Ac a De m Vene eol 95
REVIEW ARTICLE
Ac a De m Vene eol 2015; 95: 917–922
© 2015 The Au ho s. doi: 10.2340/00015555-2162
Jou nal Compila ion © 2015 Ac a De ma o-Vene eologica. ISSN 0001-5555
De ma i is he pe i o mis (DH) is an i chy, blis e ing skin
disease wi h si es o p edilec ion a he elbows, knees
and bu ocks. Al hough DH is mos ly asymp oma ic, all
pa ien s exhibi small bowel illous a ophy o a leas
coeliac- ype in lamma o y changes. Deposi ion o im-
munoglobulin A (IgA) in he papilla y de mis is a key
diagnos ic ea u e o DH. Epide mal ansglu aminase
(TG3) is he an igen o IgA deposi ed in he skin, and
issue ansglu aminase (TG2) is he an igen o IgA de-
posi ed in he small bowel mucosa. Clinically silen , bu
immunologically ac i e coeliac disease in he gu appea s
o esul in IgA TG3 an ibody complexes agg ega ed in o
DH skin. The p e alence o DH in no he n Eu ope is
high (30–75/100,000), bu i s incidence is dec easing,
possibly due o inc eased ecogni ion o subclinical co-
eliac disease. The ash and small bowel heal on a glu en-
ee die , which is a li e-long ea men . The isk o non-
Hodgkin’s lymphoma is inc eased, bu in pa ien s wi h
DH who adhe e s ic ly o a glu en- ee die long- e m
p ognosis is excellen . Key wo ds: de ma i is he pe i o -
mis; coeliac disease; glu en- ee die ; ansglu aminase
au oan ibodies; immunoglobulin A deposi s.
Accep ed Jun 3, 2015; Epub ahead o p in Jun 10, 2015
Ac a De m Vene eol 2015; 95: 917–922.
Timo Reunala, Medical School, Uni e si y o Tampe e,
FIN-33014 Tampe e, Finland. E-mail: [email p o ec ed]
De ma i is he pe i o mis (DH) was i s desc ibed as a
clinical en i y by Louis Duh ing in 1884, and was associa-
ed wi h coeliac disease (CD) in 1966 when en e opa hy
was disco e ed in he small bowel o DH pa ien s (1, 2).
Subsequen ly, he blis e ing ash wi h si es o p edilec ion
on he elbows, knees and bu ocks was ound o espond
o a glu en- ee die (GFD) (3, 4). Fu he e idence o he
ela ionship be ween DH and CD came om immuno-
gene ic and amily s udies. Bo h diseases we e ound o
ha e he same s ong associa ion wi h human leukocy e
an igen (HLA) DQ2, which is ca ied by up o 100% o
pa ien s wi h DH (5, 6). Mo eo e , DH and CD clus e in
he same amilies, and monozygo ic wins (1 wi h DH and
he o he wi h CD) ha e been epo ed (7, 8).
Demons a ion o g anula immunoglobulin A (IgA)
deposi s in he unin ol ed skin is an easy way o di-
agnose DH, whe eas small bowel biopsy is needed o
con i m he diagnosis o CD (9–11). In bo h diseases
pa ien s ha e IgA class ci cula ing an ibodies, i s de-
sc ibed o e iculin, hen o endomysium (EmA) and,
inally, o issue ansglu aminase (TG2; 12, 13). The
b eak h ough in CD esea ch was he inding by Schup-
pan and co-wo ke s in 1997 ha issue ansglu aminase
(TG2) enzyme, which is p esen in he gu mucosa, was
he au o-an igen (14). In 2002 Sá dy e al. (15) p esen ed
e idence ha epide mal ansglu aminase (TG3) was an
au o-an igen o IgA deposi ed in DH skin. The ea e ,
IgA TG2 deposi s ha e been shown o occu in he
small bowel mucosa o mos un ea ed pa ien s ei he
wi h CD o DH (16, 17).
Se e al expe e iews (18–22), 2 na ional guidelines
(23, 24), a con inuous medical examina ion (25), and a
clinical p ac ice a icle (26) ha e been published on DH
in ecen yea s. The p esen e iew ocuses on he la es
esea ch indings and p o ides u he e idence ha DH
is a speci ic skin mani es a ion o CD.
IMMUNOPATHOGENESIS OF DERMATITIS
HERPETIFORMIS
The IgA deposi s in he papilla y de mis o DH skin ha e
long been suspec ed o de i e om he gu . Following
disco e y o he glu en-sensi i e en e opa hy, Seah e al.
(27) p oposed, in 1971, ha IgA o igina es om he gu in
glu en-an iglu en immune complexes. These a e hen ap-
ped in he skin as a esul o c oss- eac i i y wi h deposi ed
e iculin an ibodies. Al hough glu en-an iglu en immune
complexes could be ound in he se um o pa ien s wi h
DH, s udies did no e eal any glu en o glu en an ibodies
in he skin (28). In 2002, Sá dy e al. (15) demons a ed
ha he an igen o deposi ed IgA was TG3 enzyme. They
used dual immunos aining o he p esence o IgA, and
showed ha TG3 and IgA co-localized. This impo an
inding was con i med by Donaldsson e al. (29). Sá dy
e al. (15) also showed ha , al hough pa ien s wi h CD
also p esen ed wi h IgA class TG3 an ibodies, he an i-
bodies in pa ien s wi h DH ecognized TG3 selec i ely
and wi h high a idi y. TG3 and TG2 a e closely ela ed
and show a high deg ee o sequence conse a ion, mos ly
wi hin enzyma ically ele an domains (20). The e o e,
c oss- eac i i y o he an ibodies agains TG3 and TG2
is no su p ising. The abili y o TG2 o deamida e and
c oss-link glu en pep ides is essen ial o he p oduc ion
De ma i is He pe i o mis: Pa hognomonic T ansglu aminase IgA
Deposi s in he Skin and Excellen P ognosis on a Glu en- ee Die
Timo REUNALA1,2, Teea T. SALMI1,2 and Kaisa HERVONEN1,2
1Depa men o De ma ology, Tampe e Uni e si y Hospi al, and 2School o Medicine, Uni e si y o Tampe e, Tampe e, Finland
918 T. Reunala e al.
o TG2 au oan ibodies in CD. TG3 o ms glu en pep ide
complexes less e icien ly, which could be a eason o he
di e en au o-an ibody esponse in DH (30). Whe he he
high a ini y IgA an ibodies o TG3 in pa ien s wi h DH
a ise agains TG3 as a p ima y an igen o a e he esul o
epi ope sp eading is s ill an open ques ion, because TG3
p o ein has no been de ec ed in he small bowel simila ly
o he TG2 enzyme (15, 20). An immunopa hogenesis o
DH, s a ing om subclinical CD in he gu and e ol ing
o immune complex deposi ion o high a idi y IgA TG3
an ibodies oge he wi h TG3 enzyme in he papilla y
de mis, is shown in Fig. 1.
One impo an poin is ha , in no mal skin, TG3 is ex-
p essed in he ke a inocy e laye s and no in he papilla y
de mis whe e he IgA deposi s a e loca ed in DH (10, 15,
29). Hence, he IgA p ecipi a es could be immune com-
plexes con aining TG3, which accumula e speci ically in
he papilla y de mis (20). Suppo ing his, TG3 deposi s
ha e also been obse ed in cu aneous essels in DH skin
(31). Recen ly, Taylo e al. (32) showed ha TG3 p esen
in IgA agg ega es in DH skin is enzyma ically ac i e and
can bind soluble ib inogen. This i s well wi h an ea lie
s udy showing ib inogen a he same si e as he IgA de-
posi s in he unin ol ed skin (33). Mo eo e , e ol ing
DH blis e s show ma ked ib in deposi ion and up egula-
ion o u okinase ype plasminogen ac i a o , sugges ing
enhanced ib inolysis (34, 35). The blis e ing ash in DH
has si es o p edilec ion a he knees, elbows and bu ocks,
al hough IgA agg ega es a e also deposi ed in si es ha
a e ne e in ol ed in lesion o ma ion (10, 29). The mos
likely explana ion o his unique dis ibu ion o he ash
in ol es he in luence o local ac o s, such as p essu e
and s e ching (Fig. 1). I is possible ha di ec ac i a-
ion o TG3 in de mal agg ega es by mechanical o ce,
simila ly o TG2 ac i a ion in ascula walls, could be
an ini ia o leading o blis e o ma ion (36). This would
esul in elease o ib inogen om he agg ega es (32,
33), which, besides being a clo ing ac o , is an in lam-
ma o y p o ein capable o a ac ing T cells, neu ophils
and mac ophages, all o which ha e been shown o in lux
in o he de eloping DH lesions (34, 37).
One in e es ing ques ion is why IgA deposi s pe sis
in DH skin in pa ien s on a GFD long a e he ash
has become asymp oma ic and ci cula ing TG3 au o-
an ibodies ha e disappea ed om he se um (38–40).
In a ecen s udy (41) we ound 3 pa ien s wi h DH
wi h IgA deposi s, despi e he ac ha hey had been
asymp oma ic on a s ic GFD o a mean o 8 yea s.
The eason o he unexpec edly long pe sis ence o
IgA TG3 agg ega es seems o be he igh binding o
he ex acellula ma ix o he papilla y de mis. Ac i e
c oss-linking is u he subs an ia ed by he obse a ion
ha TG3 e ains a leas pa o i s enzyma ic ac i i y
in DH skin (32). In con as o he long ime aken o
IgA deposi s o disappea a e wi hd awal o glu en,
hese seem o eappea mo e apidly, wi hin one yea on
glu en challenge (42). Fu he glu en challenge s udies,
ocusing on he eappea ance o IgA TG3 agg ega es in
he skin and TG2 agg ega es in he small bowel, would
p o ide impo an knowledge abou he ini ial e en s in
he immunopa hogenesis o DH.
CLINICAL PRESENTATION AND DIAGNOSIS OF
DERMATITIS HERPETIFORMIS
DH can appea a any age. The age o he younges pa ien
in ou Tampe e se ies is 3 yea s and he oldes 84 yea s
(43). Mean age a diagnosis o DH was 43 yea s, bo h in
Fig. 1. Immunopa hogenesis o de ma i is he pe i o mis s a ing
om subclinical coeliac disease in he gu . Small bowel mucosa:
gliadin pep ides a e modi ied by issue ansglu aminase (TG2)
enzyme and ecognized by human leukocy e an igen (HLA) DQ2/8-
posi i e an igen p esen ing cells a e which B cells/plasma cells
p oduce immunoglobulin A (IgA) an ibodies o gliadin pep ides
and TG2. Blood: ci cula ing IgA class an ibodies o gliadin, TG2
and epide mal ansglu aminase (TG3) a e p esen . High-a idi y
TG3 an ibodies may a ise om TG2 an ibodies by epi ope
sp eading. Unin ol ed skin: immune complexes consis ing o IgA
TG3 an ibodies and TG3 enzyme a e deposi ed in he papilla y
de mis. S e ching/p essu e, o possibly o he ac o s, ac i a e
deposi ed TG3 enzyme, which is capable o binding ib inogen.
This and/o o he ac o s a ac in lamma o y cells, such as T
lymphocy es and polymo phonuclea leucocy es (PMNs), o
in lux in o he papilla y de mis. These cells sec e e in lamma o y
media o s, such as a ious cy okines and p o eases, which inally
cause subepide mal blis e o ma ion.
Ac a De m Vene eol 95
919
De ma i is he pe i o mis: ansglu aminase IgA deposi s and glu en- ee die
men and women, bu i has inc eased signi ican ly du ing
ecen yea s. Simila mean ages ha e been epo ed in DH
se ies om Eu ope, No h Ame ica and Asia. Recen DH
se ies om I aly (44) include many child en, and he mean
age o he pa ien s is only 32 yea s. I is possible ha DH
appea s in childhood mo e o en in sou he n han no he n
Eu ope, since in Finland childhood DH is a e, comp ising
only 4% o all pa ien s (45). Males sligh ly o ma kedly
p edomina e in adul s wi h DH (Table I), whe eas he op-
posi e is ue in child en (45, 46) and in CD (11, 47).
The ypical si es o p edilec ion o DH a e he elbows,
knees and bu ocks (Fig. 2). In addi ion, he uppe back,
abdomen, g oin, axillae, scalp and ace can be a ec ed,
bu o al lesions a e a e (48). The ash is polymo phic wi h
small blis e s (Fig. 2). These a e, howe e , o en e oded
and c us ed because o in ense i ch and sc a ching. Palma
o ac al pu pu ic lesions may appea on he hands (49).
The p esen a ion and ac i i y o he ash a ies g ea ly
om pa ien o pa ien , bu comple e emission is in e-
quen on a no mal, glu en-con aining die .
The clinical pic u e is o en highly sugges i e o
DH al hough, linea IgA disease is always a diag-
nos ic p oblem (50). The symp oms and signs o mild
DH a e easily masked i he pa ien has a concomi an
i chy skin diso de , such as a opic de ma i is (45). The
bu ning i ch el du ing he de elopmen o blis e s is,
howe e , usually se e e enough o aise suspicion o
DH. The ideal me hod o diagnosis o DH is a di ec
immuno luo escence biopsy o una ec ed skin in close
p oximi y o an ac i e lesion. This e eals pa hogno-
monic g anula IgA deposi s a he de mo-epide mal
junc ion (Fig. 2), and he diagnosis o DH should no
be made wi hou his inding (10, 18, 19).
SMALL BOWEL AND SEROLOGICAL FINDINGS
IN DERMATITIS HERPETIFORMIS
Pa ien s wi h DH a ely p esen wi h ab up gas oin-
es inal symp oms o signs o malabso p ion (18, 19, 51).
Consis en wi h CD, app oxima ely 70% o pa ien s wi h
DH ha e illous a ophy and c yp hype plasia in small
bowel mucosal samples om uppe gas oin es inal en-
doscopy (18, 19, 51; Table I). The emaining pa ien s ha e
ma ke s o ea ly-s age CD, such as inc eased densi y o
gamma/del a posi i e in aepi helial T lymphocy es (52,
53). Fu he mo e, in 1988, Ká pá i e al. (54) showed ha
child en wi h DH had IgA deposi s in he p oximal jeju-
num. In 2004, Ko ponay-Szabó e al. (16) epo ed ha he
in es inal IgA deposi s we e di ec ed agains TG2, in
bo h CD and DH. Subsequen s udies showed ha
almos all un ea ed pa ien s wi h CD and 80% o
pa ien s wi h DH ha e TG2- a ge ed IgA deposi s
in he small bowel mucosa, and ha hese deposi s
a e glu en-dependen (17, 55).
Pa ien s wi h un ea ed CD o DH p esen wi h
ci cula ing IgA au oan ibodies. An i- e iculin
an ibody es was he i s CD-speci ic es and
he EmA es he second (12, 56). When TG2 was
iden i ied as he au o-an igen in CD, an enzyme-
linked immunoso ben assay (ELISA) me hod was
es ablished o de ec ing IgA-class TG2 an ibodies
in he se um (13, 14). TG2 an ibody ELISA es
has p o en highly sensi i e and speci ic o CD.
In DH TG2 an ibodies a e ound a a somewha
Table I. Compa ison o de ma i is he pe i o mis (DH) and coeliac disease (CD)
DH CD
Sex Sligh ly mo e males Females p edomina e
Age a onse Mainly adul s Child en and adul s
1s -deg ee ela i es wi h CD o DH Yes Yes
HLA DQ2 95–100% 95%
IgA deposi s in he skin 100% (by de ini ion) 0%
Small bowel illous a ophy 70% 100% (by de ini ion)
IgA deposi s in bowel mucosaa79% 95–100%
IgA TG3 an ibodies in se umb86% 24%
IgA TG2 an ibodies in se umb86% 92%
IgA EmA an ibodies in se umb89% 95%
P ognosis on a glu en- ee die Excellen cInc eased all-cause and
lymphoma mo ali yd
aSalmi e al. (17), bReunala e al. (40), cHe onen e al. (62), dTio e al. (66).
HLA DQ2: human leukocy e an igen DQ2; IgA: immunoglobulin A; TG3: epide mal
ansglu aminase; TG2: issue ansglu aminase; EmA: endomysium.
Fig. 2. De ma i is he pe i o mis. (a) Polymo phic ash wi h exco ia ed
blis e s on he elbows and knees. (b) Typical small blis e s on he elbow.
(c) G anula immunoglobulin A (IgA) deposi s a he de mo–epide mal
junc ion. Di ec immuno luo escence examina ion o unin ol ed skin.
Ac a De m Vene eol 95
920 T. Reunala e al.
lowe pe cen age han in CD, and posi i e indings a e
con ined mos ly o pa ien s wi h small bowel illous
a ophy (57). The majo i y o pa ien s wi h un ea ed DH
also ha e ci cula ing an ibodies agains TG3, whe eas
he equency is much lowe , up o 24%, in pa ien s wi h
CD (40, 58, 59; Table I). In pa ien s wi h DH adhe ing
o a GFD IgA an ibodies o TG3 dec ease in pa allel
wi h TG2 and EmA an ibodies (40). This indica es ha
he measu emen o TG3 an ibodies does no o e any
ad an age o e he widely used TG2 an ibody assay o
moni o ing GFD ea men .
GLUTEN-FREE DIET AND LONG-TERM
PROGNOSIS OF DERMATITIS HERPETIFORMIS
A GFD is he ea men o choice o pa ien s wi h DH,
leading o healing o he ash and small bowel en e opa-
hy (3, 4, 38). Howe e , i akes se e al weeks o mon hs
o he ash o espond o a s ic GFD and, he e o e,
65% o ou pa ien s also s a dapsone (4,4’-diamino-
diphenylsul one) ea men . The ini ial daily dose is
25–50 mg, which causes apid elie o i ching and
he ash subsides wi hin 2–3 days. I he e is no e ec ,
he dose is inc eased o 100 mg daily. Dapsone has a
dose- ela ed isk o haema ological side-e ec s, such
as me haemoglobinaemia and haemolysis, bu hese a e
a e in doses below 100 mg daily.
Pa ien s on a GFD we e p e iously ad ised o a oid
whea , ye, ba ley and oa s. A p esen hey can consume
oa s, which has been shown o be non- oxic (60, 61).
Long- e m ollow-up o ou pa ien s wi h DH showed
ha 98% adhe ed o he GFD, 72% o hem s ic ly (62).
The eason o his excellen compliance appea s o be
egula isi s o he specialis ou pa ien clinic un by
expe ienced de ma ologis s, o a leas 1–2 yea s o
longe , un il dapsone could be s opped. Recen ly, we
analysed whe he some o ou pa ien s wi h DH could be
non- esponsi e o a s ic GFD (41). We ound 7 (1.7%)
pa ien s who s ill used dapsone o ac i e ash, al hough
hey had been on a s ic GFD o a mean o 16 yea s. In
con as o he ash, he small bowel mucosa had eco e-
ed. This indica es ha he condi ion in DH is di e en
om e ac o y CD, which is associa ed wi h a ious
complica ions and occu ence o in es inal lymphoma
(63). The ash in DH eappea s on glu en challenge (42),
and he e is gene al ag eemen ha adhe ence o a GFD
should be li elong. The e a e, howe e , some s udies
sugges ing ha a ew child en and adul s wi h DH may
go in o emission and ole a e glu en (64, 65).
CD is known o inc eased isk o all-cause mo ali y
and non-Hodgkin’s lymphoma mo ali y (66). Recen ly,
we analysed he mo ali y a e in ou p ospec i ely collec-
ed coho o 476 pa ien s wi h DH (62). The pa ien s we e
ollowed up o a o al o 9,079 pe son yea s and almos
all o hem adhe ed o a GFD. Unexpec edly, he s anda -
dized mo ali y a e (SMR 0.70) was signi ican ly educed
compa ed wi h he gene al popula ion. P e iously, Lewis
e al. (67) s udied 846 pa ien s wi h DH in No ingham,
UK, and ound a sligh ly, bu non-signi ican ly, educed
mo ali y a e (haza d a io 0.93). Howe e , one- hi d o
hei pa ien s had no da a on adhe ence o a GFD, which
could be a eason o he non-signi ican mo ali y a e.
In DH he isk o non-Hodgkin’s lymphoma is signi-
ican ly inc eased (up o 10 imes), bu ollowing a GFD
o mo e han 5 yea s seems o be p o ec i e (68–70). In
ag eemen wi h his, we ound in ou ecen DH se ies
(62), in which almos all pa ien s adhe ed o a GFD, a
signi ican ly inc eased lymphoma mo ali y a e du ing
he i s 5 yea s o ollow-up, bu no he ea e . A sig-
ni ican ly educed mo ali y a e due o ce eb o ascula
diseases (SMR 0.38) was also obse ed, which migh
be ela ed o he GFD o o he lowe le el o smoking
in pa ien s wi h DH.
CONCLUSION
DH is ela i ely common, especially among people in
no he n Eu ope and in U ah, USA (43, 71, 72). I also
occu s in Sou h Ame ica, bu is ex emely a e in Asia,
and appea s o be non-exis en among na i e people in
A ica due o low consump ion o whea and absence o
HLA DQ2 (73–76). Two ecen s udies o DH, he i s
om Finland wi h 477 pa ien s (43) and he second om
he UK wi h 1,160 pa ien s (71) ound p e alences o
75/100,000 and 30/100,000. In e es ingly, he p e alence
o DH in he UK is 8 imes lowe han o CD (71). In
Finland bo h diseases appea ed a app oxima ely he
same equency in he 1980s, whe eas a p esen he p e-
alence o DH is 6 imes lowe han ha o CD (43, 77).
Recen se ological sc eening s udies ha e documen ed
ha he p e alence o CD is as high as 1%, hus o e e y
pa ien iden i ied 7–8 emain undiagnosed (11, 47, 78).
This la ge pool o undiagnosed, and mos ly subclinical,
CD seems o be he basis om which DH e ol es. In
suppo o his heo y, we ha e seen pa ien s who ini ially
de eloped CD, hen ollowed o did no ollow a GFD,
and inally de eloped DH (79). Mo eo e , pa ien s wi h
DH equen ly ha e coeliac- ype den al enamel de ec s
(80), which de elop ea ly in childhood as a esul o mal-
abso p ion o immune al e a ion caused by undiagnosed
CD. The dec easing incidence o DH since he 1990s in
Finland and he UK, wi h a simul aneous apid inc ease
in CD (43, 71), i s ou hypo hesis ha clinically silen
CD is a p e equisi e o he de elopmen o DH (18, 81).
The ash, wi h IgA deposi s in he skin, is he main ea-
u e ha di e en ia es DH om CD, whe eas small bowel
indings a e gene ally simila in bo h condi ions. Tha TG3
enzyme is he au o-an igen o IgA deposi s in DH skin
and TG2 o IgA deposi s in coeliac mucosa a e impo an
obse a ions (15–17, 29). Whe he IgA TG3 agg ega es
in DH skin a e in ol ed in he ini ial e en s o blis e o -
ma ion is unknown. G anula IgA deposi s a e, howe e ,
Ac a De m Vene eol 95
921
De ma i is he pe i o mis: ansglu aminase IgA deposi s and glu en- ee die
he key diagnos ic ea u e o DH ha di e en ia es his
blis e ing disease om all o he de ma ological diso de s.
The ea men o choice o DH is a GFD and, i ca e ully
ollowed, he long- e m p ognosis is excellen (62).
ACKNOWLEDGEMENTS
The au ho s would like o hank nu ses Sanna Sällinen and Tiina
Kallio o hei help in unning he specialis ou pa ien clinic o
he pa ien s wi h DH. P o Raimo Suhonen p o ided he blis e
pho og aph o DH. Tiina Rauha i a, PhD, is acknowledged o
he help in p epa ing he diag am abou immunopa hogenesis
o DH. The s udy was inancially suppo ed by he Compe i i e
Resea ch Funding o Tampe e Uni e si y Hospi al (g an 9N062).
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