Dermatitis Herpetiformis & Linear IgA Disease
Dermatology · Vesiculobullous · lean revision notes
Dermatitis Herpetiformis & Linear IgA Disease
Two subepidermal, IgA-mediated vesiculobullous disorders that are perennial NEET PG favourites. They are most often tested as a contrast pair on direct immunofluorescence (DIF) pattern, autoantibody profile, systemic associations, and the dramatic response to dapsone. Master the immunofluorescence "granular vs linear" split and you can crack most questions.
Orientation: where they sit among bullous diseases
The autoimmune bullous diseases split into intra-epidermal (pemphigus group — acantholysis, IgG against desmogleins) and subepidermal (split below the epidermis — bullous pemphigoid, DH, linear IgA disease, EBA). Both DH and linear IgA disease are subepidermal and IgA-driven, but they are completely distinct entities with different antigens, DIF patterns, and disease associations.
High-yield: Dermatitis herpetiformis (DH) and coeliac disease are the same disease in different organs — both are gluten-sensitive enteropathies. DH is essentially "coeliac disease of the skin."
Dermatitis Herpetiformis (DH) — definition & epidemiology
DH (also called Duhring disease) is a chronic, intensely pruritic, papulovesicular eruption that is the cutaneous expression of gluten sensitivity. The name "herpetiformis" refers to the grouped (herpes-like) clustering of vesicles — it has nothing to do with herpes virus.
- Onset typically second to fourth decade; can occur in children.
- Male predominance (unusual for an autoimmune disease; M:F roughly 2:1).
- Strong link with Northern European ancestry; rarer in Asians/Africans.
- Tightly associated with HLA-DQ2 (~90%) and HLA-DQ8 — the same haplotypes as coeliac disease.
Etiology & pathophysiology
- Dietary gluten (gliadin) is deamidated by tissue transglutaminase (tTG, transglutaminase-2) in the gut.
- This generates neo-epitopes that drive an IgA response in genetically susceptible (DQ2/DQ8) individuals.
- In DH, the dominant autoantigen is epidermal transglutaminase (transglutaminase-3, eTG/TG3) — a paralogue of gut tTG. Antibodies cross-react.
- IgA–eTG immune complexes deposit in the dermal papillae (papillary tips).
- They recruit neutrophils, which release proteases (elastase, collagenase) → papillary microabscesses → subepidermal split → vesicle.
Flow: Gluten ingestion → gut tTG deamidates gliadin → IgA anti-tTG/anti-eTG produced → IgA–eTG complexes lodge at dermal papillae → neutrophil influx & papillary microabscesses → subepidermal blister + intense pruritus.
High-yield: The target antigen of DH is epidermal transglutaminase (TG3); the target in coeliac disease is tissue transglutaminase (TG2). They are related but distinct — a classic distractor.
Clinical features
- Symmetrical, grouped papules, urticarial plaques, and tense vesicles on an erythematous base.
- Distribution is the giveaway: extensor surfaces — elbows, knees, buttocks, sacrum, scalp, posterior shoulders.
- Intractable pruritus and burning — often so severe the patient presents with only excoriations and crusts because intact vesicles are scratched away ("the rash you can't find").
- Heals with post-inflammatory hyper/hypopigmentation; scarring is uncommon unless excoriated.
- Most patients have no GI symptoms despite enteropathy on biopsy (silent/subclinical coeliac disease).
High-yield: Distribution mnemonic — DH loves the "E" surfaces and the bony bumps: Elbows, Extensor knees, buttocks/sacrum, scalp. Symmetry + extensor + savage itch = DH until proven otherwise.
Diagnosis & investigation of choice
| Test | Finding in DH | Comment |
|---|---|---|
| DIF of perilesional skin | Granular IgA deposits at the tips of dermal papillae (and along BMZ) | Gold standard / investigation of choice; biopsy uninvolved perilesional skin, NOT the blister |
| Histopathology (H&E) | Neutrophilic microabscesses in dermal papillae + subepidermal cleft | Earliest lesion finding |
| Serology | Anti-tissue transglutaminase IgA (anti-tTG IgA) — most useful screen; anti-endomysial IgA (EMA) highly specific; anti-epidermal transglutaminase (anti-eTG) most specific for DH | Anti-tTG is the practical first serology |
| Total serum IgA | Exclude IgA deficiency (causes false-negative IgA serology) | If deficient, use IgG-based tests |
| Small bowel biopsy | Villous atrophy (often patchy/partial) | Frequently asymptomatic enteropathy |
High-yield: Granular IgA at the dermal papillary tips on DIF is pathognomonic of DH and is the single most-tested fact. Always biopsy perilesional (normal-appearing) skin — taking the blister itself can give a false-negative because neutrophil enzymes degrade the deposits.
High-yield: Best serological screen = anti-tTG IgA; most specific antibody = anti-endomysial IgA (EMA); antibody most specific for the skin disease = anti-epidermal transglutaminase (anti-eTG/TG3).
Management / drug of choice
- Dapsone is the drug of choice for rapid symptom control — itch and new lesions settle within 24–72 hours (a near-diagnostic therapeutic response).
- Dose ~ 50–150 mg/day, titrated.
- Check G6PD before starting — dapsone causes dose-dependent haemolysis and methaemoglobinaemia; G6PD-deficient patients haemolyse severely.
- Monitor CBC (agranulocytosis, usually first 3 months), reticulocytes, LFTs; watch for dapsone hypersensitivity syndrome (DRESS-like).
- Dapsone treats the skin only — it does not treat the gut enteropathy.
- Lifelong strict gluten-free diet (GFD) is the only treatment that addresses the underlying disease, reduces lymphoma risk, and allows the dapsone dose to be tapered/stopped over months to years.
- Avoid iodine (can flare DH) and certain NSAIDs.
- Alternatives if dapsone not tolerated: sulfapyridine / sulfasalazine.
High-yield: Dapsone = symptomatic relief (fast); gluten-free diet = definitive disease control. Only the GFD reduces the long-term risk of enteropathy-associated T-cell lymphoma (EATL).
Complications & associations
- Coeliac disease / villous atrophy (almost universal subclinically).
- Enteropathy-associated T-cell lymphoma (EATL) and increased non-Hodgkin lymphoma risk — lowered by GFD.
- Other autoimmune diseases: autoimmune thyroid disease (Hashimoto/Graves), type 1 diabetes, pernicious anaemia/atrophic gastritis, vitiligo, Addison disease.
- Dapsone toxicity: haemolytic anaemia, methaemoglobinaemia, agranulocytosis, peripheral neuropathy, hypersensitivity syndrome.
- Nutritional sequelae of enteropathy: iron/folate deficiency.
Linear IgA Disease (LAD) — definition & epidemiology
Linear IgA bullous dermatosis (LABD) is a subepidermal blistering disease defined by linear deposition of IgA along the basement membrane zone (BMZ). It has two age peaks:
- Children — historically called Chronic Bullous Disease of Childhood (CBDC); usually <5 years.
- Adults — often drug-induced.
Crucially, LAD is NOT associated with gluten sensitivity or coeliac disease — this is the single most important point separating it from DH.
Etiology & pathophysiology
- Autoantibodies are IgA directed against the BMZ, classically against a 97-kDa / 120-kDa cleavage fragment of BP180 (BPAG2, collagen XVII) within the lamina lucida.
- IgA binding → complement and neutrophil recruitment → subepidermal separation.
- Drug-induced LAD is the most common cause in adults — the classic culprit is vancomycin. Others: amiodarone, captopril, penicillins, NSAIDs (diclofenac), phenytoin, lithium.
High-yield: The commonest drug causing linear IgA disease is vancomycin. Suspect drug-induced LAD in any adult who blisters after starting vancomycin — withdrawal usually resolves it.
Clinical features
- Tense vesicles and bullae arising on normal or erythematous skin.
- The hallmark is the "string of pearls" (cluster of jewels / crown of jewels) sign — new blisters arranged annularly around the periphery of older, healing/crusted lesions, forming a rosette/collarette.
- Childhood LAD: predilection for the lower abdomen, perineum, genitalia, perioral and inner thighs ("sexual abuse mimic" in the genital area — exam trap); often the "cluster of jewels" is most florid here.
- Mucosal involvement (oral, ocular/conjunctival) is more common than in DH, and can scar.
- Itch is variable — usually less ferocious than DH.
High-yield: "String of pearls / cluster of jewels" annular blisters = linear IgA disease, especially chronic bullous disease of childhood. This visual cue is a frequent single-best-answer stem.
Diagnosis & investigation of choice
| Test | Finding in LAD |
|---|---|
| DIF (investigation of choice) | Linear (homogeneous) IgA along the basement membrane zone |
| Histopathology | Subepidermal blister with neutrophil-predominant infiltrate, often neutrophils along the BMZ; can mimic DH |
| Salt-split skin IIF | IgA usually on the epidermal (roof) side (BP180 fragment); some show dermal/floor binding |
| Serology | Circulating IgA anti-BMZ antibodies (lower titres than DH-related serology); no anti-tTG/EMA |
| Coeliac workup | Negative — no gluten link |
High-yield: DIF distinguishes the pair instantly — granular IgA at dermal papillae = DH; linear IgA along the BMZ = linear IgA disease. "Granular = grains in the papillae; linear = a line at the basement."
Management / drug of choice
- Identify and stop any offending drug (especially vancomycin) — first step in adults; often curative.
- Dapsone is the drug of choice for idiopathic LAD (again check G6PD first). Sulfapyridine is an alternative.
- Severe/refractory: add systemic corticosteroids; consider colchicine, mycophenolate, IVIG.
- Childhood LAD often remits spontaneously within 2–4 years, around or before puberty — generally good prognosis.
High-yield: Dapsone works in both DH and LAD (both are neutrophil-rich, IgA-mediated), but only DH requires a gluten-free diet. LAD has no dietary component.
Head-to-head comparison (the core exam table)
| Feature | Dermatitis Herpetiformis | Linear IgA Disease |
|---|---|---|
| Eponym | Duhring disease | CBDC (childhood form) / LABD |
| Age | Young–middle adults; M>F | Bimodal: children <5 yr & adults |
| DIF pattern | Granular IgA at dermal papillary tips | Linear IgA along BMZ |
| Target antigen | Epidermal transglutaminase (TG3) | BP180 fragment (97/120 kDa, collagen XVII) |
| Serology | Anti-tTG, anti-endomysial (EMA), anti-eTG | IgA anti-BMZ (low titre); no anti-tTG |
| Gluten/coeliac link | Yes — strong (DQ2/DQ8) | No |
| Drug trigger | Iodine can flare | Vancomycin (commonest), others |
| Classic morphology | Grouped vesicles, extensor (elbows/knees/buttocks), excoriated | "String of pearls" annular bullae |
| Mucosa | Rare | More common, may scar |
| Itch | Severe/burning | Variable, usually milder |
| Treatment | Dapsone + lifelong gluten-free diet | Stop drug + dapsone |
| Histology | Neutrophilic papillary microabscesses | Subepidermal blister, BMZ neutrophils |
High-yield: If the stem gives DIF result, answer immediately on pattern: granular papillary IgA → DH; linear BMZ IgA → LAD. If it gives morphology, use extensor grouped excoriated vesicles → DH; annular "cluster of jewels" → LAD.
Key differentials
- Bullous pemphigoid — tense bullae in the elderly, linear IgG + C3 at BMZ on DIF, anti-BP180/BP230, eosinophil-rich, salt-split roof pattern. (LAD is the IgA counterpart of BP.)
- Pemphigus vulgaris — flaccid bullae, mucosal involvement, intraepidermal/acantholytic, intercellular ("fishnet/chicken-wire") IgG, positive Nikolsky.
- Epidermolysis bullosa acquisita (EBA) — subepidermal, IgG against type VII collagen, dermal (floor) binding on salt-split skin, trauma-prone sites, scarring with milia.
- Bullous SLE — neutrophilic subepidermal bullae, anti-type VII collagen, dapsone-responsive; look for other lupus criteria.
- Scabies / papular urticaria / atopic dermatitis — itchy papulovesicles but no IgA on DIF; consider when DH is on the differential.
- Erythema multiforme / SJS — when LAD is drug-induced and bullous, but DIF and target lesions distinguish.
High-yield: On salt-split skin IIF: roof (epidermal) binding → BP and most LAD; floor (dermal) binding → EBA and bullous SLE. A neat discriminator for the subepidermal group.
Mnemonics & named signs
- DH → "Duhring's Hungry for gluten" — gluten-sensitive, granular IgA, extensor itch.
- Linear IgA → "a Line of pearls" — linear DIF + string-of-pearls (cluster of jewels) sign; Vancomycin is the Villain.
- "GRanular = papillary; LInear = basement Line."
- Dapsone safety: "Check G6PD or get haemolysis + methaemoglobinaemia."
Recently asked / exam angle
- Single-best-answer on DIF: a clinical photo of grouped vesicles on elbows with the line "granular IgA at tips of dermal papillae" → answer Dermatitis herpetiformis; contrasted against a stem with "linear IgA along basement membrane" → Linear IgA disease.
- Best site for skin biopsy in DH = perilesional uninvolved skin for DIF (high-yield trap — not the blister).
- Investigation of choice for DH = DIF; best serological screen = anti-tTG IgA; most specific = anti-endomysial antibody.
- Drug causing linear IgA disease = vancomycin (classic one-liner MCQ).
- Target antigen matching: DH ↔ epidermal transglutaminase (TG3); LAD ↔ BP180 fragment; BP ↔ BP180/BP230; PV ↔ desmoglein 3 (±1); EBA ↔ type VII collagen.
- DH systemic association = coeliac disease / gluten-sensitive enteropathy, and increased risk of EATL lymphoma; reduced by gluten-free diet.
- Why check G6PD before dapsone — to avoid severe haemolysis; also expect methaemoglobinaemia.
- Image-based "cluster of jewels" in a child's perineum/lower abdomen → chronic bullous disease of childhood (linear IgA).
Rapid revision
- DH = gluten-sensitive, IgA-mediated, subepidermal blistering disease = "coeliac of the skin"; HLA-DQ2/DQ8.
- DH morphology = intensely itchy grouped vesicles on extensors (elbows, knees, buttocks, sacrum, scalp), often only excoriations visible.
- DH DIF = granular IgA at dermal papillary tips — pathognomonic; biopsy perilesional normal skin.
- DH antigen = epidermal transglutaminase (TG3); serology = anti-tTG / anti-endomysial / anti-eTG IgA.
- DH treatment = dapsone (itch settles in 24–72 h) plus lifelong gluten-free diet (only the diet treats gut & cuts lymphoma risk).
- Always check G6PD before dapsone — haemolysis + methaemoglobinaemia; monitor CBC for agranulocytosis.
- DH complication = enteropathy-associated T-cell lymphoma (EATL); associated with autoimmune thyroid disease & T1DM.
- Linear IgA disease = linear IgA along the BMZ; antigen = BP180 fragment (97/120 kDa); NO gluten link.
- LAD morphology = "string of pearls / cluster of jewels" annular tense bullae; childhood form = CBDC, favours perineum/lower abdomen.
- Vancomycin is the commonest drug-induced cause of LAD — stop the drug first; dapsone for idiopathic disease.
- Childhood LAD often remits by puberty; LAD has more mucosal involvement than DH.
- DIF is the great discriminator: granular papillary IgA = DH; linear BMZ IgA = LAD; linear IgG+C3 = bullous pemphigoid.