Clinical dermatology Review article CED

Clinical and Experimental Dermatology

CPD

Epidermolysis bullosa acquisita and inflammatory bowel disease: a

review of the literature
H. Reddy,1 A. R. Shipman2 and F. Wojnarowska1,3
1
Department of Dermatology, James Cook University Hospital, Middlesborough, UK; 2Department of Dermatology, Worcestershire Royal Hospital,
Worcester, UK; and 3Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

doi:10.1111/ced.12114

Summary We present a review of all previously reported cases of epidermolysis bullosa acquisita
(EBA) and inflammatory bowel disease (IBD). We found 42 cases of coincident EBA
and IBD in the literature: 35 cases of Crohn disease (CD) and 7 of ulcerative colitis
(UC). The clinical and immunopathological features of the cases are described and
the demographics collected. In the majority of cases, the diagnosis of IBD predated
the development of the skin condition. The association between EBA and IBD was
more common for CD than for UC. We discuss the immunopathogenesis of IBD and
EBA, and also the link between them, namely type VII collagen.

or ethnicity, although there are reports of associations

Introduction
Epidermolysis bullosa acquisita (EBA) is an auto-
immune blistering disease of the skin and mucous mem-
branes, caused by IgG autoantibodies directed against
the 145-kDa noncollagenous amino-terminal (NC-1)
domain of collagen VII, a major component of anchor-
ing fibrils.1 Type VII collagen is composed of three
identical a-chains, each consisting of a 145-kDa cen-
tral collagenous triple-helix portion, flanked by a large
(145 kDa) amino terminal noncollagenous domain
(NC-1) and a smaller (34 kDa) carboxy-terminal non-
collagenous domain (NC-2). The triple-helix strands of
type VII collagen dimerize in an antiparallel tail-to-tail
arrangement.1 The circulating IgG autoantibodies for
EBA react with a 290-kDa dermal protein, type VII
collagen, as detected by immunoblot analysis using
dermal extracts. EBA is a rare disease, with an esti-
mated incidence of 0.170.26 new cases/million
inhabitants/year.2 There is no predilection for gender
Correspondence: Dr Hari Reddy, Department of Dermatology, James Cook
University Hospital, Middlesborough, UK
E-mail: hari.reddy@nhs.net
Conflict of interest: none declared.
Accepted for publication 20 November 2012
with human leucocyte antigen (HLA)-DRB1*133 and
HLA-DR2.4
An association between EBA and inflammatory
bowel disease (IBD) has been extensively documented.
Crohn disease (CD) has been described in approxi-
mately 30% of patients with EBA1 and autoantibodies
against type VII collagen have been found in up to
68% of patients with CD.5 Ulcerative colitis (UC) is also
associated with autoantibodies against type VII colla-
gen and with EBA, although with a lower frequency
than for CD.5,6 Occasionally, EBA is associated with
other systemic diseases, including rheumatoid arthritis,
diabetes mellitus1 and psoriasis.7
IBD occurs in clinically immunocompetent individuals,
and its characteristic symptoms arise from an
aggressive, cytokine-driven, noninfectious inflamma-
tion of the gut. In particular, T cells and antigen-
presenting cells produce pro-inflammatory cytokines,
including interleukin-6 and tumour necrosis factor-a,
which cause mucosal inflammation and destruction.8
IBD is frequently associated with autoimmune disease,
including primary sclerosing cholangitis, rheumatoid
arthritis, vasculitides, autoimmune hepatitis and pan-
creatitis.9 Cutaneous symptoms occur frequently in
IBD, with an incidence of up to 40%.9 The most

The Author(s)
CED 2013 British Association of Dermatologists  Clinical and Experimental Dermatology, 38, 225230 225
EBA and IBD: a review of the literature  H. Reddy et al.

common dermatological conditions associated with
IBD include erythema nodosum and pyoderma gangre-
nosum,10 although an association with autoimmune
subepidermal blistering disease associated with colla-
gen XVII has recently been described.11
In this article, we examine the association of IBD
and EBA with autoimmunity against type VII collagen.
Methods
We hand-searched the literature on the association of
the subepidermal autoimmune blistering disease EBA
with IBD, specifically UC and CD, using PubMed. Non-
English papers were translated. Papers that failed to
specify the gastrointestinal diagnosis were not
included. A diagnosis of regional enterocolitis was
taken to mean CD. The data were extracted into tables
and evaluated for demographic, clinical and immuno-
pathological features.
Results
We found 42 cases of patients with coexisting EBA
and IBD in the literature, from 1969 onwards. Of the
42 cases, individual clinical data could be extracted
for 20 cases: 23 patients had CD and EBA,1231
(Table 1) and 6 had UC and EBA6,3033 (Table 2). The
demographic features of these cases were collected
(Table 3). A further 13 patients (12 with CD and 1
with UC) were discussed collectively in one paper,5
which mentioned that all but 2 of the patients had a
diagnosis of IBD at least 2 years before EBA developed,
and most had antibodies against type VII collagen and
positive results on indirect immunofluorescence. In the
majority of cases, the IBD diagnosis predated the
development of the skin condition, with only 5 out of
the 23 patients with CD and one of the 6 patients
with UC developing EBA before the IBD (Table 3).
There was a male preponderance for CD cases (15
male, 8 female) whereas for UC, the reverse was true
(5 female, 1 male). Age at presentation ranged from
11 to 45 years.
Discussion
This review has confirmed the association of EBA with
IBD, particularly with CD, and shown that the IBD
usually precedes the onset of blistering. This contrasts
with the findings for collagen XVII-associated immuno-
bullous diseases, which are usually associated with

Table 1 Summary of case reports of patients with Crohn disease (CD) and epidermolysis bullosa acquisita (EBA).

Age at diagnosis, years

Mucosal
Patient* Gender CD EBA involvement DIMF IIIF Comorbidities

112
M Years previously 45 Yes
213 M 37 34 Yes DM, DU
313 M 21 26 No Neg
414 M 2627 27 Yes IgG,C3 Neg
515 M 25 27 No Neg Anaemia
616 M 21 22 Yes IgG, IgM Neg
717 M 19 18 Yes IgG, C3 Neg
818 F 22 25 IgG,IgM C3, Psoriasis
919 M 45 43 No Neg Neg Ankylosing sponylitis
1019 F 20 28 No IgG, C3 Neg Marfan syndrome, arthritis
1120 M 32 33 No IgG, C1q, C3, C4 Neg
1221 F 30 29 Yes IgG, C3
1321 M 24 25 No IgG Neg
1421 M 11 11 No IgG Neg
1522 F 23 22
1623 M 24 25 No IgG, IgM
1724 F 24 27 No IgG, C3 Neg
1825 M 27 28 Yes IgG, C3 Neg
1926 M 23 24 Yes
2027 F 24 24 Yes IgG
2128 M 21 22 Yes IgG, C3
2229 F 20 22 Yes IgG Neg RPC
2330 F 26 30 Yes IgG, IgA, C3 Neg

*Superscript numbers are references. DIMF, direct immunofluorescence; DM, diabetes mellitus; DU, duodenal ulcer; IIMF, indirect
immunofluorescence; IMB, immunoblotting; Neg, negative; RPC, relapsing polychondritis.

The Author(s)
226 CED 2013 British Association of Dermatologists  Clinical and Experimental Dermatology, 38, 225230
 EBA and IBD: a review of the literature  H. Reddy et al.

Table 2 Summary of case reports of patients with ulcerative colitis (UC) and epidermolysis bullosa acquisita (EBA).

Patient number and reference

130 26 332 433 531 631

Gender F F M F F F
Age at UC diagnosis, years 21 42 18 34 Before Before
Age at EBA diagnosis, years 23 43 31 33 11 26
Duration of UC, prior to EBA, years 2 1 13
Mucosal involvement Yes Yes Yes Yes
Direct immunofluorescence Neg Complement IgG, C3
Indirect immunofluorescence Neg IgG1, IgG3, IgG4
Indirect immunofluorescence NC-1 of C7
Comorbidities Anaemia, depression

Table 3 Demographics of patients with epidermolysis bullosa the activation of nave collagen VII-reactive T cells
acquisita (EBA) and inflammatory bowel disease. may be related to mechanisms akin to molecular
CD and EBA UC and EBA
mimicry. This immune response, possibly directed against
pathogens or commensal intestinal flora, induces the
Patients, n 23 6 initial activation of T and B cells, which are crossre-
Age, years
active with type VII collagen epitope(s), events that
Minimum 11 11
Maximum 45 42 may be followed by epitope spreading and recogni-
Males, n 15 1 tion of multiple epitopes. These newly exposed anti-
Females, n 8 5 genic epitopes may invoke production of autoantibodies,
Time before onset of which, in some patients, also crossreact with type VII
second disease, years
collagen and trigger blister formation in the skin.
Minimum Simultaneous 1
Maximum 8 13 EBA is more frequently associated with CD than
EBA preceded IBD, n 5 1 with UC because of the higher incidence of type VII
collagen autoimmunity in CD. In Europe, the overall
CD, Crohn disease; UC, ulcerative colitis.
incidence of IBD in people aged 1564 years was 10.4
per 100 000 for UC and 5.6 per 100 000 for CD.34
UC, although similarly the IBD usually precedes the Although UC has a similar or higher incidence com-
blistering, and the mechanisms involved may be pared with CD in he general population, EBA is more
comparable.11 frequently associated with CD.
Autoimmunity to type VII collagen is associated Interestingly, the isotypes of the IgG autoantibodies
with several human diseases, including EBA, IBD and to type VII collagen show different distribution pat-
bullous systemic lupus erythematosus, and it is also a terns in EBA and IBD. In EBA, the autoantibodies
target in autoimmune bullous diseases. The major mainly belong to the IgG1 and IG4 subclasses,
antigenic epitopes of type VII collagen are located whereas autoantibodies against type VII collagen in
within the NC1 domain.1 Type VII collagen is IBD were mainly found to be IgG3.35 This finding is
expressed in the basement membranes of stratified difficult to interpret, but suggests that progression
squamous cells, not only in skin but also in the towards skin blistering diseases is associated with gen-
oesophagus, oral and anal mucosa, and colonic eration of IgG1 and IgG4 autoantibodies against type
epithelium.5 VII collagen.35,36 Alternatively, the epitopes on type
The possible pathomechanisms underlying the VII collagen targeted by autoantibodies in EBA and
association of EBA with IBD are manifold. Most sim- IBD may differ, which could further explain the
ply, exposure of type VII collagen to inflammation in absence of skin-blistering in the majority of patients
the bowel creates antibodies that can recognise the with IBD.
antigen in all of its different locations. It is also pos- Analysis of the reports of EBA associated with IBD
sible that type VII collagen expressed in the colonic shows that in of the majority of cases, the onset of the
mucosa is altered by the chronic inflammation of gastrointestinal symptoms preceded or occured
IBD, and thus reveals cryptic epitopes5 or generates simultaneously with the skin blistering disease. It is
neo-epitopes. Alternatively, the mechanism leading to conceivable that in some patients, milder gastrointestinal

The Author(s)
CED 2013 British Association of Dermatologists  Clinical and Experimental Dermatology, 38, 225230 227
EBA and IBD: a review of the literature  H. Reddy et al.
symptoms were overlooked or misdiagnosed as
habitual diarrhoea or irritable bowel syndrome. We
therefore favour the hypothesis that chronic, but occa-
sionally subclinical, inflammation of the gut can pre-
cede the development of EBA in all patients.
Conclusion
We found that EBA and IBD can co-exist. Because early
symptoms may be overlooked, we propose that EBA
should therefore be considered as a possible complication
of IBD, particularly CD. Future research should
provide new insights into pathomechanisms, and should
facilitate the development of more specific and effective
immunotherapeutic strategies for both conditions.
Learning points
EBA and IBD, particularly CD, are associated.
The IBD usually precedes the EBA, which could
be seen as a complication of the IBD.
Type VII collagen is the shared antigen that
may drive this association.
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 EBA and IBD: a review of the literature  H. Reddy et al.

26 Spraul CW, Buchwald H, Lang GK et al. Recurrent
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a) Interleukin (IL)-6 and IL-10.

CPD questions
b) Interleukin-8 and interferon-c.
c) Interleukin-12 and tumour necrosis factor-a.
Learning objective
d) Tumour necrosis factor-a and interleukin-23.
To demonstrate up-to-date knowledge of the associa- e) Interleukin-6 and tumour necrosis factor-a.
tion between epidermolysis bullosa acquisita and
inflammatory bowel disease.
Question 4

Question 1 What is the incidence of epidermolysis bullosa acquisita?

a) 0.050.1/million/year.
In epidermolysis bullosa acquisita, antibodies are pri-
b) 0.170.26/million/year.
marily directed against which antigen?
c) 0.250.37 1/million/year.
a) Laminin 322.
d) 1.72.6 1/million/year.
b) Collagen IV.
e) 1726 1/million/year.
c) Collagen VII.
d) Keratin 14.
e) Desmoplakin 1.
Question 5

What type of antibody drives epidermolysis bullosa

Question 2 acquisita?
a) IgA.
Collagen VII is a constituent of which part of the epi-
b) IgG.
dermis?
c) IgM.
a) Anchoring fibril.
d) IgD.
b) Hemidesmosome.
e) IgE.
c) Desmosome.
d) Gap junction.
e) Basement membrane.
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Crohn disease (CD) is driven by which cytokines?

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EBA and IBD: a review of the literature  H. Reddy et al.

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230 CED 2013 British Association of Dermatologists  Clinical and Experimental Dermatology, 38, 225230