ARTICLE
History and landmarks
Dermatitis herpetiformis (DH) was first described as a clinical entity
by Louis Duhring, a Philadelphia dermatologist in 1884. It was subsequently
grouped with pemphigus and pemphigoid and collectively, these were termed
the "bullous disorders". In 1943 Civatte showed that pemphigus was a different
disorder as the blister formation occurred intraepidermally, whilst in
pemphigoid and DH the blisters were subepidermal. A clear distinction
between pemphigoid and DH was made on clinical features and the clearance
of the rash in DH with sulphonamides [1] and dapsone [2].
The association with coeliac disease (CD) was first established in 1967
[3] when it was shown that the enteropathy in the small intestine in DH
was identical to that in CD and that DH patients had increased faecal
fat excretion, low serum levels of folate, low iron stores in the bone
marrow, Howell-Jolly bodies in the blood indicative of splenic atrophy
and low serum IgM levels, all features of CD. In the following two years,
it was shown that the enteropathy was indeed due to gluten as it resolved
with gluten withdraw and recurred on the re-introduction of gluten [4,
5]. It was subsequently shown that the skin lesions of DH were also gluten
dependent and cleared with gluten withdrawal [6]. In 1974, it was shown
that the presence of IgA in the upper dermis of uninvolved skin was the
most reliable diagnostic criterion [7] and this is now accepted as the
"gold standard" for the diagnosis of DH.
Connective tissue antibodies (anti-reticulin) were first described in
DH in 1971 [8] and were subsequently demonstrated in CD. The anti-endomysical
antibodies (Fig. 1) were
described later [9].
Clinical features
Sex incidence
DH is slightly more common in males (3:2) although in young patients
(< 20 years) females predominate (3:2).
Age of onset
DH usually begins in young adults (15-40). However, it may commence
at any age, the youngest recorded being ten months [10] and the oldest
being 90 years [11].
Epidemiology
DH is predominately a disorder of Caucasians and is relatively rare.
In a study from Scotland the incidence was found to be 11.5 per 100,000
[12] and ranging from 19.6 to 39.2 per 100,000 in Sweden [13]. CD is more
common than DH in a ratio of 5:1. The highest incidence of CD is in the
west of Ireland where it has been reported as 1:300. Recent population
studies of screening for latent CD have shown that CD is more common than
previously appreciated. Greco et al. [14] have postulated that
the ratio of symptomatic to asymptomatic CD is 1:5, giving an incidence
of 1:60 in the West of Ireland.
Skin lesions
The commonest site is the extensor surface of the elbows and proximal
forearms (Fig. 2), followed
by the buttocks (Fig. 3)
and extensor surface of the knees (Fig.
4). However, in severe disease the lesions may occur anywhere. The
face and scalp are often involved. The typical lesions are urticarial
plaques upon which are found groups of blisters, usually 2-10 mm. As DH
causes severe irritation and therefore, scratching, it is not infrequent
to find superficial erosions and excoriation rather than intact blisters.
Diagnosis
The test for establishing the diagnosis of DH is a biopsy from uninvolved
skin for the detection of IgA. The diagnosis cannot be accepted in the
absence of IgA. In less than 5% of individuals with typical DH lesions,
the IgA is not found on the first section. Serial sections of the biopsy
should then be undertaken and if still negative, a second biopsy should
be taken and invariably the IgA will then be detected The IgA may be found
in two sites. The commonest is in the dermal papillae where the IgA is
seen as granular or fibrillar deposits (Fig.
5). The second, less common pattern, is of granular deposits in a
linear distribution along the line of the basement membrane (Fig.
6). This pattern has to be distinguished from the homogenous linear
band of IgA found in linear IgA disease (Fig.
7), which is a different clinical entity.
Associated diseases
There is an increased incidence of autoimmune disorders in patients
with DH, particularly autoimmune thyroid disease, pernicious anaemia,
and type I diabetes. Patients should have an autoantibody screen every
two years and if positive, patients should be screened for the relevant
disorders. Patients should also be routinely screened for diabetes.
There is an increased incidence of lymphoma in patients with DH as there
is in patients with CD. The lymphoma appears to be derived from T cells
and although it is found in the small intestine, it is not confined to
this site. It has been shown that a gluten free diet is protective against
the development of lymphoma both in CD and DH [15].
DH and gluten-sensitive enteropathy
In the majority of patients with DH, the enteropathy is mild and patients
do not have symptoms usually associated with CD. DH patients fall into
the category of latent coeliac disease, which is now considered to be
10 times more common than CD patients with gastro-intestinal symptoms.
All patients with DH have evidence of gluten sensitivity in the intestine.
However, only two-thirds of patients with DH will have villous atrophy
detected on intestinal biopsy. The other third will show raised intra-epithelial
lymphocyte counts and/or an increase in the TCR gamma delta intraepithelial
lymphocytes. This latter increase remains even after successful treatment
with a gluten free diet.
Management
Gluten withdrawal
Since the observation that a gluten free diet (GFD) could clear the
skin lesions of DH [6], this has become or should have become, the treatment
of choice. However there are certain aspects of this treatment that are
not always appreciated.
1. The GFD must be strict otherwise complete control of the disease
is unlikely to be obtained. However, a decrease in drug requirement may
be achieved with a nearly strict diet.
2. It takes on average 6-9 months on a strict GFD before a significant
reduction in the dose of drug to control the rash occurs.
3. It takes on average two years to control the rash with a GFD alone.
Although a GFD imposes a number of social restrictions on the patient,
it does have advantages over drug treatment. First, there is a relatively
high incidence of side effects with dapsone and sulphonamides. Second,
there is a subjective improvement with a feeling of well-being and patients
reporting more energy. Third, it has been shown that a GFD is protective
against lymphoma in these patients [15].
However, GFD does not appear to protect against the development of autoimmune
diseases associated with DH [16] and CD [17].
A GFD is a difficult diet for patients because wheat flour is added
to so many different foods. It is imperative that DH patients who take
a GFD must be instructed and supervised by a dietician experienced in
a GFD and that they join a coeliac society, which is a patient support
group. These societies have an up to date list of gluten free foods and
will also be able to tell patients when gluten may have been added to
previously gluten free foods. Most dermatologists do not have experience
of GFDs and should not attempt to supervise these diets without the help
of experienced dieticians.
Drug therapy
The drugs currently used to control the rash of DH are dapsone, sulphapyridine
and sulphamethoxypridazine. The dose should be titrated until the lowest
to suppress the rash is found (Table
I). The mechanism by which these drugs achieve their beneficial result
has not been elucidated; however, it is likely that they exert their effect
on the end stage of the pathogenetic mechanisms as they can control the
itching within 48 hrs and clear the rash within a week. Equally, relapse
of the rash occurs within a week of stopping the drugs. It is thought
dapsone and sulphonamides either affect the migration of neutrophils from
the capillaries to the IgA in the skin or they affect binding of the neurophils
to the IgA and their subsequent activation.
It is now normal practice to commence drug treatment with the GFD for
the first six months of the diet and then gradually reduce the dose of
the drugs until they are no longer required. Occasionally patients are
unable to tolerate dapsone and sulphonamides. In these instances, heparin
can control the eruption and there have also been anecdotal reports of
nicotinamide and tetracycline having a beneficial effect.
Oats and a gluten free
diet
Until recently it has been normal practice to advise patients taking
a gluten free diet to avoid wheat, barley, rye and oats. This advice was
based on challenge studies, measuring steatorrhoea and xylose absorption
without intestinal biopsies. In addition, the purity of the oats was not
ascertained. Oats are often contaminated with wheat either due to crop
rotation in the fields or milling of the cereals. However, two recent
studies [18, 19] found no toxicity from pure oats in patients with CD.
More recently, it has been shown that in patients with DH controlled with
a GFD, the addition of oats to the diet was not toxic [20, 21]. There
was no deleterious effect on the intestine or skin and no induction of
the antiendomysial antibodies (AEA). In addition, in patients who had
lost the IgA deposits in the skin with a GFD, the IgA did not reappear.
The cereal species whose proteins are toxic to patients with CD are
grasses of the species Triticeae, which includes wheat, rye or barley.
Oats belong to a different species, Avenae. The seed storage proteins
of oats differ structurally from those of grasses belonging to other species.
The toxic proteins are rich in prolines and glutamines and hence are named
prolamines. Oat-prolamine (avenin) has a lower proline content than prolamines
in wheat, rye and barley (gliadin, secalin, and hordein, respectively).
The sequence of glutamine-glutamine-glutamine-proline-phenylalanine-proline
is found in prolamines of wheat, rye and barley but has not been found
in oats. This sequence may be part of the toxic core in gluten sensitivity.
Avenin accounts for only 5-15% of the total protein found in oats where
as gliadin accounts for 40% of the total protein in wheat. It has been
argued that since there are fewer toxic sequences per unit weight of avenin,
large daily amounts of oats (100 to 160 g) might prove toxic in CD and
DH. To investigate this possibility 2.5 g avenin (equivalent to 300 g
of oats, or 10 bowls of oatmeal) per day were given to two subjects with
DH, controlled on a GFD, for five days and then a further 2.5 g nine days
later. No deleterious effects were shown to the intestinal mucosa and
no skin lesions developed. In addition, no antiendomysial, antireticulin
or antiglidain antibodies were induced [22]. Thus, it has been shown that
oat avenin is not toxic to patients with DH and can be taken in the diet,
which is helpful to patients taking a GFD but the purity of the oats must
be guaranteed.
The skin lesion
The classical histological features are those of subepidermal blisters
with an infiltrate of neutrophils and some eosinophils. In the adjoining
skin are microabscesses in the dermal papillae, consisting mainly of neutrophils.
IgA is found in the uninvolved skin, in the dermal papillae or along the
line of the basement membrane but it is not detected in the involved skin.
It is thought the IgA is destroyed by proteolytic enzymes produced by
leucocytes or other cells. It is not known what initiates a lesion or
why the uninvolved skin, which also contains IgA remains unaffected.
It has been known for sometime that apart from infiltration with neutrophils,
there is also a lymphocytic infiltrate in the dermis, particularly around
the capillaries. This infiltrate was largely ignored until recently. It
has now been shown that this infiltrate is made up of predominately CD4
T cells (the ration of CD4/CD8 being 5:1) and that 20-40% are activated.
Activated CD4 cells are not found in the uninvolved skin. However, when
T cell lines were established from the skin there was no proliferative
response to gliadin (Frazer fraction III) [23]. In addition, intradermal
skin testing with Frazer fraction III did not produce any evidence of
delayed hypersensitivity [24]. These studies suggest that T cells sensitised
to gluten are not present in the skin. It is also pertinent to point out
that gluten has never been found in the skin despite attempts to demonstrate
its presence. However, T cell VB expression is restricted in the T cell
cell infiltrate in lesional skin with over representation of VB2, VB5.2/5.3
and VB 5.3 [25]. These results suggest recognition of a specific antigen
or that a superantigen is involved in the pathogenesis of the skin lesions.
If the antigen is not gluten, then possible candidates are connective
tissue antigens such as reticulin or tissue transglutaminase, the recently
suggested auto-antigen in CD. Elastin has also been suggested as a possible
auto-antigen because of the cross reactivity between glutenin and dermal
elastin [26].
The role of cytokines and enzymes in the pathogenesis of the skin lesions
has been investigated over the last few years. One of the first reports
demonstrated IL-8 in the basal layer of keratinocytes and GM-CSF was expressed
by the junctional dendritic cells at the derma-epidermal junction [27].
IL-8 is known to be a chemoattractant for neutrophils and GM-CSF can induce
IgA Fc receptors on the surface of neutrophils enabling these cells to
bind to the IgA in the skin and become activated and release proteolytic
enzymes which could result in blister formation.
More recent studies have suggested that the activated CD4 T cells produce
a Th2 cytokine profile as IL-4 and IL-5 have been shown to be present
in the upper dermis and bullae respectively [28]. Eotoxin, a chemokine,
which is a chemoattractant for eosinophils, has been demonstrated in the
dermal papillae in lesional skin and in the mid dermal lymphocytic infiltrate.
Eotoxin can be induced by IL-4, IL-13 and TNFalpha. Both the latter two
cytokines have been found in the mid dermal infiltrate [29].
Matrix metalloproteinases are enzymes, which can break down the extracellular
matrix of tissue. In DH, there is a breakdown of the basement membrane
and this in part could be due to metalloproteinases. Metalloelastase MMP-12
has been shown to be expressed by dermal and epidermal migrating macrophages
in DH lesions [30]. However, it has been shown that degradation of the
basement membrane occurs before the appearance of MMP-12 and is probably
due to proteolytic enzymes produced by the activated neutrophils.
Other metalloproteinases, collagenases, and stromolysins have been found
in DH skin and may well play a part in destruction of tissue. They may
well be induced by urokinase plasminogen activator found in the basal
keratinocytes in DH [31, 32]. The induction of these enzymes is likely
to be secondary to the activation of lymphocytes and neutrophils and not
be concerned with initiation of the skin lesions.
Tissue transglutaminase
In 1997 Dieterich and her colleagues [33] suggested that tissue transglutaminase
(tTG) was the autoantigen in CD. Immuno-precipitation of human fibrosarcoma
lysates and the IgA fraction from serum samples of patients with CD, resulted
in a single protein band of molecular weight 85 kDA. This was found exclusively
in sera from patients with CD and not in controls. After sequence analysis
the protein was identified as tTG. They confirmed this finding by absorbing
out the IgA antibody in coeliac sera with tTg. They concluded that the
anti endomysical antibody (AEA) was in fact binding to tissue transglutaminase
in the endomysium of monkey oesophagus used as the substrate for detecting
IgA-AEA.
A good correlation between the incidence of IgA-AEA and IgA-tissue transglutaminase
antibody[tTGA] has been found in CD. In untreated CD an incidence of 93-97
percent for IgA tTG-A has been found [34-36], which is similar to that
reported for IgA-AEA (89-100%) [37] in untreated CD. However the specificity
of IgA-tTG-A is slightly lower that that of AEA as tTGA have been reported
in approximately 5% of controls [34, 36].
tTGA has also been found in DH but as with AEA the incidence is lower
than that found in CD. The first study reported an incidence of 75% for
IgA-tTGA and 67% for AEA [38] and a second 66% for tTGA and 72% for AEA
in DH patients taking a normal diet [39]. The titre of tTGA falls with
a strict gluten free diet and is not detected after two years. This is
similar to the findings reported for the antireticulin antibody (ARA)
and AEA. The lower incidence of ARA and AEA in DH compared to CD is thought
to reflect the milder enteropathy found in DH. The same is probably true
for tTGA.
tTG plays an important role in cross-linking of connective tissue fibres.
This enzyme is found throughout the body and plays an active role in wound
healing. tTG is synthesised by fibroblasts and keratinocytes and its primary
role is stabilising extra cellular protein assemblies, such as collagen
fibrils, microfibrils pericelluar fibronection matrix and basement membrane.
In the healing skin tTG is active in the dermal papillae and anchoring
fibrils at the dermo-epidermal junction [40]. Interestingly, these are
the sites of IgA deposition in the skin in DH. Type VII collagen is the
major connective tissue component of anchoring fibrils and is a potential
substrate for tTG.
Although it has now been claimed that tTG is the autoantigen in CD and
antibodies to tTG are present in the circulation, the mechanism of how
it induces the enteropathy has still to be elucidated. In addition, as
patients with DH also have CD and tTGA, do the latter play a role in the
production of the skin lesions?
It has been shown that gliadin binds to reticulin in the skin [41].
In addition gliadin is a substrate for tTG, so it is possible that the
gliadin is not binding to the connective tissue fibres but to the tTG,
which is present predominately at the sites of reticulin in the skin.
It is even possible that the gliadin is capable of binding to both the
reticulin and tTG. As a result of the binding, it has been suggested that
neo-epitopes are produced. These neo-epitopes can be presented to T cells
and then B cells, which in turn will produce antibodies to tTG. In addition,
these neo-epitopes could act as self-antigens and stimulate T cells to
produce cytokines, which damage the small intestine and produce the characteristic
enteropathy as seen in CD. One of the cytokines that is involved in the
reversal of damage to cells and repair of connective tissue is TGF-B.
However tTG is necessary for the activation of TGF-B and in CD this process
may be inhibited by the presence of the tTGA. The collapse of the villi
characteristic of CD enteropathy could well be due to the destruction
of the connective tissue of the villus by inflammatory cytokines and it
cannot be repaired as the normal function of tTG and TGF-B are inhibited
by the tTG antibodies. In addition, TGF-B is necessary for the activity
of T suppressor cells and this is another factor in the continuing inflammation
in the intestinal mucosa.
Finally, another role for tTG in the enteropathy has been demonstrated.
It has been shown that tTG can deamidate gluten peptides. These de-amidated
peptides compared to non-deaminated ones, produce a greater response by
T cells clones isolated from the intestine and reactive to gliadin [42].
It was shown that in the gluten peptide 134-153, the conversion of glutamine
to glutamic acid at position 148 increased the binding of the peptide
to HLA-DQ2, which then provoked a greater stimulatory response by the
gluten sensitive T cells. This is in keeping with the requirement of a
negatively charged anchor residue at position 148 for optimal binding
of the gliadin peptide to HLA-DQ2.
So what, if any, is the role of tTG in DH skin lesions? It is possible
that a tTG/gliadin complex formed in the intestine could be carried to
the skin where it is capable of binding to the sites of maximal tTG concentration
in the skin, i.e. the dermal papilla and anchoring fibrils of the
BM. If T cells, primed to react to the neoepitopes of tTG, arrived in
the skin, they could be activated by the tTG/gliadin complex. It is even
possible that the tTGA produced in the gut could bind to the tTG in the
skin, which in turn damages the tTG and which will result in the formation
of neo-epitopes to be recognised by T cells primed for these epitopes
in the gut (Fig. 8).
The problem with this hypothesis is, why does the tTGA or complex only
bind to the connective tissue or tTG of the skin? One would have to invoke
a structural or chemical difference in the dermal papillae and anchoring
fibrils. However, once activated these T cells could certainly set in
motion the inflammatory reaction seen in DH skin. Architecturally there
are similarities between the dermal papillae and villi of the intestine.
Both are rich in connective tissue, which act as a support for surrounding
cells. Thus it is possible there is a connective tissue component, which
is susceptible to damage by tTGA or neo-epitopes from gluten/tTG complexes.
Genetic studies
Since it was first suggested by Fry and colleagues in 1967 that the
enteropathy seen in DH was identical to that found in CD, it has been
debated whether DH and CD have a common basis or are two separate entities.
The evidence now points strongly to the suggestion that indeed both DH
and CD have a common genetic basis even though one group of individuals
have a gluten sensitive enteropathy with a rash and another group does
not.
Family studies
The most important family studies in DH have been carried out by Reunala
in Finland [43]. In a study of 1,018 patients with DH, 999 were unrelated
and of these, 105 (10.5%) had a first-degree relative who either had CD
(6.1%) or DH (4.4%). Thus, in first-degree relatives, there are approximately
a similar number affected with DH and CD of patients with DH. This implies
a similar genetic background for both disorders.
In the propositi of DH patients, the proportion who had an affected
parent with either CD or DH was 13.6%, for siblings 18.7% and children
14.0%. These figures are suggestive of a Mendelian dominant mode of inheritance.
It is possible then that the incidence of CD may have been underestimated
in this study. The diagnosis of CD was based on the demonstration of partial
or subtotale villous atrophy on intestinal biopsy. These biopsies were
probably not carried out on asymptomatic relatives. Yet it has been shown
that in the asymptomatic relatives of DH patients, 40% may have evidence
of a gluten sensitive enteropathy on intestinal biopsy.
Gender may also be important in determining inheritance of these disorders
[43]. In the DH population with no affected relatives the male: female
ratio was 6:5 However, it was lower in DH patients with affected relatives
and even lower in the relatives who developed DH. A female predominance
(2:1) is well known for CD patients and a similar ratio was also found
in the family members, who developed CD. The reason why familial DH was
more common in females has yet to be determined.
Studies of monozygotic twins also suggest a common genetic basis for
DH and CD. In a study of six monozygotic twins, three sets were concordant
for DH, in two sets, one twin had DH and the other twin CD; and in the
remaining set, one twin had DH and the other did not have DH or CD [44].
In this latter individual the diagnosis of CD had been excluded by serology
tests for AEA and intestinal biopsy, which showed no villous atrophy;
no raised intraepithelial lymphocytes count and normal number of gamma
delta T cells. There have also been two other reports of monozygotic twins
in whom one had DH and the other CD [45, 46]. These studies appear to
be conclusive evidence for showing a common genetic basis for CD and DH.
All patients with DH have evidence of a gluten sensitive enteropathy even
if it is mild. It would thus appear that if a patient with CD develops
DH then it may be due to environmental rather than genetic factors. It
is known that in monozygotic twins, the development of the immune system
may be different and this may be due to the range of exposure to different
antigens, which can be dietary or microrganisms. Thus, whether individuals
with CD develop DH could depend on immune responses, which are different
in DH subjects.
HLA studies
It has been known for nearly 30 years that there is an HLA association
in DH. At first, it was with A1 and B8, and then it was shown that this
was secondary to DR3, which in turn was due to linkage disequilibrium
with DQ2 alleles. Two recent studies have shown that the allele DQ (A1*0501,
B1*02) i.e. DQ2 or DQ (Al*03, B1*0302) i.e. DQ8 are present
in patients with both CD and DH. In one study of DH patients the DQ2 allele
was present in 43 of 50 (86%) patients and the DQ8 allele in 6 (12%) of
the remaining 7 patients [47]. In the second study all 55 patients with
DH and 201 of 212 (95%) patients with CD had DQA1*0501, DQB0*02 and 9
of the remaining 11 patients had DQA1*03, DQB1*0302 [48]. These heterodimers
of DQ2 and DQ8, which have previously been shown to associate with CD,
have now been found in DH, in a similar frequency, which is further evidence
for a similar genetic basis.
Genome scans and candidate regions
To date there have been no published reports of genome scans in DH alone.
However, results on DH have been included in a study on CD [49]. The first
scan on CD [50] was that of Irish families. Apart from the known HLA locus
they reported several possible candidate regions: 6p12, 3q27, 5q33.3,
7q 31.3, 11p11, 15q26, 19p13.3, 19q 13.4 and 22 cen. As with all polygenic
disorders, confirmation from other studies does not always follow. Linkage
for CD has also been reported for 2q33 (the CD28/CTLA4) region [51] Confirmation
for 15q26 has been reported [52]. In another genome scan in Italians linkage
was reported for 5q and 11q [53]. In the most recent study from Finland
[49], they stratified their material and included DH patients. The group
consisted of 102 sibpairs and they found linkage to 11q. However the results
suggested heterogeneity and they stratified their patients into only CD
(69 families) and those who had DH (33 families). They found that in the
CD group there was linkage mainly to 2q33 but in the DH group linkage
to 5q and 11q but not 2q 33. They also divided the patients into groups
depending on gender. They had 46 families in which only females were affected
and 36 families in which at least one male was affected. Linkage to all
3 loci, 2q, 5q and 11q were strongest in families with male patients but
HLA-DQ2 conferred stronger susceptibility to females. This is the first
study to suggest possible genetic differences between DH and CD. Undoubtedly,
the HLA association with DQ2/DQ8 plays an important part in the pathogenesis
of both diseases but it is possible as previously suggested that there
may be other genes which determine whether patients have only CD or DH.
CONCLUSION
The major significant advances in our understanding of DH have been the
demonstration that DH patients also have CD (mild in most instances) and
that the rash is also gluten dependent. As a result, it is now possible
to cure patients by gluten withdrawal from the diet. The other major significant
finding has been the presence of IgA in the uninvolved, now used as the
diagnostic criterion for the disease.
Despite the fact that it has been known for over fifty years that gluten
causes the enteropathy of CD, and for over thirty years the rash of DH,
it is still not known how gluten produces these effects. Future immunological
studies may look at ways of inducing tolerance to gluten peptides once
the toxic ones have been identified. Vaccination against gluten peptides
may also be possible in those affected with gluten sensitive disorders.
Gene therapy, once the genes have been identified, has so far not been
rewarding in other disorders. However, blocking the action of proteins
resulting from the expression of gene mutations may be more readily achieved.
In addition, studies are underway to try and produce cereals which do
not contain the toxic peptides.
Which line of research is likely to prove most rewarding in the future
is difficult to know. However, it is possible to heal the enteropathy
and skin lesions by gluten withdrawal from the diet. This can be considered
to be a cure, which is quite an achievement compared to only modifying
the disease process with drugs, which is the current way of dealing with
most chronic disorders.
Article accepted on 22/6/02
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