Chapter 60. Epidermolysis Bullosa Acquisita

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.1 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 HLA-DR2 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.1

EBA is a chronic, subepidermal 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 (Ig) G 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 (see Chapter 53).3,4

Anchoring fibrils anchor the epidermis and its underlying BMZ to the papillary dermis. Patients with hereditary forms of dystrophic EB (see Chapter 62) 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, subepidermal 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.5,6 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.6 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 triple-helical 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 kDa, and the collagen consists of a homotrimer of three identical α chains (see Chapter 53). Each α chain consists of a large globular noncollagenous amino terminus called the noncollagenous 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.10,11 There may be something intrinsically “antigenic” about the NC-1 domain because the available monoclonal antibodies that have been generated against type VII collagen specifically recognize only NC-1 subdomains.

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.12 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.13 The mice developed subepidermal 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.13 Another study by Sitaru and colleagues14 showed that the injection of rabbit polyclonal antibodies to the NC-1 domain of mouse type VII collagen into mice also induced subepidermal skin blisters that were reminiscent of human EBA.14 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.15 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.

In addition to a passive transfer animal model of EBA, Sitaru and colleagues16 have established an active EBA animal model by immunizing certain strains of mice with fragments of the noncollagen domain (NC-1) of murine type VII collagen. In these animal models, activation of complement by the alternative pathway and NADPH oxidase for neutrophil action are required for the development of murine EBA.17,18 The murine models of EBA with these requirements for components of inflammation may better reflect the inflammatory subsets of EBA than the classical noninflammatory mechanobullous EBA phenotype since it is known that not all EBA patients have complement-fixing antibodies or a pathology involving neutrophils. Alternatively, the murine model could reflect early processes in the development of all EBA that is later modulated in certain EBA patients by their intrinsic immune regulatory processes. The next advance in understanding the pathogenesis of EBA will be linking the pathogenic mechanistic steps involved in the disease with the patient's clinical phenotype of disease (see Section “Clinical Findings”).

(Fig. 60-1)

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: (1) a skin biopsy for routine hematoxylin and eosin histology, (2) a second biopsy juxtaposed to a lesion but on normal-appearing skin for DIF, and (3) 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 pemphigoid (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 (Figs. 60-2 and 60-3A) 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 (PCT; see Chapter 132) when it is mild and of the hereditary form of recessive dystrophic EB when it is severe (see Chapter 62). 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 (see Figs. 60-2, 60-3A, and 60-4). 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 (see Fig. 60-3A). 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.19

Bullous Pemphigoid-Like Presentation

(See Chapter 56)

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.20 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 (see Figs. 60-3B and 60-4) 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

(See Chapter 57)

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 (see Fig. 60-3C).24 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

(See Chapter 57)

Brunsting–Perry cicatricial BP is a chronic, recurrent vesiculobullous eruption localized to the head and neck and characterized by residual scars, subepidermal bullae, IgG deposits at the DEJ, and minimal or no mucosal involvement. However, the antigenic target for the IgG autoantibodies has not been defined. Nevertheless, a patient reported with this constellation of findings had IgG autoantibodies directed to anchoring fibrils below the lamina densa.22 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 (see Fig. 60-3D).

Immunoglobulin A Bullous Dermatosis-Like Presentation

(See Chapter 58)

IgA bullous dermatosis-like presentation of EBA is manifested by a subepidermal 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.23 The autoantibodies are usually IgA, IgG, or both.

The diagnosis of these subepidermal blistering cases with IgA antitype 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% 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 coexist in the same patient (Fig. 60-5). The clinical phenotype of EBA that is reminiscent of pure CP occurs in fewer than 10% 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 diseases24 such as inflammatory bowel disease, SLE, amyloidosis, thyroiditis, multiple endocrinopathy syndrome, rheumatoid arthritis, pulmonary fibrosis, chronic lymphocytic leukemia, thymoma, diabetes, multiple myeloma, and other diseases in which an autoimmune pathogenesis has been implicated. At the University of North Carolina, University of Stanford, University of 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.

Histopathology

Routine histologic examination of lesional skin obtained from EBA patients shows a subepidermal 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.3,19 This is best detected by DIF of a biopsy specimen obtained from a perilesional site (Fig. 60-6). 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 al2 have suggested that a positive DIF and IgG deposits within the sublamina 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 (see Chapter 132). 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.15

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 al25 and Yaoita et al,2 patients with EBA have immune deposits within the sublamina 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 (see Chapters 56 and 57).

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.3

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.19 If the patient has EBA, immune deposits are detected on the dermal side of the separation by a routine DIF method using fluorescein-conjugated antihuman IgG.

Western Immunoblotting

Antibodies in EBA sera bind to a 290-kDa band in Western blots of human skin basement membrane proteins containing type VII collagen, whereas sera from all other primary blistering diseases do not.3 This band is the α chain of type VII collagen. Often, a second band of 145 kDa 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.10

Enzyme-Linked Immunosorbent Assay

Chen et al26 have produced milligram quantities of recombinant, purified, posttranslationally 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.

(Box 60-1)

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 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).

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.

The diagnostic criteria developed by Yaoita et al2 for the diagnosis of EBA still stand. These criteria, with slightly updated modifications, are shown in Table 60-1.

Alternatives for the last item are indirect or direct salt-split skin immunofluorescence, Western blotting, and ELISA.

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 and even laryngeal scarring.

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 over wash 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.27 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.28 This is often used as a first-line drug because its side effects are relatively benign compared with other therapeutic choices. However, diarrhea is a common side effect of colchicine, 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 Chapter 238). Photopheresis improves the clinical features of EBA and remarkably lengthens the suction blistering times of the patients, suggesting an improvement in their epidermal–dermal adherence.29

In addition to photopheresis, plasmapheresis and removal of the antibodies to type VII collagen in an EBA patient's plasma is useful for gaining control of EBA patients similar to pemphigus patients. Given that the autoantibodies are pathogenic, this is not surprising, but when plasmapheresis is performed it is necessary to have the patient also treated with a chemotherapy agent (such as azathiaprine, cyclophosphamide, mycotile mofelate, methotrexate).

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.30 The mechanism by which γ globulin may invoke a positive response in EBA is unknown.

The anti-TNF-α biologics (such as infliximab; see Chapter 234) and anti-CD antibodies against B cells have been tried in EBA with some success in limited open trials. Box 60-2 outlines treatment options in EBA that have some support in the medical literature.

Recently, anecdotal reports have also shown that, riuximab, a monoclonal antibody to the CD20 receptor on B lymphocytes is effective in treating recalcitrant patients with EBA.