Dermatitis Herpetiformis

Question 1

DDx for papules on b/l elbows?

Answer 1

DH, papular GA, perforating dz, palisading neutrophilic granulomatous dermatitis (hx of RA).

Question 2

What is the antigenic component of gluten?

Answer 2

Gliadin

Question 3

What tissue transglutaminases are involved in the gut and skin disease?

Answer 3

TTG-2 in the gut and TTG-3 in the skin. Gut one forms first and then you get TTG-3 in the skin via epitope spreading

Question 4

Where do you want to bx for DH?

Answer 4

You want the blister edge for H&E and then 1cm away from blister for DIF

Question 5

DDx for subepidermal blisters w/ neuts?

Answer 5

DEBB LIPS: DH, EBA, bullous urticaria, bullous acute vasculitis, lupus (bullous), IGA LINEAR –> LABD, pemphigoid cicatricial (p200 pemphigoid), Sweets

Question 6

Where is TTG-3 the densest in the skin?

Answer 6

In the dermal papillae, that is why you get the neuts in the dermal papillae

Question 7

Why do you not want to do a DIF too close to the blister?

Answer 7

The inflammation from the neuts and such can destroy the IgA depositions

Question 8

What is the primary tx for DH?

Answer 8

Dapsone (skin but not gut findings), and the second-line is sulfapyridine (less chance of hemolysis)

Question 9

What is the half-life of the IgA antibodies?

Answer 9

3 weeks (so you need ~5 half-lives to clear the antibodies) (3 months or more)

Question 10

What is disease progression like on dapsone?

Answer 10

It inhibits the neuts, but you still have antibodies for ~15 weeks so if you have an occurrence of 1-2 lesions per week that is ok. But this is reduced

Question 11

Dosing of dapsone for DH?

Answer 11

25-50mg in adults and .5mg/kg in children. Average maintenance dose in adults is 100mg daily

Question 12

How do you tx DH lesions on the face?

Answer 12

They are refractory to dapsone so you break blisters and apply topical CS

Question 13

What should be avoided in DH pt’s?

Answer 13

Application or ingestion of iodine as this stimulates neutrophil production

Question 14

Where can you bx if DH patients have had gluten in the last 6 months?

Answer 14

You can bx literally anywhere and get + DIF since the IgA and TTG-3 is everywhere

Question 15

What are the two main HLA II alleles a/w DH?

Answer 15

HLA-DQ2 and HLA-DQ8

Question 16

What percentage of DH patients have evidence of gluten-sensitive enteropathy?

Answer 16

90% have evidence of gluten-sensitive enteropathy but only about 20% have intestinal symptoms of celiac disease.

Question 17

What is the clinical presentation of DH?

Answer 17

Chronic, relapsing, severely pruritic, grouped symmetrical, polymorphous, erythematous-based lesions (often extensor surfaces)

May be papular, papulovesicular, vesiculobullous, bullous, or urticarial. Can see linear petechial lesions on palms and fingers.

Question 18

What is the classic distribution of DH?

Answer 18

Symmetric extensor extremities, buttocks, and back/neck (>face/scalp)

Hemorrhagic palmoplantar lesions (helpful clue)

Question 19

What 4 findings support the dx of DH?

Answer 19

1. Pruritic papulovesicles or excoriated papules on extensor surfaces
2. Neutrophilic infiltrate in the dermal papillae w/ vesicle formation at the dermal-epidermal junction
3. Granular deposition of IgA within the dermal papillae of clinically normal-appearing skin adjacent to a lesion
4. A response of the skin disease, but not the intestinal disease, to dapsone therapy.

Question 20

What are the 5 HLA types involved in DH and what is the most common HLA type?

Answer 20

HLA-DQ2 (90%) HLA-DQ8 (7%) HLA-B8 HLA-DR3 HLA-DR5, DR-7

Question 21

What is gluten found in?

Answer 21

Wheat, rye, and barley (not oats, rice, or corn)

Question 22

What is the antigenic component of gluten?

Answer 22

Gliadin, an alcohol-soluble fraction of gluten

Question 23

What is the protein that the antibodies are formed against in the gut and cutaneous findings in DH?

Answer 23

TTG2 (tissue transglutaminase protein is present in GI lamina propria) for the gut enteropathy and then the TTG3 is where you get anti-TTG3 IgA antibodies responsible for skin involvement in DH (epitope spreading)

Question 24

Pathogenesis of DH?

Answer 24

Ingestion of gluten-containing grains → gluten broken down into gliadin inside GI lumen → gliadin transported across GI mucosa to lamina propria → TTG2 in lamina propria deamidates gliadin → deamidated gliadin forms a covalent bond w/ TTG2 → TTG2-gliadin complex is a neoantigen recognized by HLA-DQ2 (or HLA-DQ8) on APCs → specific Th and B-cells activated → production of IgA autoantibodies against TTG2 or TTG2-gliadin complex → IgA antibodies bind to TTG2 complexes in lamina propria → neutrophil recruitment, damage to intestinal villi → enteropathy and villous atrophy → later, epitope spreading results in IgA autoantibodies against epidermal transglutaminase (TTG3) → circulating anti-TTG3 IgA binds locally to TTG3 within dermal papillae → neutrophils recruited to dermal papillae (“neutrophilic papillitis”) → release elastase and MMPs → subepidermal blister most prominent above papillae

Question 25

What other diseases are DH associated with?

Answer 25

Strongly associated with other autoimmune diseases

Hashimoto’s thyroiditis (MC, 50%)>insulin dependent diabetes mellitus >Pernicious anemia >> Addison’s, alopecia areata, myasthenia gravis, vitiligo, and SLE

Question 26

What malignancy is a/w DH?

Answer 26

Incidence of enteropathy-associated T-cell lymphoma and non-Hodgkin’s lymphoma is increased in patients with DH

Question 27

Where do you want to biopsy lesions for histologic analysis?

Answer 27

The typical histologic features are best observed in erythematous skin adjacent to early blisters

Question 28

Histology of DH?

Answer 28

Apoptotic keratinocytes may be noted above the papillary microabscesses.

Neutrophilic microabscesses in dermal papillae, ± subepidermal Vesicles

indistinguishable often from LABD, need DIF!

Question 29

What is the DIF of DH?

Answer 29

DIF: granular IgA > C3 deposition in dermal papillae

IgA is not uniformly distributed throughout the skin. IgA deposits are present in greater amounts near active lesions

Granular IgA +/- C3 deposits localized to the dermal papillae are found in 85% of cases of DH

Continuous granular deposition of IgA along the basement membrane occurs in 5% to 10% of cases

Question 30

What antibody tests can be performed for DH?

Answer 30

Anti-endomysial antibodies (IgA antibodies to TG2) are very specific for DH (80%) and celiac disease (>95%)

Question 31

Do Titers of anti-endomysial antibodies correlate with disease activity in DH?

Answer 31

Titers correlate w/ severity of the gluten-sensitive enteropathy

good for monitoring responses to gluten-free diet

Question 32

What other antibodies can be tested in DH?

Answer 32

IgA class antireticulin can also be looked at. Studies have suggested high sensitivity and specificity for these in DH patients with villous atrophy.

Anti-gliadin antibodies have high false + rates.

Question 33

What is the physiologic role of tissue transglutaminase?

Answer 33

The normal physiologic function of transglutaminase is to repair injured tissue by cross-linking extracellular matrix proteins in the tissue, protecting the surrounding tissue from further damage.

As antibodies to transglutaminase are produced, the normal function of transglutaminase in repairing the damaged intestinal mucosa is impaired.

Question 34

What is the treatment of choice for DH?

Answer 34

A gluten-free diet is the only real treatment

Sx’s can be relieved rapidly (for skin dz) with dapsone or sulfapyridine

Question 35

What chemical must people with DH avoid?

Answer 35

Must AVOID IODINE/IODIDE (ingestion or topical)

Iodine stimulates neutrophils –> Worsening & production of new lesions

Question 36

What part of the intestines are the IgA antibodies formed for DH?

Answer 36

Jejunum

Question 37

How long on a gluten-free diet is needed to see the full response?

Answer 37

Several months (for the enteropathy it depends on how long they have had sx’s) but 6 months at least.