Petersen, Marta J.

Zone, John J.

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AUTOIMMUNE BULLOUS DISEASES
The Relationship between Autoimmune Bullous
Disease and Systemic Disorders
Marta J. Petersen1 and John J. Zone1
1Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
Correspondence: Marta J. Petersen, E-mail: marta.petersen@hsc.utah.edu
doi:10.1038/skinbio.2008.6
The mystery of the association of skin
disease with systemic disease has been
a matter of fascination to dermatolo-
gists for hundreds of years. There are a
myriad of articles and case reports
linking various cutaneous findings to
internal disease. The implication has
always been that some soluble or
cellular factor is being produced that
results in a cutaneous disease. Immu-
nobullous disease associates a particu-
lar antibody with a cutaneous disease
and so the responsible factor for asso-
ciating an immunobullous disease with
a systemic disease is production of an
antibody. We will review the mile-
stones in immunobullous disease that
have refined our understanding of these
associations and consider possible
pathogenic mechanisms.
Dermatitis herpetiformis (DH) is a
papulovesicular skin disease with glu-
ten-sensitive enteropathy (celiac dis-
ease, CD) and a unique HLA type
(HLADQ2 and DQ8) associated in
virtually all cases. Granular deposition
of IgA is the immunopathological hall-
mark. Marks et al. (1966) are generally
credited with describing the associa-
tion of CD with DH. Marks, Fry, and
others established that the skin disease
with its IgA deposition as well as the
intestinal disorder responded to
gluten restriction and recurred with
the reinstitution of a gluten-containing
diet culminating in a landmark
paper on gluten challenge in 1983
(Leonard et al., 1983). Katz and
Strober (1978) clarified the association
of HLA B8/DR3 with the entire spec-
trum of CD with DH. Kumar et al.
(1987) established the presence of IgA
endomysial antibodies in DH and CD
patients. The endomysial antigen
was found to be tissue transglutami-
nase, and now testing for IgA tissue
transglutaminase antibody has become
the standard for the serological diag-
nosis of CD. The link between the
intestine and the skin in genetically
predisposed individuals is twofold.
First, Hall et al. (2007) have established
that cytokines elaborated at the site of
intestinal inflammation are likely criti-
cal to the inflammatory process in the
skin. Second, Sardy et al. (2002) have
shown that epidermal transglutaminase
is the antigen bound to the IgA
stimulated by the intestinal inflamma-
tory process.
The association between DH and
thyroid disease is even more intricate.
In 1983, Cunningham and Zone (Cun-
ningham and Zone, 1985) closely
evaluated 50 DH patients, and showed
that these patients had a high incidence
of thyroid autoantibodies as well as
hyperthyroidism, hypothyroidism, and
thyroid enlargement. Gaspari et al.,
1990. showed that this association
was not related to the underlying HLA
B8/DR3 genotype but was likely related
to a high prevalence of Hashimoto’s
thyroiditis manifested by thyroid auto-
antibodies and was independently as-
sociated with DH. Whether or not the
intestinal inflammation in DH patients
is responsible for stimulating the thyr-
oid autoimmune process by a cellular
or humoral mechanism remains to be
determined (Gaspari et al., 1990).
Since the 1980s, several immuno-
bullous disorders have been linked to
inflammatory bowel disease including
bullous pemphigoid, epidermolysis
bullosa acquisita (EBA), and linear IgA
bullous disease in case reports and case
series. Of these, EBA appears to have
the strongest association with inflam-
matory bowel disease. EBA, an immu-
nobullous disorder is characterized by
autoantibodies to type VII collagen, the
major structural protein of anchoring
fibrils, and clinical presentations re-
sembling bullous pemphigoid, cicatri-
cial pemphigoid, or epidermolysis
bullosa. EBA has been described in
patients with both Crohn’s disease and
UC, with Crohn’s disease being the
predominant association. In a study of
51 EBA patients, Chen et al. (2002)
found that 25% (13 of 51) had inflam-
matory bowel disease: 12 had Crohn’s
disease and 1 had UC. They also
demonstrated full-length (290 kDa)
type VII collagen in normal colonic
extracts from four patients and type VII
collagen immunoreactivity in the colo-
nic basement membrane. Of 19 pa-
tients, 13 patients with Crohn’s disease
and 4 of 31 patients with UC were
found to have elevated levels of circu-
lating antibodies to the immunodomi-
nant NC1 domain of type VII collagen
by ELISA. Despite these findings, there
is no evidence linking an autoantibody
to the pathogenesis of inflammatory
bowel disease. The presence of type VII
collagen antibodies is thought to re-
present epitope spreading, resulting
from exposure of type VII collagen
epitopes due to damage to the over-
lying colonic mucosa.
Immunobullous diseases have also
been linked to malignancies. The quin-
tessential disorder is paraneoplastic
pemphigus (PNP), described by Anhalt
et al. (1990). PNP is characterized by pain-
ful mucosal erosions and polymorphous
E28 OCTOBER 2008 MILESTONES | CUTANEOUS BIOLOGY
skin lesions that may resemble pem-
phigus vulgaris, bullous pemphigoid,
erythema multiforme, graft vs host or
lichenoid eruptions and a mortality rate
approaching 90% (Nousari et al.,
1999). More recently, it has been
recognized as a multisystem disease
involving lung, kidney, and muscles, in
addition to skin and mucosa. In the
landmark paper by Anhalt, all the five
patients had a related disease: four
malignancies (chronic lymphocytic
leukemia, one; non-Hodgkin’s lympho-
ma, two; poorly differentiated sarcoma,
two) and one benign thymoma. At
present, PNP is largely seen in con-
junction with lymphoproliferative neo-
plasms including non-Hodgkin’s
lymphoma and chronic lymphocytic
leukemia (two of three cases), Castle-
man’s disease, benign and malignant
thymomas, sarcomas, and Walden
stro¨m’s macroglobulinemia. PNP in
association with solid tumors such as
lung, breast, and colon cancer has also
been reported.
Anhalt et al. (1990) initially de-
scribed four autoantigens with molecu-
lar weights of 250, 230, 210, and
190 kDa, which are now recognized
as desmoplakin I, BPAg1, envoplakin,
and periplakin, respectively. Since
then, other autoantigens have been
identified including desmoglein-1 and
-3, plectin, and desmoplakin II. The
polymorphous nature of the skin and
mucosal lesions can be attributed to
this potpourri of autoantigens. Cyto-
toxic T cells, natural killer cells, and
macrophages have been identified in
involved tissue, suggesting a function
for cell-mediated immunity in the
pathogenesis of PNP.
Anti-epiligrin cicatricial pemphigoid
is an autoimmune blistering disease
with autoantibodies against the base-
ment membrane protein, laminin 5.
Egan et al. (2001) described an in-
creased risk of malignancy in patients
with anti-epiligrin cicatricial pemphi-
goid. A total of 35 patients met the case
definition for anti-epiligrin cicatricial
pemphigoid: presence of erosive or
blistering lesions of the mucous
membranes with or without cutaneous
involvement; deposition of IgG in the
epidermal or mucosal basement mem-
brane and/or circulating IgG autoanti-
bodies that bound to the dermal side of
1 M NaCl split human skin; and circu-
lating IgG that immunoprecipitated
laminin 5 from extracts or conditioned
media from cultured human keratino-
cytes. A total of 10 patients (28.6%)
developed a solid cancer (lung, three;
gastric, three; colon, two; endometrial,
two). Of these ten cancers, 9 were
adenocarcinomas. Nine patients devel-
oped cancer ±14 months from the
onset of blistering. Eight cancers oc-
curred after onset of blistering, the
majority (six of eight) within the first
year. The median observation period
was 2.67 years. In the general popula-
tion, 1.48 cancers would be expected
to occur in this time frame, yielding a
relative risk of cancer of 6.8 in these
patients with anti-epiligrin cicatricial
pemphigoid. This cancer risk is similar to
that of patients with dermatomyositis.
Two patients’ clinical disease improved
with resection of the primary tumor.
Systemic lupus erythematosus exhi-
bits a panoply of deranged immunolo-
gic processes. The association of
systemic lupus with bullous lupus
erythematosus is just another manifes-
tation of this immune regulation gone
awry. Bullous lupus erythematosus is a
widespread inflammatory subepider-
mal vesiculobullous eruption that is
associated with systemic lupus erythe-
matosus. It may occur with or without
an exacerbation of the systemic lupus.
Gammon and Briggaman (1993) de-
fined an immunopathologic process in
a portion of the patients when they
found that many cases of bullous lupus
have circulating antibodies that bind to
type VII collagen, as is characteristic of
EBA. However, the association with the
wide range of immunologic abnormal-
ities seen in bullous lupus erythemato-
sus is absent in EBA.
Immunopathologically, some cases
of bullous lupus may be indistinguish-
able from dermatitis herpetiformis
although other Igs in combination with
IgA are usually seen in the basement
membrane zone. In addition, no asso-
ciation with gluten-sensitive enteropa-
thy in patients with bullous lupus has
been described. In a landmark study,
Hall et al. (1982) reported rapid and
complete response of patients to dap-
sone.
In conclusion, our understanding of
the relationship between immunobul-
lous disease and systemic disorders has
expanded dramatically over the past 30
years. We have summarized the mile-
stones that have paved the way to our
current insights.
CONFLICT OF INTEREST
The authors state no conflict of interest.
TO CITE THIS ARTICLE
Petersen MJ, Zone JJ (2008) The relationship
between autoimmune bullous disease and systemic
disorders. J Invest Dermatol 128: E28–E30
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The Relationship between Autoimmune Bullous Disease and Systemic Disorders 

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The Relationship between Autoimmune Bullous Disease and Systemic Disorders

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