Dermatitis Herpetiformis

  • Most common in patients with Northern European origin; uncommon in African-American and Asians
  • Onset in 4th decade of life, but can occur at any age (uncommon in children and adolescents)
  • M>F 
  • Associated with familial incidence: 10% have ≥1 affected 1st degree relative

Genetic predisposition:

  • Specific HLA genes encode molecules that ↑ gliadin antigenicity by interacting with T-cell receptors 
    • DQ2 (A1*0501, B1*02) – present in 90% of patients with Celiac Disease (CD) and Dermatitis Herpetiformis (DH)
    • DQ8 (A1*03, B1*03) – present in 10% of patients with DH
  • Proposed susceptibility locus for Celiac Disease: chromosome 4q27 that encodes IL-2, IL-21
  • Environmental and genetic factors influence development of CD and DH

Gluten-sensitive enteropathy: 

Triggered by gliadin (antigenic component of gluten – found in wheat, rye, barley, kamut, spelt, triticale but NOT oats)

Steps: 

  1. GI processing of ingested wheat: gluten processed into gliadin 🡪 absorption via lamina propria 🡪 deamidation of glutamine residues by tissue transglutaminase TG2 (critical step) 🡪 covalent cross-linking between TG2 lysine residues and glutamine
  2. Stimulation of GI immune response: 
    • CD4+ T-cells recognize deamidated gliadin presented by HLA DQ2/DQ8 MHC II molecules on antigen presenting cells 🡪 production of Th1 cytokines and matric metalloproteinases 🡪 mucosal damage and tissue remodeling 🡪 villous atrophy and crypt hyperplasia 
    • TG2-specific B-cells present gliadin peptides to T-helper cells 🡪 production of IgA anti-TG2 by B-cells
  3. Stimulation of circulating immune response:  continuous exposure to gliadin 🡪 epitope spreading 🡪 production of IgA anti-TG3 🡪 release of IgA anti-TG2 and anti-TG3 into blood
  4. Development of skin pathology: IgA anti-TG3 reaches dermis 🡪 complexing of anti-TG3 with keratinocyte-produced TG3 antigens in papillary dermis 🡪 neutrophil chemotaxis 🡪 proteolytic cleavage of lamina lucida and subepidermal blister formation 

Iodine 

  • Iodine ingestion (amiodarone, potassium iodine) and application of topical iodide on normal skin can lead to DH lesions by stimulating neutrophilic infiltration into skin 

Associations

  • Thyroid disease (especially Hashimoto’s thyroiditis) and insulin-dependent diabetes mellitus (common) 
  • Pernicious anemia (uncommon) 
  • Enteropathy-associated T-cell lymphoma: increased surveillance needed but gluten-free diet protects against lymphoma development

  • Grouped (“herpetiform”) papulovesicles on erythematous base in symmetrical distribution 
  • Urticarial plaques, papules and vesicles also possible 
  • Sites: elbows, knees, extensor forearms, back, buttocks
  • Pruritus leading to excoriation and crusting 
  • Less common cutaneous presentations: isolated scalp variant, isolated facial variant, isolated macular lesions, hemorrhagic acral macules 
  • 90% of DH patients have gluten-sensitive enteropathy but only 20% have symptomatic malabsorption 
  • Course: lifelong disease that waxes and wanes – 10% have spontaneous resolution

4 dx findings needed:

  1. Typical clinical presentation
  2. Compatible histologic features: biopsy a small intact vesicle or area of erythema
    • Papillary dermal edema, infiltrate of neutrophils sparing tips of rete ridges, superficial perivascular lymphocytes and subepidermal blister with predominant neutrophils
  3. Positive DIF: biopsy adjacent to normal appearing 
    • Granular IgA (anti-TG3 antibodies) deposition within dermal papillae (in 85%, hallmark of DH) vs continuous granular IgA deposition along BMZ (5-10%) vs IgA fibrillar pattern (rare)
  4. Improvement of cutaneous disease with dapsone and worsening with gluten ingestion  

Laboratory Investigations: 

  • Total serum IgA level
  • If IgA level normal, measure serum levels of IgA anti-TG2 antibodies 🡪 if positive, measure serum levels of IgA anti-endomysial antibodies 
    • Anti-endomysial antibodies – very specific; correlates with severity of disease and response to gluten-free diet; found in 80% of DH and >95% of active CD 
  • If IgA level deficient, measure serum levels of IgG anti-TG2 antibodies 🡪 if positive, measure serum levels of IgG anti-endomysial antibodies

Urticarial/papular lesions:

  • Arthropod bites, scabies, urticarial vasculitis
  • Granulomatosis with polyangiitis – crusted papules on elbows and knees, vasculitis on histology 
  • Eosinophilic granulomatosis with polyangiitis – crusted papules on elbows and knees, vasculitis on histology

Vesiculobullous lesions:

  • Erythema multiforme – target lesions, acral distribution, vacuolar degeneration and epidermal necrosis, no BMZ IgA deposition 
  • Bullous LE – urticarial papules/vesicles, LABD/DH-like histology, SLE serologic findings, multiple Ig’s in band-like granular pattern along BMZ
  • LABD – fine linear IgA deposition along BMZ
  • Bullous pemphigoid

  • Gluten-free diet (allows corn, rice, oats, soy) 
    • Required for several months to respond, then once stable, can decrease/stop dapsone
    • Decreases granular IgA deposits and eventually eliminates them completely, but return if gluten is re-introduced into diet
    • Helps control intestinal and cutaneous disease
    • Dapsone – start with gluten-free diet 
    • Screen for G6PD deficiency first then start at 25-50 mg po die in adults (0.5 mg/kg in children) then increase weekly until 100 mg po die is reached
    • Relieves pruritus within 48-72 hours but lesions recur within 24-48 hours if discontinued (facial disease can be refractory to treatment)
    • No effect on intestinal disease 
    • Most important side effects: hemolytic anemia, methemoglobinemia, fatal agranulocytosis, Dapsone hypersensitivity syndrome, peripheral neuropathy
    • If anemia persists despite discontinuation of dapsone treatment, screen for other causes
  • Sulfapyridine – start at 50 mg po tid then ↑ to 2 g po tid (patient must drink adequate fluids for alkalinization of urine to reduce risk of nephrolithiasis)
    • Topical potent corticosteroid gel can be applied to broken blisters 
    • Patient support group