Epidermolysis Bullosa
Acquisita
▪ EPIDEMIOLOGY
Epidermolysis bullosa acquisita (EBA) is a sporadic autoimmune bullous disease of unknown etiology and with no gender, ethnic, or geographic predisposition. Although EBA does not have a Mendelian pattern type of inheritance, there may be some genetic predisposition to EBA and autoimmunity in African Americans who live in the southeastern part of the United States. African American patients in the southeastern part of the United States who have either EBA or bullous systemic lupus erythematosus (SLE) have a high incidence of the HLA-DR2 phenotype. The calculated relative risk for EBA in HLA-DR2+ individuals is 13.1 in these patients. These results also suggest that EBA and bullous SLE are immunogenetically related and that either the HLADR2 gene is involved with autoimmunity to anchoring fibril collagen or is some sort of a marker for some other gene that exists in linkage disequilibrium with it.
▪ ETIOLOGY AND PATHOGENESIS
EBA is a chronic, sub-epidermal blistering disease associated with autoimmunity to the collagen (type VII collagen) within anchoring fibril structures that are located at the dermal-epidermal junction (DEJ). Although the precise etiology of EBA is unknown, most of the evidence suggests an autoimmune etiology. The immunoglobulin G (IgG) autoantibodies to type VII collagen are associated with a paucity of normal anchoring fibrils at the basement membrane zone (BMZ) separating the epidermis from the dermis and poor epidermal-dermal adherence. Although it is an acquired disease that usually begins in adulthood, it was placed in the category epidermolysis bullosa (EB) approximately 100 years ago because physicians were struck by how similar the clinical lesions of EBA were to those seen in children with hereditary dystrophic forms of EB. Direct immunofluorescence (DIF) of perilesional skin biopsies from EBA patients reveals IgG deposits at the DEJ.2 EBA antibodies bind to type VII collagen within anchoring fibrils
Anchoring fibrils anchor the epidermis and its underlying BMZ to the papillary dermis. Patients with hereditary forms of dystrophic EB and EBA have decreased numbers of anchoring fibrils in their DEJ. This paucity of anchoring fibrils is associated with two similar clinical phenotypes, EBA and dystrophic forms of hereditary EB, because both diseases are characterized by skin fragility, sub-epidermal blisters, milia formation, and scarring. Although both EBA and hereditary forms of dystrophic EB are etiologically unrelated in terms of their underlying pathogenesis, they share the common feature of decreased anchoring fibrils. In the case of dystrophic forms of hereditary EB, the cause of decreased or absent anchoring fibrils is a genetic defect in the gene that encodes for type VII collagen α chains that ultimately results in small, nonfunctional or decreased anchoring fibrils. The gene coding for type VII collagen is located on the short arm of chromosome 3, approximately 21 cm from zero.7 The gene defects involved in hereditary forms of dystrophic EB have been identified at variable locations, but the severity of the disease appears to correlate with the degree of type VII collagen and anchoring fibril perturbations. In EBA, the IgG autoantibodies binding to the type VII collagen α chains result in decreased anchoring fibrils, but the pathway leading to this reduction is unknown. It may be that type VII collagen α chains that are newly synthesized but decorated with EBA autoantibodies cannot form triplehelical structures and stable anchoring fibrils. Healed burn wounds that have been covered with cultured keratinocyte sheets also have decreased numbers of anchoring fibrils within the first year after transplantation, and this is associated with spontaneous blister formation, shortened suction blistering times, and skin fragility.8 These observations provide indirect evidence that anchoring fibrils play a role in maintaining adherence between the epidermis and dermis.
The type VII collagen α chain has a molecular mass between 250 and 320 kd, and the collagen consists of a homotrimer of three identical α chains. Each α chain consists of a large globular noncollagenous amino terminus called the non-collagenous 1 (NC-1) domain that is approximately one-half the entire mass of the α chain. Next, there is a helical domain with typical glycine-X-Y repeats. At the carboxyl terminus is a second globular noncollagenous domain, NC-2, that is much smaller than NC-1.9 Most EBA autoantibodies recognize four predominant antigenic epitopes within the NC-1 domain and do not recognize the helical or NC-2 domains. There may be something intrinsically “antigenic” about the NC-1 domain because the available monoclonal antibodies that have been generated against type VII collagen (anti-C-VII antibodies) specifically recognize only NC-1 subdomains.
EPIDERMOLYSIS BULLOSA
ACQUISITA AT A GLANCE
- Rare, autoimmune sub-epidermal bullous disease due to immunoglobulin G autoantibodies to type VII collagen.
- Etiology is unknown.
- Skin fragility, sub-epidermal blisters, residual scarring, and milia formation. Common sites are trauma-prone areas such as hands, feet, elbows, knees, sacrum, nails, and mouth.
- Related features may include an underlying systemic disease such as inflammatory bowel disease. May have erosions of the mucosa and esophageal stenosis.
- Pathology shows sub-epidermal bulla, fibrosis, milia formation, and positive direct immunofluorescence for immunoglobulin G deposits at the epidermal-dermal junction.
- Treatment options limited and often difficult.
A reduction in the number of anchoring fibrils is seen in lesional and perilesional skin of EBA patients, but the pathway leading to this reduction is unknown.
Several independent lines of evidence have implicated autoimmune responses
as a key element in the pathogenesis of EBA. First, the pathogenic role of EBA antibodies is suggested by the observation that when patients with SLE develop autoantibodies to the EBA antigen, they develop widespread skin blisters and fall into a subset of SLE called bullous SLE.16 This “experiment of nature” suggests that EBA autoantibodies are pathogenic and capable of inducing disadherence between the epidermis and dermis. Secondly, direct proof that EBA autoantibodies are pathogenic comes from recent passive transfer studies. We immunized rabbits and raised a high titer antiserum to the NC-1 domain of human type VII collagen. We injected this antibody into hairless immune competent mice, and the mice developed bullous skin disease with many of the features of EBA in humans.17 The mice developed sub-epidermal blisters and lost nails on their feet. They also had circulating NC-1 antibodies in their blood and anti-NC-1 IgG antibody deposits at their DEJ. In addition, the mice had murine complement deposits at the DEJ induced by the autoantibody-antigen complex. Another study by Sitaru and colleagues18 showed that the injection of rabbit polyclonal antibodies to the NC-1 domain of mouse type VII collagen into mice also induced sub-epidermal skin blisters that were reminiscent of human EBA. Further, we have also affinity purified human EBA autoantibodies against an NC-1 column and injected them into mice. The mice then developed clinical, histologic, immunologic and ultrastructural features akin to human EBA.19 Taken together, these successful passive transfer experiments and the observations with bullous SLE strongly suggest that EBA autoantibodies are “pathogenic” and capable of causing epidermal-dermal separation in skin.
▪ CLINICAL FINDINGS
If a patient presents with bullae on the skin with no reasonable explanation despite a thorough history and physical examination, three tests should be done: a skin biopsy for routine hematoxylin and eosin histology, a second biopsy juxtaposed to a lesion but on normal-appearing skin for DIF and a blood draw to test for antibodies against the BMZ and/or type VII collagen
by indirect immunofluorescence (IIF) or enzyme-linked immunosorbent assay (ELISA).
History
Cutaneous Lesions
The cutaneous lesions of EBA can be quite varied and can mimic other types of acquired autoimmune bullous diseases. The common denominator for patients with EBA is autoimmunity to type VII (anchoring fibril) collagen. Although the clinical spectrum of EBA is still being defined, there are at least five clinical presentations: (1) a classic presentation, (2) a bullous pemphioid (BP)-like presentation, (3) a cicatricial pemphigoid (CP)-like presentation, (4) a presentation reminiscent of Brunsting-Perry pemphigoid with scarring lesions and a predominant head and neck distribution, and (5) a presentation reminiscent of linear IgA bullous dermatosis or chronic bullous disease of childhood.
Classic Presentation
The classic presentation is of a noninflammatory bullous disease with an acral distribution that heals with scarring and milia formation. This presentation is reminiscent of porphyria cutanea tarda when it is mild and of the hereditary form of recessive dystrophic EB when it is severe . The classic form of EBA is thus a mechanobullous disease marked by skin fragility. These patients have erosions, tense blisters within noninflamed skin, and scars over trauma-prone surfaces such as the backs of the hands, knuckles, elbows, knees, sacral area, and toes . Some blisters may be hemorrhagic or develop scales, crusts, or erosions. The lesions heal with scarring and frequently with the formation of pearl-like milia cysts within the scarred areas . Although this presentation may be reminiscent of PCT, these patients do not have other hallmarks of PCT, such as hirsutism, a photodistribution of the eruption, or scleroderma-like changes, and their urinary porphyrins are within normal limits. A scarring alopecia and some degree of nail dystrophy may be seen.
Although the disease is usually not as severe as that of patients with hereditary forms of recessive dystrophic EB, EBA patients with the classic form of the disease may have many of the same sequelae, such as scarring, loss of scalp hair, loss of nails, fibrosis of the hands and fingers, and esophageal stenosis.
Bullous Pemphigoid-Like Presentation A second clinical presentation of EBA is of a widespread, inflammatory vesiculobullous eruption involving the trunk, central body, and skin folds in addition to the extremities.15 The bullous lesions are tense and surrounded by inflamed or even urticarial skin. Large areas of inflamed skin may be seen without any blisters and only erythema or urticarial plaques. These patients often complain of pruritus and do not demonstrate prominent skin fragility, scarring, or milia formation. This clinical constellation is more reminiscent of BP than a mechanobullous disorder. Similar to BP, the distribution of the lesions may show an accentuation within flexural areas and skin folds.
Cicatricial Pemphigoid-Like Presentation
Both the classic and BP-like forms of EBA may have involvement of mucosal surfaces. However, EBA also may present with such predominant mucosal involvement that the clinical appearance is reminiscent of CP These patients usually have erosions and scars on the mucosal surfaces of the mouth, upper esophagus, conjunctiva, anus, or vagina with or without similar lesions on the glabrous skin.
Brunsting-Perry Pemphigoid-Like Presentation
Brunsting-Perry cicatricial BP is a chronic, recurrent vesiculobullous eruption localized to the head and neck and characterized by residual scars, sub-epidermal bullae, IgG deposits at the DEJ, and minimal or no mucosal involvement. The antigenic target for the IgG autoantibodies, however, has not been defined. Nevertheless, a patient reported with this constellation of findings had IgG autoantibodies directed to anchoring fibrils below the lamina densa.We have seen three additional patients with the features of Brunsting-Perry pemphigoid and autoantibodies directed to type VII collagen (unpublished observations). Therefore, it appears that EBA patients may present with a clinical phenotype of Brunsting-Perry pemphigoid .
Immunoglobulin A Bullous Dermatosis-Like Presentation IgA bullous dermatosis-like presentation of EBA is manifested by a sub-epidermal bullous eruption, a neutrophilic infiltrate, and linear IgA deposits at the BMZ when viewed by DIF. It may resemble linear IgA bullous dermatosis (LABD), dermatitis herpetiformis, or chronic bullous disease of childhood and may feature tense vesicles arranged in an annular fashion and involvement of mucous membranes. The autoantibodies are usually IgA, IgG, or both.
The diagnosis of these sub-epidermal blistering cases with IgA anti-type VII collagen antibodies showing linear IgA deposition at the BMZ is disputable. Some clinicians regard the patients as having purely LABD, whereas others regard them as having a subset of EBA. Further, the majority of EBA patients have low titer IgA antibodies in their blood directed against type VII collagen.
Childhood EBA is a rare disease. It has a variable presentation, including an LABD-like disease, a BP-like disease, and the classic mechanobullous EBA presentation. Although mucosal involvement is frequent and severe in
childhood EBA, the overall prognosis is more favorable than in adult EBA.
Incidence of the Clinical Presentations of Epidermolysis Bullosa Acquisita
According to the authors' experience, approximately 25 percent of patients with EBA may present with a BP-like clinical appearance. The disease of some of these patients eventually smolders into a more noninflammatory mechanobullous form. However, both the classic and BP-like forms of the disease may co-exist in the same patient . The clinical phenotype of EBA that is reminiscent of pure CP occurs in fewer than 10 percent of all EBA cases.
Related Physical Findings
EBA patients may have many physical findings similar to patients with hereditary dystrophic EB due to gene defects in the type VII collagen gene. These include oral erosions, esophageal strictures, hypo- and hyperpigmentation skin mottling, nail loss, milia formation, scarring, and a degree of fibrosis of the hands.
A number of published reports suggest that EBA may be associated with various systemic diseases such as inflammatory bowel disease, SLE, amyloidosis, thyroiditis, multiple endocrinopathy syndrome, rheumatoid arthritis, pulmonary fibrosis, chronic lymphocytic leukemia, thymoma, diabetes, and other diseases in which an autoimmune pathogenesis has been implicated. At the University of North Carolina, Stanford, Northwestern, and University of Southern California, with a combined experience of following over 62 EBA patients,
it appears that inflammatory bowel disease is the systemic disease most frequently associated with EBA.
▪ LABORATORY TESTS
Histopathology
Routine histologic examination of lesional skin obtained from EBA patients shows a sub-epidermal blister and a clean separation between the epidermis and dermis. The degree of inflammatory infiltrate within the dermis usually reflects the degree of inflammation of the lesion observed by the clinician. Lesions that are reminiscent of recessive dystrophic EB or PCT usually have a notable scarcity of inflammatory cells within the dermis. Lesions that are clinically reminiscent of BP usually have significantly more inflammatory cells within the dermis, and these cells may be a mixture of lymphocytes, monocytes, neutrophils, and eosinophils. The histology of EBA skin specimens obtained from BP-like lesions may be difficult to distinguish from BP itself.
Immunofluorescence
Patients with EBA have IgG deposits within the DEJ of their skin. This is best detected by DIF of a biopsy specimen obtained from a perilesional site (Fig. 58-6). IgG is the predominant immunoglobulin class, but deposits of complement, IgA, IgM, factor B, and properdin also may be detected. The DIF staining demonstrates an intense linear fluorescent band at the DEJ. Yaoita et al. have suggested that a positive DIF and IgG deposits within the sub-lamina densa zone are necessary criteria for the diagnosis of EBA.
Patients with PCT, which may mimic EBA clinically, frequently have IgG and complement deposits at the DEJ similar to those of EBA patients. However, the DIF feature that distinguishes PCT from EBA is that PCT skin also demonstrates immune deposits around the dermal blood vessels.
Patients with EBA may have autoantibodies in their blood directed against the DEJ.3 These antibodies can be detected by IIF of the patient's serum on a substrate of monkey or rabbit esophagus or human skin and stain the DEJ in a linear fashion that may be indistinguishable from BP sera.
Immunoelectron Microscopy
The localization of the immune deposits within the DEJ of the skin of EBA patients by immunoelectron microscopy is the “gold standard” for the diagnosis. As demonstrated by Nieboer et al.22 and Yaoita et al.,2 patients with EBA have immune deposits within the sub-lamina densa zone of the cutaneous BMZ. This localization is clearly distinct from the deposits in BP, which are higher up in the hemidesmosome area or lamina lucida area of the basement membrane. It is also distinct from CP, which has antigenic targets confined to the lamina lucida .
Indirect Salt-Split Skin Immunofluorescence
When human skin is incubated in 1 M NaCl, the DEJ fractures cleanly through the lamina lucida zone. This fracture places the BP antigen on the epidermal side of the split and all other basement membrane structures on the dermal side of the separation. Salt-split skin substrate can be used to distinguish EBA and BP sera.
If the serum antibody is IgG and labels the epidermal roof, the patient does not have EBA, and BP should be considered. If, on the other hand, the antibody labels the dermal side of the separation, the patient usually has either EBA or bullous SLE. The latter can be ruled out by other serology and by clinical criteria.
Direct Salt-Split Skin Immunofluorescence
Perilesional skin incubated in cold 1 M NaCl is fractured through the DEJ, which effectively places the BP antigen (and any associated immune deposits) on the epidermal roof and the EBA antigen (and any associated immune deposits) on the dermal floor of the separation.23 If the patient has EBA, immune deposits are detected on the dermal side of the separation by a routine DIF method using fluorescein-conjugated anti-human IgG.
Western Immunoblotting
Antibodies in EBA sera bind to a 290-kd band in Western blots of human skin basement membrane proteins containing type VII collagen, whereas sera from all other primary blistering diseases do not. This band is the α chain of type VII collagen. Often, a second band of 145 kd is labeled with EBA antibodies. This band is the amino-terminal globular NC-1 domain of the type VII collagen α chain, which is rich in carbohydrate and contains the antigenic epitopes of EBA autoantibodies, bullous SLE autoantibodies, and monoclonal antibodies against type VII collagen.
Enzyme-Linked Immunosorbent Assay
Chen et al. have produced milligram quantities of recombinant, purified, post-translationally modified NC-1 in stably transfected human cells and have used this NC-1 to develop an ELISA for autoantibody detection in EBA patients and in patients with bullous SLE. This new ELISA is more sensitive than immunofluorescence and Western blotting, and yet it is very specific for antibodies to type VII collagen.
▪ DIFFERENTIAL DIAGNOSIS
Because EBA has been described in infants and children, it is worth considering that a patient thought to have genetic dystrophic EB just might be a rare childhood patient with EBA. This can be ruled out by the antibody tests outlined
in the section Laboratory Tests. PCT can look clinically very much like classic EBA and can be ruled out by a urine or plasma test for uroporphyrins. Pseudo-PCT, usually caused by drugs such as nonsteroidal anti-inflammatory agents, can look similar to EBA with skin fragility, erosions, and blisters over trauma-prone areas, scarring, and milia formation. Nevertheless, the DIF appears different in that pseudo-PCT, like PCT, shows IgG deposits at both the BMZ at the DEJ and around dermal blood vessels (which are not stained in EBA).
Box 58-1 Differential Diagnosis of Epidermolysis Bullosa Acquisita
Most Likely
- Porphyria cutanea tarda
- Pseudo-porphyria cutanea tarda
- Bullous pemphigoid
- Cicatricial pemphigoid
Consider
- Linear immunoglobulin A bullous disease
- Brunsting-Perry pemphigoid
- Bullous systemic lupus erythematosus
The BP-like EBA can be eliminated by several methods listed above, but the first-line test would be indirect and direct salt-split immunofluorescence.
▪ DIAGNOSIS
The diagnostic criteria developed by Yaoita et al.2 for the diagnosis of EBA still stand. These criteria, with slightly updated modifications, are shown in Table .
Alternatives for the last item are indirect or direct salt-split skin immunofluorescence, Western blotting, and ELISA.
▪ COMPLICATIONS
The complications caused by EBA include secondary skin infections, usually due to Staphylococcus or Streptococcus, because the blisters and erosions compromise the skin's barrier. Scarring and milia formation are naturally occurring complications or sequelae of the deep blistering process. Severe EBA patients may develop significant fibrosis of the hands with decreased range of motion of the palm and digits. Because of wounds and fibrosis of the soles of the feet and toes, some EBA patients have difficulty walking. Many patients with EBA lose their fingernails. EBA patients with significant mucosal involvement may develop esophageal strictures.
Diagnostic Criteria for Epidermolysis Bullosa Acquisita
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- A bullous disorder within the clinical spectrum outlined earlier (see Clinical Findings).
- No family history of a bullous disorder.
- Histology showing a sub-epidermal blister.
- Deposition of immunoglobulin G deposits within the dermal-epidermal junction (i.e., a positive direct immunofluorescence of perilesional skin).
- Immunoglobulin G deposits localized to the lower lamina densa and/or sub-lamina densa zone of the dermal-epidermal junction when perilesional skin is examined by direct immunoelectron microscopy.
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▪ TREATMENT
EBA usually responds poorly to treatment. Supportive therapy is warranted in all patients with EBA. This includes instruction in open wound care and strategies for avoiding trauma. Patients should be warned not to overwash or overuse hot water or harsh soaps and to avoid prolonged or vigorous rubbing of their skin with a washcloth or towel. In some patients, it appears that prolonged sun exposure may aggravate or promote new lesions on the dorsal hands and knuckles. Thus, avoidance of prolonged sun exposure and the use of sunscreens are helpful. The patient should be educated to recognize localized skin infections and to seek medical care and antibiotic therapy promptly when they occur.
EBA patients are often refractory to high doses of systemic glucocorticoids, azathioprine, methotrexate, and cyclophosphamide, especially when they have the classic mechanobullous form of the disease. These agents may be somewhat helpful in controlling EBA when it appears as an inflammatory BP-like disease. Some EBA patients improve on dapsone, especially when neutrophils are present in their dermal infiltrate.
Cyclosporine has been shown to be beneficial in EBA. However, the long-term toxicity of this drug limits its use.
There are also independent reports of EBA patients responding to high doses of colchicine.34 This is often used as a first-line drug because its side effects are relatively benign compared with other therapeutic choices. Diarrhea is a common side effect of colchicine, however, which makes it difficult for many patients to achieve a high enough dose to control the disease. Moreover, because of this side effect, we are hesitant to use colchicine in EBA patients who also have inflammatory bowel disease. In addition, there are patients who do not respond to colchicine. Colchicine is a well-known microtubule inhibitor, but it also appears to have properties that have the potential to inhibit antigen presentation to T cells, which could downregulate autoimmunity.
Photopheresis has been used in Sézary syndrome, mycosis fungoides, and a variety of autoimmune bullous diseases (see Chap. 239). Photopheresis improves the clinical features of EBA and remarkably lengthens the suction blistering times of the patients, suggesting an improvement in their dermal-epidermal adherence.
Intravenous Ig has been used in dermatomyositis, an entity in which autoimmunity may play a role. Intravenous Ig has been reported to be effective in some patients with EBA. The mechanism by which γ globulin may invoke a positive response in EBA is unknown.
The anti-TNF-α biologics and anti CD antibodies against B cells have been tried in EBA with some success in limited open trials. Box 58-2 outlines treatment options in EBA that have some support in the medical literature
.
Box 58-2 Treatments for Epidermolysis Bullosa Acquisita (EBA)
MEDICATION
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DOSE RANGE
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Colchicinea
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0.6-3.0 mg/day
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Cyclosporine A
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6 mg/kg/day
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Dapsoneb
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100-300 mg/day
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Cytoxan
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50-200 mg/day
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Prednisonec
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1.0-1.5 mg/kg
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Intravenous immunoglobulind
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3 g/kg divided over 5 days
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Infliximab
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5 mg/kg at 0, 2, 4, and 6 wk
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a Must start with 0.4-0.6 mg/day and each 1-2 wk double this dose as tolerated. When patient develops diarrhea, back off 1 tablet (0.4-0.6 mg).
b Begin at 25 mg/day and double each week after the complete blood count and liver function tests. Most patients need between 100-250 mg/day. Increasing the dose slowly helps the patient tolerate the anemia that develops (i.e., less orthostatic light-headedness, etc.). Expect a 1- to 2-g drop in the patient's hemoglobin on therapeutic doses.
c Usually does not help the classic, mechanobullous type of EBA with minimal inflammation. However, it may be somewhat helpful in the bullous pemphigoid-like type of EBA.
d Intravenous immunoglobulin is given over 4-5 days every month for 5 or 6 mo to give it an adequate trial.
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