Page 897 - Clinical Immunology_ Principles and Practice ( PDFDrive )

868 Part SEVEN Organ-Specific Inflammatory Disease

frequency of the HLA-DR3/DQ2 haplotype. Attempts to under- reduction in patients on gluten-free diets. Strict adherence to a
stand DH must integrate all these factors. gluten-free diet controls the cutaneous manifestations of DH in
The mechanism of IgA binding to DH skin is uncertain. most patients, reverses the morphological changes in the small
Circulating antibodies that bind to normal human skin in vitro intestine and, after many years, may result in disappearance of
have not been detected in DH. Also, the IgA deposits do not the cutaneous IgA deposits. Cutaneous IgA has been shown to
appear to be caused by IgA-containing circulating immune return after rechallenge with dietary gluten. 59
complexes. Another mechanism by which IgA might bind to Rarely, patients with DH fail to respond to a gluten-free diet
DH skin is that IgA produced in the gut, in response to wheat despite what appears to be total dietary compliance. This has
or other dietary antigens, may reach the circulation, where it also been reported in patients with isolated GSE and other dietary
could bind to wheat protein deposited in skin or cross-react factors have been postulated to play a role. In support of this
with normal skin structures or molecules. DH sera contain IgA concept, the skin lesions and GI changes of DH may also respond
antibodies against endomysium, a connective tissue element to an elemental diet, often within only 2–3 weeks of starting the
surrounding smooth muscle, and are directed against tissue diet. These results imply that other proteins besides gluten play
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transglutaminase. Patients with DH also have IgA antibodies a role in the DH pathogenesis. Although a gluten-free diet is an
against epidermal transglutaminase, with higher avidity compared attractive alternative to medication for many patients, it is difficult
with those found in patients with isolated GSE. The IgA deposits to maintain. Gluten is present in most common grains (wheat,
in DH skin colocalize with epidermal transglutaminase, suggesting rye, barley) but not in rice and maize. Eating oats appears to be
epidermal transglutaminase-3 (eTG3) is the IgA target in the safe for patients with DH, but oat products may be contaminated
skin of patients with DH. Development of IgA anti-eTG3 antibod- with wheat protein. Patients should be informed that the success
ies is associated with prolonged periods of gluten exposure, or failure of the diet cannot generally be assessed until they have
suggesting that these antibodies result from epitope spreading. been on the diet for at least a year.
In a mouse model in which normal human skin is grafted onto
SCID mice, human IgA anti-eTG3 antibody binds in a pattern TRANSLATIONAL RESEARCH
identical to that seen in patients with DH. These observations
suggest that IgA anti-eTG binds and slowly accumulates in the
dermis, resulting in the pathognomonic IgA deposits seen in ON tHE HOrIZON
patients with DH. 58
The presence of an ongoing mucosal immune response in Precise characterization of the antigenic targets of autoantibodies and
patients with DH has been shown to result in systemic signs of correlation with clinical presentations and outcomes
inflammation, including elevated serum levels of soluble IL-2 Identification of markers or disease activity and response to therapy
receptor and IL-8, increased neutrophil expression of CD11b, Specific immunoabsorption therapy with faster responses and less
treatment-associated morbidity
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and increased expression of endothelial cell E-selectin in skin. Increased use of targeted biologic therapy (e.g., anti–B-cell therapy) to
These findings suggest that the mucosal immune response results provide rapid, long-lasting remission while minimizing morbidity and
in a proinflammatory environment in skin, which, when coupled mortality.
with cutaneous IgA deposits, can result in development of typical
DH skin lesions. The next 5–10 years should see further advances in the treatment
of autoimmune blistering skin diseases. Anti–B-cell therapies,
Therapy such as rituximab, offer a more targeted, steroid-sparing approach,
DH can be treated either with dapsone or a gluten-free diet; the and we can expect to see the development of more efficient ways
choice of therapy should be individualized to each patient. The of delivering these therapies. Translational studies of immunologi-
treatment of choice for most patients with DH is dapsone or cal changes among patients successfully treated with anti–B-cell
sulfapyridine because of the lack of GI symptoms in most cases therapies will yield insights into the role of different B-cell
and difficulty adhering to a strict gluten-free diet. Dapsone populations in the pathogenesis of autoimmune blistering disease.
(100–200 mg/day) is sufficient to control cutaneous eruptions We can expect to see more precise determination of the antigenic
in most cases, with minimal side effects. Dapsone therapy results targets of the autoantibodies and correlation with clinical pre-
in almost immediate cessation of DH skin symptoms, but it sentations, response to therapy, and clinical outcomes.
does not affect the GI mucosal defect or symptoms. Patients An improved understanding of the clinical response to biolog-
with DH who are on dapsone therefore have ongoing (albeit ics and the mechanisms of those responses will lead to discovery
low-grade) GSE. Dapsone is potentially toxic, and if the disease of new combinations and earlier initiation of biological therapy.
flares up, patients should not increase the dose without consulting Early or immediate use of specific biological therapies, such as
their physician. rituximab, may allow shorter courses of systemic corticosteroid
Strict adherence to a gluten-free diet will also control DH therapy, long-lasting remissions, and potentially lead to “cures”
skin lesions. Nearly 80% of patients with DH who follow such of these severe autoimmune diseases.
a diet can stop or substantially reduce the dose of dapsone required Please check your eBook at https://expertconsult.inkling.com/
59
to control their skin disease. Patients may need to be on a for self-assessment questions. See inside cover for registration
gluten-free diet for at least 5 months before being able to reduce details.
their dose of dapsone; being on this diet for 8–48 months is
necessary before discontinuation of dapsone. Gluten-reduced REFERENCES
diets, in which gluten content is not totally eliminated, are less
effective in controlling DH skin lesions but may provide some 1. Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and
relief. Patients on gluten-reduced diets are able to decrease their pemphigus vulgaris—incidence and mortality in the UK: population
dapsone dosage by approximately 50% compared with ≥75% based cohort study. BMJ 2008;337:160–3.