibodies directed against sublamina densa structures, as would be seen in EBA. In contrast, one would expect to see collagen IV staining of the floor of the blister in BP and AECP, as BP antigens (BP 230 and BP 180, also known as collagen XVII) and laminin-332 are located above the lamina densa. When tested in a series of patients with autoimmune subepidermal blistering disorders, this method correlated with human salt-split skin (HSSS) findings in 20 of 21 patients.28 Additionally, collagen IV mapping was found to be more sensitive than IIF with HSSS testing in this study. This method may be particularly helpful in subclassifying CSEAIBD when a circulating autoantibody is undetectable. While this technique has a role in the diagnosis of pauci- or noninflammatory cases of EBA, it may be less reliable in inflammatory cases, as inflammation in EBA has been shown to degrade the basement membrane at many sites.29 This technique involves DIF staining of IgG and several BMZ proteins using different fluorescent stains with or without the use of LSCM. Following computer analysis, the IgG stain and the BMZ protein stains are overlaid, and the relationship of the site of IgG deposition to that of the particular BMZ protein then is compared. In EBA, IgG deposits on the dermal side of β4-integrin and collagen IV, while it co-localizes with collagen VII. This method is particularly useful in patients without circulating serum antibody.30 Additional findings on LSCM consistent with EBA include prominent invaginations of the lamina densa and vertically oriented clumps of anchoring fibrils at and below the dermal–epidermal junction.31 Scanning electron microscopy of early blisters from patients with EBA will show the split of the blister at a level below the lamina densa, which remains attached to the basal keratinocytes.32 Founded on principle similar to that of DIF, DIEM permits visualization of IgG, tagged with colloidal gold or peroxidase, on perilesional normal skin. The advantage of this technique over DIF is the demonstration of the ultrastructural localization of the IgG deposits within the BMZ. In EBA, electron dense deposits will be observed on the anchoring fibrils.21,22 IIF with monkey esophagus substrate may demonstrate the presence of serum anti-BMZ IgG antibodies in patients with EBA (Fig. 6). However, this finding is not specific and may be seen in virtually all IgG-mediated CSEAIBD.33 For example, in a study involving 100 consecutive patients with serum BMZ antibodies, 5% were found to have EBA or BSLE.34 IIF using patient serum and HSSS may differentiate EBA from pemphigoid in seropositive cases.26,34 In this technique, normal human skin is incubated with 1 mol/l NaCl, leading to an artefactual split at the lamina lucida. Labeled patient sera then is applied to the HSSS substrate. Because the pathogenic antibodies in EBA localize to the anchoring fibrils of the lamina densa and sublamina densa, antibody deposition is seen at the dermal side of the skin split (Fig. 7).34 Basement membrane zone deposition of IgG antibody on monkey esophagus substrate with indirect immunofluorescence testing. This finding is consistent with epidermolysis bullosa acquisita Immunoglobulin deposition on the base of sodium chloride-induced split human skin substrate using indirect immunofluorescence, as can be found in epidermolysis bullosa acquisita Although testing for circulating anti-BMZ antibodies by IIF with HSSS readily distinguishes EBA from BP and its variants, a dermal pattern of staining may be seen in other CSEAIBD, including BSLE, AECP, and other rare disorders, including anti-p200, anti-p105 and anti-collagen IV pemphigoid. To help differentiate EBA and BSLE from AECP and other rare CSEAIBD in this setting, one can repeat IIF using salt-split skin from patients with dystrophic epidermolysis bullosa (a condition marked by the congenital absence of collagen VII) as substrate. The use of this collagen VII “knock-out” substrate will result in negative staining if the patient has EBA or BSLE.35 Immunoblotting can be used to identify autoantibodies directed against the α-chain (290-kDa) or globular chain of the α-chain (145-kDa) of collagen VII.1,2,4,5,36 While this test can be helpful in the diagnosis of EBA, test sensitivity drops in seronegative cases.26 More recently, Chen et al.37 developed an ELISA to detect collagen VII autoantibodies. When used in EBA, ELISA is more sensitive than immunoblotting, likely because ELISA identifies nondenatured, nonreduced proteins, whereas immunoblotting only detects denatured, reduced proteins.37 ELISA shows promise, as it has the potential to be readily available and is quantitative when positive, thus rendering it particularly useful in monitoring of disease. Similar to IIF, IIEM uses colloidal gold- or immunoperoxidase-tagged antihuman IgG antibody with human skin substrate to facilitate localization of IgG deposition. With enhanced anatomic resolution over standard IIF, IIEM can define the precise ultrastructural location of IgG deposits. In EBA and BSLE, electron dense deposits are observed on the anchoring fibrils.5,36 EBA is notoriously difficult to treat and may have a prolonged course. Long-term disease complications include cutaneous and mucosal scarring, which may lead to blindness, esophageal stricture, or joint contractures.15,38–40 These complications may be avoided by early institution of appropriate treatment. EBA often is refractory to the conventional treatment approach of high-dose corticosteroids and corticosteroid-sparing agents. Difficulty in selecting optimal treatments for patients with EBA is compounded by the absence of published randomized, controlled therapeutic trials.41 Therefore, much of the available information is derived from case reports and series, and therefore is subject to publication bias inherently. A literature review of previously reported cases of EBA treated with cyclosporine, colchicine, extracorporeal photochemotherapy, and intravenous immunoglobulin (IVIg) found favorable responses with each treatment.42 The authors asserted that conventional therapy with prolonged, high-dose corticosteroids subjects patients to significant risk without consistent benefit. Therefore, they proposed that colchicine or IVIg be considered as first-line treatments in mild or advanced cases, respectively.42 Other treatments with anecdotal documented efficacy include: super-potent topical steroids,43 mycophenolate mofetil,44,45 dapsone,46 rituximab with or without immunoadsorption,47–50 and other immunosuppressive medications. None of these medications is without risk or adverse effects, so pharmacotherapy must be selected carefully based on patient co-morbidities and disease severity. Patients should be followed closely with appropriate laboratory monitoring. By correlating clinical findings with results from tests used in a systematic diagnostic algorithm (Fig. 3, Table 2), the diagnosis of EBA can be made with relative certainty. Although results of the aforementioned tests can be identical between EBA and BSLE as a consequence of having a common antibody target (i.e. collagen VII), molecular methods can be used to determine whether antibodies are directed to the noncollagenous amino-terminal domain of collagen VII (as in EBA) or the collagenous amino-terminal domain (as in BSLE). Moreover, BSLE, unlike EBA, is associated with the clinical presentation and autoimmune serology profile of SLE. Obstacles to testing outlined in the proposed diagnostic algorithm are twofold, however. First, test availability may be limited in many areas (Table 3). Although routine histology is available widely, other assays may require transportation of tissue or serum specimens to a referral or research laboratory in certain practice settings. Second, such testing is expensive (Table 3), and this is compounded by the fact that several of these tests have not been approved by the Food and Drug Administration, and therefore are unlikely to be covered by medical insurance. Despite these drawbacks, we advocate establishment of an accurate diagnosis in patients with immunobullous disorders such as EBA with thorough laboratory investigations for several reasons. One important advantage to elucidating the correct diagnosis is to better predict disease prognosis. For example, the identification of EBA portends a chronic course with decreased responsiveness to therapy when compared with other subepidermal autoimmune disorders.12,42 Moreover, the patient must be monitored closely for long-term serious disease sequelae, such as blindness and esophageal strictures.15,38–40 Accurate diagnosis is critically important in optimizing treatment strategy. Thoughtful, evidence-based pharmacologic strategies tailored to EBA may avoid unnecessary exposure to potentially harmful immunosuppressive medications, which might otherwise be used to treat other similar immunobullous disorders. Furthermore, recognition of EBA may prompt evaluation for associated conditions. In a series of 51 patients with EBA, approximately one-quarter also had inflammatory bowel disease.51 Interestingly, EBA antigen (i.e. collagen VII) not only is present in anchoring fibrils of the cutaneous BMZ and dermis but also is present in the junction between the epithelium and lamina propria in the intestine.52 In case reports and series, EBA also has been associated with several other conditions, such as amyloidosis, lymphoma, and systemic lupus erythematosus.8,10 Finally, determination of anticollagen VII antibody titers offers information that may help to guide disease management. These antibodies have been shown to be directly pathogenic in EBA,3 so it follows that antibody titers may be correlated with disease activity and response to treatment. Indeed, declining serum autoantibody titers have been correlated with clinical improvement previously.42,48 A diverse collection of conditions may mimic epidermolysis bullosa acquisita clinically and histologically. In recent decades, advanced laboratory tests, including immunofluorescence, molecular techniques, immunoelectron microscopy, and variations thereof have been developed to improve classification of CSEAIBD. We contend that accurate diagnosis of epidermolysis bullosa acquisita can be established by following a systematic diagnostic algorithm, such as that proposed herein, and can yield important information with regards to disease prognosis and approach to treatment. Special thanks to Ms Patricia Krause for her help with obtaining test price information. Trade names of medications mentioned in this article: Cyclosporine – Sandimmune®, Neoral®, Cicloral®, Gengraf® Colchicine – Colchicindon®, Goutnil® Mycophenolate mofetil – CellCept® Rituximab – Rituxan® Questions for readers: Anti-collagen VII antibodies are identified in the serum of a patient with a mucocutaneous immunobullous disorder. Of the choices below, which is the most likely diagnosis? Epidermolysis bullosa acquisita Anti-epiligrin cicatricial pemphigoid Bullous pemphigoid Pemphigus vulgaris Which of the following represents the most accurate description of the clinical findings in classic epidermolysis bullosa acquisita? Collections of tense and ruptured blisters in an annular configuration Tense blisters confined to the head and neck distribution Flaccid blisters and erosions arising initially in the mouth and later on the glabrous skin Tense blisters in trauma-prone areas, with scarring and milia formation Of the histopathologic findings listed below, which is most suggestive of epidermolysis bullosa acquisita? Subcorneal vesicle Subepidermal blister with eosinophilic spongiosis Subepidermal blister with few perivascular lymphocytes Subepidermal blister with neutrophilic abscesses in the dermal papillae Which of the following testing modalities is available in most reference laboratories and can reliably distinguish bullous pemphigoid from epidermolysis bullosa acquisita? Direct immunofluorescence Indirect immunofluorescence with human salt-split skin testing Laser scanning confocal microscopy Direct immunoelectron microscopy Of the following choices, which can most consistently differentiate epidermolysis bullosa acquisita from antiepiligrin cicatricial pemphigoid? Indirect immunofluorescence Indirect immunofluorescence using human salt-split skin Collagen IV immunoperoxidase mapping Clinical findings Which of the answers below is most helpful in diagnosing epidermolysis bullosa acquisita in seronegative patients? Indirect immunofluorescence Immunoblotting Laser scanning confocal microscopy Indirect immunoelectron microscopy Which is most likely to be associated with epidermolysis bullosa acquisita? Carcinoma of the upper aerodigestive tract Breast cancer Diabetes mellitus Inflammatory bowel disease Which is true regarding the anatomy of the basement membrane zone? Anchoring fibrils are comprised of collagen VII Lamina densa is composed of collagen XVII arranged in a lattice-like configuration Laminin-332 is superficial to α6β4 integrin Anchoring plaques are present in the lamina lucida Treatment of epidermolysis bullosa acquisita is most accurately characterized by which of the following statements? High-dose corticosteroids reliably lead to disease control The combination of tetracycline and niacinamide is reasonably effective and offers relatively low risk to the patient Non-inflammatory epidermolysis bullosa acquisita responds more readily to treatment than inflammatory epidermolysis bullosa acquisita To date, the only available evidence regarding treatment of epidermolysis bullosa acquisita is contained within case reports, case series, and review articles Complications of inadequately treated epidermolysis bullosa acquisita include: Blindness Dysphagia Loss of joint range of motion All of the above Answers: 1 a, 2 d, 3 c, 4 b, 5 c, 6 c, 7 d, 8 a, 9 d, 10 d" @default.
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• W2073236410 date "2009-02-19" @default.
• W2073236410 modified "2023-10-16" @default.
• W2073236410 title "Epidermolysis bullosa acquisita: concise review and practical considerations" @default.
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