Dermatitis Herpetiformis

Overview

Dermatitis herpetiformis (DH) is a chronic, intensely pruritic vesiculobullous skin disease characterized by grouped vesicles and papules distributed symmetrically over extensor surfaces. It represents the cutaneous manifestation of gluten sensitivity and is pathognomonic for coeliac disease, though gastrointestinal symptoms may be minimal or absent. [1,2]

The condition is distinguished by its unique immunopathological signature: granular deposits of immunoglobulin A (IgA) at the dermal-epidermal junction on direct immunofluorescence, a finding considered the diagnostic gold standard. [3] Despite its name suggesting a herpetic aetiology, DH is unrelated to herpes viruses; the term "herpetiformis" refers to the grouped arrangement of lesions.

DH is highly responsive to both pharmacological therapy with dapsone and dietary gluten restriction, though lifelong treatment is typically required. Recognition is critical as patients carry the same long-term risks as those with classical coeliac disease, including malignancy and osteoporosis. [4,5]

Epidemiology

Dermatitis herpetiformis is the most common immunobullous disease in some Northern European populations, though it remains relatively rare overall. The epidemiological profile closely parallels that of coeliac disease, reflecting their shared pathogenic mechanisms.

Demographic Characteristics

Age Distribution: While DH can occur at any age, onset is most common in the third to fifth decades of life. Childhood onset is rare but well-documented, with approximately 5% of cases presenting before age 10. [10,49]

Sex Predilection: Unlike most autoimmune conditions, DH demonstrates a male predominance with a male-to-female ratio of approximately 1.5-2:1. The reason for this sex difference remains unclear. [8]

Geographic Variation: DH shows marked geographic variation, with highest incidence in populations of Northern European ancestry, particularly Scandinavia, Ireland, and the United Kingdom. The condition is rare in Asian and African populations. [7,11,51]

Genetic Associations: Strong association with HLA-DQ2 (present in 90-95% of patients) and HLA-DQ8 (5-10% of patients), identical to the HLA haplotypes associated with coeliac disease. [12]

Risk Factors

• First-degree relative with coeliac disease or DH: 10-fold increased risk [13]
• HLA-DQ2 or DQ8 positivity: Present in > 95% of cases [12]
• Northern European ancestry: 5-10 fold higher prevalence than other populations [11]
• Other autoimmune conditions: Particularly thyroid disease (10-15% of DH patients) [14]

Aetiology and Pathophysiology

Dermatitis herpetiformis results from an immune-mediated response to gluten (specifically gliadin) that manifests primarily in the skin. The condition represents a unique variant of coeliac disease with distinct immunological features.

Primary Pathogenic Mechanism

The development of DH follows a multi-step pathogenic cascade:

1. Gluten Ingestion and Intestinal Sensitization: Dietary gluten is deamidated by tissue transglutaminase (TG2) in the small intestinal mucosa, creating immunogenic peptides. [15]

2. Autoantibody Production: B cells produce IgA antibodies against:

   • Epidermal transglutaminase (TG3) - predominant target in DH [16]
   • Tissue transglutaminase (TG2) - present in most cases [17]
   • Endomysial antibodies (EMA) - correlates with intestinal involvement [2]

3. Cutaneous Deposition: IgA antibodies and IgA-antigen complexes deposit in the dermal papillae, particularly around dermal microvessels. The mechanism of selective cutaneous deposition remains incompletely understood but may involve:

   • Cross-reactivity between TG2 and TG3 [18]
   • Local factors promoting immune complex deposition
   • Trauma or pressure on extensor surfaces

4. Inflammatory Cascade: IgA deposits activate complement via the alternative pathway, recruiting neutrophils to the dermal-epidermal junction. Neutrophil proteases cause papillary microabscesses and subepidermal blister formation. [3]

Exam Detail: ### Molecular Pathophysiology

Transglutaminase Biology: The transglutaminase family includes at least nine isoforms. TG2 (tissue transglutaminase) is ubiquitously expressed and catalyzes deamidation of gliadin in the gut. TG3 (epidermal transglutaminase) is primarily expressed in keratinocytes and plays a role in epidermal differentiation. [16]

Epitope Spreading: Initial immune response targets TG2 in the gut, followed by epitope spreading to TG3. Anti-TG3 antibodies show higher specificity for DH than coeliac disease without skin manifestations. Some studies suggest anti-TG3 antibodies may predict DH development in coeliac patients. [19]

Complement Activation: Unlike other IgA-mediated diseases, DH demonstrates robust complement activation despite IgA's traditionally weak complement-fixing ability. This likely occurs through the alternative pathway, with C3 and properdin deposition evident on immunofluorescence. [20]

Neutrophil Recruitment: Complement fragments (C3a, C5a) act as potent chemoattractants for neutrophils. Neutrophil elastase and other proteases released in dermal papillae create characteristic papillary microabscesses and induce subepidermal cleavage. [21]

Relationship to Coeliac Disease

DH is considered the cutaneous manifestation of gluten-sensitive enteropathy. Key features of this relationship include:

• Universal Enteropathy: 100% of DH patients have gluten-sensitive enteropathy on small bowel biopsy, though villous atrophy may be patchy or subtle (Marsh 1-2 in many cases). [22]
• Shared Genetics: Identical HLA associations (DQ2/DQ8) and similar non-HLA susceptibility loci. [12]
• Gluten Dependency: Both conditions respond to gluten withdrawal and relapse with gluten reintroduction. [23]
• Antibody Profile: Overlapping but distinct - anti-TG3 predominates in DH, anti-TG2 in coeliac disease. [17]

Environmental Triggers

Gluten: The sine qua non of DH pathogenesis. Gliadin (the alcohol-soluble fraction of gluten) contains the critical immunogenic sequences. [15]

Iodine: Historically recognized to precipitate or exacerbate DH lesions, though the mechanism remains unclear. Some evidence suggests iodine may enhance neutrophil chemotaxis or alter antigen presentation. [24]

NSAIDs: Case reports describe DH exacerbation with nonsteroidal anti-inflammatory drugs, possibly through enhanced neutrophil activation. [25]

Clinical Presentation

Cardinal Features

Dermatitis herpetiformis presents with a characteristic clinical triad:

1. Intense Pruritus: Often described as burning or stinging, frequently preceding visible lesions by hours to days
2. Symmetrical Distribution: Predilection for extensor surfaces and areas of trauma/pressure
3. Grouped Vesicles: Herpetiform (clustered) arrangement of vesicles and papules

Cutaneous Manifestations

Primary Lesions:

• Vesicles: 2-5mm tense vesicles on erythematous or normal-appearing skin base
• Papules: Erythematous, urticarial papules, often with central vesiculation
• Grouped configuration: Vesicles clustered in herpetiform groups

Secondary Lesions (more commonly observed due to scratching):

• Excoriations: Linear scratch marks with crusting
• Erosions: Secondary to vesicle rupture or excoriation
• Post-inflammatory hyperpigmentation: Common in darker skin types
• Crusts: Yellow-brown crusts overlying erosions

Distribution Pattern:

Classic sites (in order of frequency):

1. Elbows (90-95% of patients) - extensor surfaces and posterior
2. Knees (80-85%) - extensor surfaces and anterior
3. Buttocks (70-80%) - often symmetrical
4. Shoulders (60-70%) - scapular regions
5. Scalp (50-60%) - particularly posterior
6. Lower back (40-50%) - sacral region

Less common sites:

• Face (rare except in children)
• Palms and soles (uncommon)
• Mucous membranes (very rare, unlike other bullous diseases)

Morphological Variants:

• Papular variant: Predominantly urticarial papules without obvious vesiculation
• Plaque variant: Confluent areas of erythema and crusting
• Purpuric variant: Haemorrhagic vesicles and purpuric macules
• Granular parakeratosis variant: Hyperkeratotic plaques (rare)

Extracutaneous Manifestations

Gastrointestinal:

• Most patients (70-80%) are asymptomatic from an intestinal perspective [1]
• When present, symptoms may include:
  • Abdominal bloating and discomfort (15-20%)
  • Diarrhoea (10-15%)
  • Weight loss (5-10%)
  • Iron deficiency anaemia (20-30%) [26]

Associated Autoimmune Conditions (reported in 10-30% of patients):

• Autoimmune thyroid disease: Most common (10-15%) [14]
• Type 1 diabetes mellitus: 1-2% [27]
• Vitiligo: 1-2%
• Alopecia areata: less than 1%
• Pernicious anaemia: less than 1%

Nutritional Deficiencies (secondary to enteropathy):

• Iron deficiency: 20-30% [26]
• Folate deficiency: 10-15%
• Vitamin B12 deficiency: 5-10%
• Fat-soluble vitamin deficiency: Uncommon due to patchy enteropathy

Natural History

Disease Course:

• Chronic relapsing: Without treatment, DH follows a chronic course with spontaneous remissions (weeks to months) and relapses
• Age-related changes: Some studies suggest disease activity may decrease with age [28]
• Gluten-free diet response: Skin manifestations typically improve over 6-24 months with strict gluten avoidance, though some patients require years [23]

Differential Diagnosis

The differential diagnosis of DH includes other pruritic vesiculobullous and papular eruptions, particularly those affecting extensor surfaces.

Primary Differential Diagnoses

Secondary Differential Diagnoses

Dyshidrotic Eczema:

• Palmoplantar vesicles
• Seasonal variation (worse in spring/summer)
• Negative immunofluorescence
• May coexist with DH

Transient Acantholytic Dermatosis (Grover's Disease):

• Trunk predominance
• Older males
• Histology shows acantholysis
• Negative immunofluorescence

Pemphigus Vulgaris/Foliaceus:

• Mucosal involvement common (vulgaris)
• Flaccid rather than tense vesicles
• Intraepidermal rather than subepidermal split
• IgG intercellular deposition on DIF

Drug Eruptions:

• Temporal relationship to medication
• Different distribution patterns
• Negative immunofluorescence
• Resolution with drug withdrawal

Clinical Pearl: Diagnostic Clue: In any patient with symmetrical, intensely pruritic papulovesicular eruption affecting the elbows and knees, DH should be the primary consideration. The intensity of pruritus is often disproportionate to the visible skin changes, and patients frequently present with excoriations rather than intact vesicles due to the compulsion to scratch.

Investigations

First-Line Investigations

Direct Immunofluorescence (DIF) of Perilesional Skin:

Direct immunofluorescence represents the diagnostic gold standard for DH, with sensitivity approaching 100% in untreated patients. [3]

Technique:

• Biopsy site: Uninvolved perilesional skin (1-2cm from active lesion), NOT the lesion itself
• Preferred sites: Normal-appearing skin adjacent to elbow or knee lesions
• Biopsy method: 3-4mm punch biopsy
• Transport: Fresh tissue in Michel's medium or saline-moistened gauze (NOT formalin)
• Processing: Frozen sections examined under fluorescence microscopy

Expected Findings:

• Granular IgA deposits in dermal papillae and along the basement membrane zone (pathognomonic) [3]
• Pattern: Granular or "string of pearls" configuration
• C3 complement: Often present in a similar pattern (70-80% of cases) [20]
• IgG and IgM: Usually absent
• Intensity: Varies from weak to strong fluorescence

Diagnostic Accuracy:

• Sensitivity: 95-100% in untreated patients [29]
• Specificity: > 95% (granular IgA pattern highly specific for DH) [3]
• Positive predictive value: > 98% when granular pattern is identified
• Negative predictive value: > 95% when properly performed
• False negatives: May occur with:
  • Prolonged gluten-free diet (IgA deposits clear over months to years)
  • Biopsy from lesional rather than perilesional skin
  • Improper specimen handling
  • Inadequate biopsy depth (must include papillary dermis)

Procedure Detail: Skin Biopsy Technique for Direct Immunofluorescence in DH:

The success of DIF diagnosis depends critically on proper biopsy technique and specimen handling. A systematic approach maximizes diagnostic yield.

Pre-biopsy Planning:

1. Patient Preparation:

   • Avoid starting dapsone or gluten-free diet before biopsy (reduces IgA deposits over time)
   • If patient already on treatment, DIF may still be positive but sensitivity decreases
   • Informed consent: Explain purpose, technique, risks (bleeding, infection, scarring)
   • Check for bleeding diathesis or anticoagulation (may require temporary cessation)

2. Site Selection (Critical for Success):

   • Optimal: Perilesional uninvolved skin 1-2cm from active lesion
   • Preferred anatomical sites: Skin adjacent to elbow or knee lesions (highest yield)
   • Avoid: Direct biopsy of vesicle/blister (destroys architecture, reduces IgA detection)
   • Avoid: Normal-appearing skin distant from lesions (lower yield)
   • Multiple biopsies: Consider 2-3 biopsies from different perilesional sites if high suspicion

3. Equipment Preparation:

   • 3-4mm punch biopsy instrument (adequate for sampling papillary dermis)
   • 1% lidocaine without epinephrine (epinephrine may cause vasoconstriction affecting results)
   • Transport medium: Michel's medium (preserves immunofluorescence for days) OR saline-moistened gauze (if processing within 4-6 hours)
   • Label specimen container clearly: "For Direct Immunofluorescence"

Biopsy Technique:

1. Local Anaesthesia:

   • Inject 0.5-1ml lidocaine intradermally (creating wheal)
   • Wait 2-3 minutes for adequate anaesthesia
   • Avoid excessive anaesthetic volume (distorts tissue architecture)

2. Punch Biopsy Execution:

   • Position punch perpendicular to skin surface
   • Apply firm downward pressure with twisting motion
   • Advance to subcutaneous fat (ensures adequate dermis)
   • Remove punch and gently elevate specimen with forceps (grasp fat, not epidermis)
   • Excise base with curved scissors or scalpel

3. Specimen Handling (Critical - Improper Handling Destroys Diagnostic Value):

   • NEVER place in formalin (destroys immunofluorescence)
   • Immediately place in Michel's medium (best) or wrap in saline-soaked gauze
   • If Michel's medium unavailable: Fresh tissue in sterile saline-moistened gauze, refrigerated, process within 4-6 hours
   • Alternatively: Snap-freeze specimen in liquid nitrogen (optimal for research but impractical clinically)
   • Label with patient details and "DIRECT IMMUNOFLUORESCENCE - DO NOT FIX IN FORMALIN"

4. Hemostasis and Wound Closure:

   • Apply pressure for 2-3 minutes
   • 3-4mm punch: Usually heals by secondary intention
   • Alternative: Single interrupted suture if hemostasis difficult
   • Apply pressure dressing
   • Remove suture (if placed) at 7-10 days

Concurrent Histopathology Biopsy:

For complete diagnostic assessment, obtain a second biopsy for routine H&E histology:

• Site: Early intact vesicle (ideally less than 24 hours old)
• Transport: Standard formalin fixation
• Purpose: Demonstrates characteristic papillary microabscesses and subepidermal cleavage
• Limitation: Histology is suggestive but NOT diagnostic (requires DIF correlation)

Laboratory Processing:

The dermatopathology laboratory performs:

1. Cryostat sectioning of frozen tissue (4-6 micron sections)
2. Incubation with fluorescein-conjugated antisera:
   • Anti-IgG
   • Anti-IgA (positive in DH)
   • Anti-IgM
   • Anti-C3 complement
   • Anti-fibrinogen
3. Fluorescence microscopy examination
4. Pattern interpretation: Granular vs. linear vs. intercellular

Quality Assurance:

• Adequate tissue depth: Must include papillary dermis
• Positive and negative controls: Run with each batch
• Experienced dermatopathologist interpretation essential
• Photography of fluorescence pattern for documentation

Common Technical Errors Leading to False Negatives:

1. Biopsy of lesional rather than perilesional skin
2. Formalin fixation (destroys immunofluorescence)
3. Inadequate biopsy depth (missing papillary dermis)
4. Delayed processing without appropriate transport medium
5. Biopsy from distant uninvolved skin
6. Patient on prolonged gluten-free diet prior to biopsy

Repeat Biopsy Indications:

• High clinical suspicion despite negative initial DIF
• Technical issues with first specimen
• Inadequate tissue sample
• Consider alternative perilesional site or wait for new lesions

Exam Detail: Immunofluorescence Pattern Interpretation:

The granular pattern of IgA deposition in dermal papillae is pathognomonic for DH and must be distinguished from:

1. Linear IgA Disease: Linear (not granular) band of IgA at BMZ
2. IgA Pemphigus: Intercellular IgA in epidermis
3. Bullous SLE: "Full house" pattern with multiple immunoreactants

Experienced dermatopathologists can reliably distinguish these patterns, but borderline cases may require additional serological and histopathological correlation.

Skin Histopathology (Lesional Biopsy):

Punch biopsy of an early vesicle (ideally less than 24 hours old) for routine H&E examination.

Characteristic Features:

• Papillary microabscesses: Collections of neutrophils and eosinophils in dermal papillae (early finding) [30]
• Subepidermal cleft: Separation at the dermal-epidermal junction
• Neutrophil-predominant infiltrate: In papillary dermis
• Fibrin deposition: In dermal papillae

Diagnostic Limitations:

• Histology is suggestive but NOT diagnostic (cannot differentiate from linear IgA disease)
• Late lesions may show non-specific changes
• Requires correlation with DIF for definitive diagnosis

Second-Line Serological Tests

Serology Panel for Coeliac Disease and DH:

Interpretation:

• Positive anti-TG3 antibodies: Highly suggestive of DH (may be negative in 25-50% of cases)
• Positive anti-TG2 or EMA: Confirms gluten-sensitive enteropathy
• Negative serology: Does NOT exclude DH (diagnosis relies on DIF)
• IgA deficiency (present in ~2% of coeliac/DH patients): Requires IgG-based testing [31]

Utility:

• Screening adjunct (not diagnostic)
• Monitoring dietary compliance and disease activity
• Anti-TG2 levels correlate with degree of intestinal damage [32]

Gastrointestinal Evaluation

Small Bowel Biopsy (Duodenal Biopsy):

Not routinely required for DH diagnosis but important for comprehensive assessment.

Indications:

• Assess degree of enteropathy
• Rule out complications (ulcerative jejunitis, lymphoma)
• Differentiate from other gluten-related disorders

Expected Findings:

• Villous atrophy: Marsh 1-3 classification [22]
  • "Marsh 1 (infiltrative): Increased intraepithelial lymphocytes (> 25 per 100 enterocytes)"
  • "Marsh 2 (hyperplastic): Crypt hyperplasia with increased IELs"
  • "Marsh 3a-c (destructive): Partial to total villous atrophy"
• Patchy distribution: DH often shows milder, patchier enteropathy than classical coeliac disease
• Recovery with gluten-free diet: Histological improvement over months to years

Technique:

• Upper endoscopy with multiple duodenal biopsies (4-6 specimens)
• Biopsy from second portion of duodenum
• Proper orientation for histological assessment

Additional Investigations

HLA Typing (HLA-DQ2/DQ8):

• Indication: Uncertain diagnosis with negative serology and equivocal DIF
• Interpretation: Negative HLA-DQ2 and DQ8 effectively excludes DH (> 95% negative predictive value)
• Limitation: Cannot confirm diagnosis (present in 30-40% of general population) [12]

Complete Blood Count and Nutritional Assessment:

• Iron studies: Iron deficiency anaemia in 20-30% [26]
• Folate and B12: Screen for deficiency
• Bone density (DEXA): If planning long-term dapsone or for enteropathy complications
• Thyroid function: Screen for associated autoimmune thyroid disease [14]

Gluten Challenge (rarely required):

• Reserved for patients on gluten-free diet with equivocal diagnosis
• Protocol: Resume gluten-containing diet for 6-12 weeks before testing
• Assess skin lesions, serology, and repeat DIF if needed

Management

Management of dermatitis herpetiformis targets both skin manifestations and the underlying gluten-sensitive enteropathy. A dual approach combining pharmacological therapy and dietary modification provides optimal outcomes.

Acute Management

Initial Symptomatic Relief:

In patients with newly diagnosed DH, immediate control of pruritus and skin lesions is essential while awaiting the slower effects of dietary intervention.

1. Topical Therapy:

   • Potent topical corticosteroids (betamethasone dipropionate 0.05% or clobetasol propionate 0.05%) to active lesions twice daily
   • Limited efficacy as monotherapy but helpful for symptomatic relief
   • Short-term use only (2-4 weeks) to avoid cutaneous atrophy

2. Systemic Antihistamines:

   • Sedating antihistamines (hydroxyzine 25-50mg at bedtime) for pruritus control
   • Limited efficacy compared to dapsone but useful as adjunct
   • Non-sedating antihistamines (cetirizine, fexofenadine) generally ineffective

Pharmacological Management: Dapsone

Dapsone remains the mainstay of pharmacological therapy for DH, providing rapid and dramatic symptom relief in the majority of patients.

Exam Detail: Dapsone Therapy Protocols:

Pre-treatment Screening (ESSENTIAL):

• Glucose-6-phosphate dehydrogenase (G6PD) activity: Severe haemolysis occurs in G6PD-deficient patients [33]
• Complete blood count with differential and reticulocyte count
• Liver function tests
• Renal function
• Pregnancy test (dapsone is FDA category C)

Contraindications:

• Absolute: G6PD deficiency, severe anaemia (Hb less than 8 g/dL)
• Relative: Pregnancy, severe cardiac/pulmonary disease, methemoglobin reductase deficiency

Dosing Regimen:

Initial Dose:

• Start with 50mg daily for adults
• Alternative: 25mg daily in patients at higher risk of adverse effects (elderly, renal impairment)
• Children: 0.5-1mg/kg/day (maximum 50mg daily)

Dose Titration:

• Increase by 25-50mg every 1-2 weeks if inadequate response
• Most patients achieve control with 50-150mg daily [34]
• Maximum dose: 200mg daily (rarely required)
• Assess response at each increment before further escalation

Maintenance Dose:

• Once controlled, maintain minimum effective dose
• Typical maintenance: 25-100mg daily
• After 1-2 years on strict gluten-free diet, attempt gradual dose reduction
• Some patients on strict GFD may discontinue dapsone after 2-5 years [23]

Monitoring Schedule:

Response Timeline:

• Pruritus improvement: 24-72 hours (dramatic and diagnostic) [35]
• New lesion formation: Ceases within 3-5 days
• Complete clearance: 1-2 weeks
• Lack of response by 1 week suggests alternative diagnosis

Mechanism of Action in DH:

• Anti-neutrophil effects: Inhibits neutrophil chemotaxis and myeloperoxidase activity [36]
• Blocks neutrophil adherence to IgA-bound targets
• Reduces neutrophil-mediated tissue damage
• Does NOT affect IgA deposition (deposits persist during dapsone therapy)

Dapsone Adverse Effects:

Dapsone Hypersensitivity Syndrome (DHS):

• Rare but potentially fatal (mortality 10% if untreated)
• Onset: Typically 2-6 weeks after starting dapsone
• Features: Fever, rash (exfoliative dermatitis), lymphadenopathy, hepatitis, eosinophilia
• Management: Immediate dapsone withdrawal, systemic corticosteroids (prednisolone 0.5-1mg/kg)
• Recovery: Usually complete if recognized early

Special Populations:

Pregnancy:

• Dapsone crosses placenta and is excreted in breast milk
• Risk/benefit discussion essential
• If used: Lowest effective dose; monitor neonatal bilirubin
• Alternative: Strict gluten-free diet alone may suffice in some patients

Elderly:

• Increased risk of haemolysis and cardiovascular complications
• Start with lower doses (25mg daily)
• More frequent monitoring

Renal Impairment:

• Dose reduction may be required (dapsone metabolites are renally excreted)
• Enhanced monitoring for haematological effects

Alternative Pharmacological Agents

For patients unable to tolerate dapsone or with contraindications:

Sulfapyridine:

• Dose: 500mg-2000mg daily in divided doses
• Efficacy: Comparable to dapsone in DH [37]
• Advantages: May be tolerated by some dapsone-intolerant patients
• Adverse effects: Similar to dapsone (haemolysis, methemoglobinemia); also nausea, crystalluria
• Availability: Limited in some countries

Sulfamethoxypyridazine:

• Dose: 250mg-1000mg daily
• Alternative sulfonamide with similar efficacy
• Used in Europe; limited availability elsewhere

Tetracyclines + Nicotinamide:

• Regimen: Tetracycline 500mg QID + nicotinamide 500mg TID
• Efficacy: Case reports suggest benefit in some patients [38]
• Mechanism: Anti-inflammatory effects; reduced neutrophil chemotaxis
• Use: Second-line for dapsone-intolerant patients
• Response: Slower than dapsone (weeks rather than days)

Systemic Corticosteroids:

• Generally NOT recommended for routine use
• Indications: Severe flares unresponsive to dapsone; dapsone hypersensitivity while establishing alternative
• Dose: Prednisolone 0.5mg/kg daily with rapid taper
• Problems: Rebound on withdrawal; long-term toxicity

Colchicine:

• Very limited evidence
• May have modest benefit through anti-neutrophil effects
• Not routinely recommended

Dietary Management: Gluten-Free Diet

Strict, lifelong gluten-free diet (GFD) represents the definitive treatment for both cutaneous and intestinal manifestations of DH.

Rationale for Gluten-Free Diet:

• Addresses underlying pathogenesis (removes antigenic trigger)
• Allows reduction or discontinuation of dapsone [23]
• Treats enteropathy and prevents long-term complications [39]
• Reduces risk of intestinal lymphoma and other malignancies [4]
• Improves bone health and nutritional status [40]

Gluten-Free Diet Principles:

Foods to Avoid (contain gluten):

• Wheat (all forms: bread, pasta, couscous, semolina, spelt, kamut)
• Barley (including malt and malt flavouring)
• Rye
• Triticale
• Hidden sources: Processed foods, sauces, communion wafers, medications (excipients)

Naturally Gluten-Free Foods:

• Rice, corn, quinoa, buckwheat, millet, amaranth
• Fruits and vegetables
• Meat, fish, eggs, dairy (unprocessed)
• Legumes and nuts

Contamination Avoidance:

• Dedicated cooking utensils and preparation surfaces
• Check labels for "may contain traces"
• Ensure "gluten-free" certification (regulations vary by country)
• Oats: Theoretically GF but often contaminated; use certified GF oats only [41]

Exam Detail: Gluten-Free Diet Response in Dermatitis Herpetiformis:

Timeline of Response:

• Intestinal mucosa: Improvement evident on biopsy at 3-6 months; normalization may take 1-2 years [22]
• Serology: Anti-TG2 and anti-TG3 antibodies decline over 6-12 months, may persist at low levels [32]
• Skin IgA deposits: Gradual clearance over months to years; may take 2-5 years for complete resolution [42,50]
• Clinical skin disease: Improvement over 3-6 months; complete control often requires 6-24 months [23,50]
• Dapsone requirement: Can often reduce dose after 6-12 months of strict GFD; some patients discontinue after 2-5 years [23]

Factors Affecting Response:

• Dietary adherence: Strict compliance essential; even small amounts of gluten trigger relapse [43]
• Baseline severity: More severe disease may take longer to clear
• Duration of disease: Longer disease duration associated with slower response
• Age: Some evidence suggests older patients may respond more slowly

Monitoring Dietary Compliance:

• Serology: Falling anti-TG2 levels indicate good compliance
• Clinical response: Persistent/recurrent lesions suggest inadvertent gluten exposure
• Dietitian input: Specialist coeliac dietitian review essential
• Patient education: Comprehensive education on hidden gluten sources

Dietary Relapse:

• Reintroduction of gluten (intentional or inadvertent) causes relapse within days to weeks
• Skin lesions typically reappear before gastrointestinal symptoms
• Suggests ongoing immune surveillance despite clinical remission

Nutritional Supplementation:

During initial phase and in patients with enteropathy:

• Iron: Ferrous sulfate 200mg daily (if deficient)
• Folate: Folic acid 5mg daily (if deficient)
• Vitamin B12: Check levels; supplement if low (oral or intramuscular)
• Calcium and Vitamin D: Calcium carbonate 1000-1500mg + vitamin D 800-1000 IU daily [40]
• Multivitamin: Consider in first 6-12 months

Combined Strategy: Dapsone + Gluten-Free Diet

The optimal management approach combines both interventions:

Phase 1 (Months 0-3): Immediate Control

• Initiate dapsone for rapid symptom control
• Begin strict gluten-free diet immediately
• Dietitian referral for education
• Baseline investigations for enteropathy and associated conditions

Phase 2 (Months 3-12): Stabilization

• Continue dapsone at maintenance dose
• Reinforce dietary adherence
• Monitor serology for evidence of GFD compliance
• Repeat nutritional screening

Phase 3 (Months 12-24): Dapsone Reduction

• After 12-18 months of strict GFD, attempt gradual dapsone dose reduction
• Reduce by 25mg increments every 2-3 months
• Monitor for disease recurrence
• Some patients achieve complete dapsone cessation

Phase 4 (Year 2+): Long-term Maintenance

• Continue strict lifelong GFD
• Annual review: Skin examination, dietary adherence, serology
• Screen for complications: Bone density, malignancy surveillance
• Minimal or no dapsone in many patients

Clinical Pearl: Practical Tip: The dramatic response to dapsone within 24-72 hours is so characteristic that it serves as a diagnostic test. Failure to respond within 1 week should prompt reconsideration of the diagnosis. However, patients must understand that dapsone treats symptoms only, while gluten-free diet addresses the underlying disease and prevents long-term complications.

Management of Special Situations

Refractory Cases:

If skin disease persists despite dapsone 150-200mg daily and documented strict GFD:

1. Verify diagnosis: Review DIF, consider alternative diagnoses
2. Assess true GFD adherence: Persistent positive serology suggests gluten exposure
3. Check for complications: Ulcerative jejunitis, enteropathy-associated T-cell lymphoma (rare)
4. Consider additional therapy: Sulfasalazine, tetracycline + nicotinamide, immunosuppression (rarely needed)
5. Exclude exacerbating factors: Iodine-rich foods/supplements, NSAIDs

Pregnancy:

• Preconception counseling essential
• Optimize with strict GFD prior to conception if possible
• Minimize dapsone or discontinue if feasible (some achieve control with GFD alone)
• If dapsone required: Use lowest effective dose; neonatal monitoring
• Folate supplementation: 5mg daily throughout pregnancy

Children:

• Early diagnosis and treatment crucial for growth and development
• Dapsone dosing: 0.5-1mg/kg/day
• Gluten-free diet compliance challenging; family education and support essential
• Growth monitoring: Height, weight, bone age
• Consider psychological support for dietary restrictions

Complications

Disease-Related Complications

Enteropathy-Associated T-Cell Lymphoma (EATL):

• Most serious complication (mortality > 90%)
• Risk factors: Long-standing untreated disease, poor GFD adherence
• Presentation: Abdominal pain, weight loss, intestinal obstruction/perforation
• Diagnosis: CT, endoscopy, biopsy
• Prevention is key: Strict lifelong GFD reduces risk to near-background levels [4]

Malignancy Risk:

• Overall increased risk of lymphoproliferative malignancies [5]
• Non-Hodgkin lymphoma (most common)
• Small bowel adenocarcinoma (rare but increased)
• Strict GFD for ≥5 years reduces risk to baseline population levels [45]

Treatment-Related Complications

Dapsone Toxicity (see Pharmacological Management section):

• Haemolytic anaemia
• Methemoglobinemia
• Peripheral neuropathy (with long-term use)
• Agranulocytosis (rare but serious)
• Dapsone hypersensitivity syndrome (rare but potentially fatal)

Gluten-Free Diet Challenges:

• Nutritional inadequacies if poorly balanced (low fiber, B vitamins)
• Social and psychological impact
• Economic burden (gluten-free products more expensive)
• Inadvertent gluten exposure from cross-contamination

Monitoring for Complications:

• Annual clinical review with dermatologist or gastroenterologist
• Serology (anti-TG2, EMA) to monitor GFD adherence
• Complete blood count, iron studies, vitamin B12, folate
• Thyroid function tests every 1-2 years
• DEXA scan at diagnosis and every 2-5 years [40]
• Consider repeat endoscopy if symptoms suggest complication

Prognosis

Natural History and Long-Term Outcomes

With Treatment (Dapsone + Gluten-Free Diet):

• Skin disease: Excellent control achievable in > 95% of patients [34]
• Dapsone requirement: Many patients (40-60%) can discontinue or significantly reduce dapsone after 2-5 years on strict GFD [23]
• Enteropathy: Improves or resolves in majority with strict GFD [22]
• Quality of life: Returns to normal with effective treatment
• Life expectancy: Normal if compliant with GFD and complications avoided [45]

Without Treatment or With Poor GFD Adherence:

• Chronic relapsing skin disease
• Persistent enteropathy with malabsorption
• Increased risk of malignancy (especially lymphoma) [4,5]
• Increased risk of osteoporosis and fractures [40]
• Nutritional deficiencies and associated morbidity

Prognostic Factors

Favorable Prognostic Indicators:

• Early diagnosis and treatment initiation
• Strict adherence to gluten-free diet
• Good response to dapsone
• Absence of severe enteropathy at diagnosis
• Regular follow-up and monitoring

Adverse Prognostic Indicators:

• Poor GFD adherence
• Long duration of untreated disease
• Severe villous atrophy at diagnosis
• Development of refractory disease
• Intolerance to dapsone requiring alternative agents

Age-Related Outcomes

Childhood-Onset DH:

• Generally good prognosis with early treatment
• Strict GFD during growth years may prevent complications
• Some case series suggest possible "outgrowing" of disease (controversial) [46]

Adult-Onset DH:

• Typically lifelong condition requiring ongoing management
• Excellent control achievable with combined therapy
• Compliance with GFD the key determinant of long-term outcomes

Elderly-Onset DH:

• May have milder enteropathy
• Increased risk of dapsone adverse effects
• Good prognosis with appropriate dose adjustment and monitoring

Disease Remission

Spontaneous Remission:

• Rare without gluten withdrawal
• Some studies report spontaneous improvement in small percentage of elderly patients [28]
• Cannot be predicted; continued monitoring required

Treatment-Induced Remission:

• Strict GFD for > 5 years may induce clinical remission in some patients
• IgA deposits may persist even when clinically inactive [42]
• Reintroduction of gluten typically causes relapse within weeks
• Lifelong GFD recommended regardless of clinical remission

Prevention and Screening

Primary Prevention

No established primary prevention strategies exist, as genetic predisposition (HLA-DQ2/DQ8) cannot be modified.

Secondary Prevention (Early Detection)

High-Risk Populations for Screening:

1. First-degree relatives of patients with DH or coeliac disease [13]
2. Patients with other autoimmune diseases, particularly:
   • Type 1 diabetes mellitus
   • Autoimmune thyroid disease
   • Down syndrome
3. Unexplained iron deficiency anaemia
4. Chronic pruritic rash affecting extensor surfaces

Screening Investigations:

• Anti-tissue transglutaminase (TG2) IgA + total IgA
• Consider anti-TG3 if high clinical suspicion for DH
• HLA typing (DQ2/DQ8) in indeterminate cases

Tertiary Prevention (Complication Prevention)

For patients with established DH:

Strict Lifelong Gluten-Free Diet:

• Most effective intervention to prevent long-term complications [39]
• Reduces lymphoma risk to near-background levels after 5 years [45]
• Improves bone density and reduces fracture risk [40]

Regular Monitoring:

• Annual review with dermatology/gastroenterology
• Serology to confirm GFD adherence
• Nutritional screening (iron, B12, folate)
• DEXA scan for bone health [40]
• Thyroid function every 1-2 years [14]

Malignancy Surveillance:

• No specific surveillance protocol established
• Low threshold for investigating new/persistent GI symptoms
• Consider periodic endoscopy in long-standing, poorly controlled disease (controversial)

Immunizations:

• Pneumococcal vaccine (associated with functional hyposplenism in some coeliac patients)
• Annual influenza vaccination
• Standard adult immunization schedule

Key Guidelines

British Association of Dermatologists (BAD) Guidelines (2022):

• Recommends DIF of perilesional skin as diagnostic gold standard
• Advises dapsone as first-line pharmacological therapy
• Emphasizes importance of strict lifelong gluten-free diet
• Recommends regular monitoring for complications

European Academy of Dermatology and Venereology (EADV) Consensus (2020) [47]:

• Granular IgA deposition in papillary dermis is pathognomonic
• Combined dapsone + GFD optimal initial management
• GFD alone may be sufficient in mild cases
• Long-term follow-up essential for complication screening

American Academy of Dermatology (AAD) Guidance (2019):

• Emphasizes need for G6PD screening before dapsone initiation
• Recommends gastroenterology referral for small bowel biopsy
• Advocates dietitian input for GFD education
• Stresses importance of malignancy risk discussion

British Society of Gastroenterology (BSG) Coeliac Disease Guidelines (2022) [48]:

• Recognizes DH as extraintestinal manifestation of coeliac disease
• Recommends same long-term management as classical coeliac disease
• Advises annual review and complication screening
• Suggests bone density assessment at diagnosis

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Exam-Focused Content

Common Exam Questions

1. "Describe the pathognomonic immunofluorescence finding in dermatitis herpetiformis."

   Model Answer: "Direct immunofluorescence of perilesional skin demonstrates granular deposits of IgA in the dermal papillae and along the basement membrane zone, often in a 'string of pearls' pattern. This finding is pathognomonic for DH. C3 complement is frequently present in a similar distribution. The biopsy must be taken from uninvolved perilesional skin (not the lesion itself) and transported in Michel's medium for optimal results. This pattern must be distinguished from linear IgA disease, which shows a linear rather than granular band."

2. "What is the relationship between dermatitis herpetiformis and coeliac disease?"

   Model Answer: "DH is considered the cutaneous manifestation of gluten-sensitive enteropathy. Essentially all patients (100%) have evidence of gluten-sensitive enteropathy on small bowel biopsy, though this is often patchy and may be subclinical (Marsh 1-2). Both conditions share identical HLA associations (HLA-DQ2 in 90-95%, DQ8 in 5-10%) and respond to gluten withdrawal. The key distinction is the antibody profile: anti-TG3 (epidermal transglutaminase) predominates in DH, while anti-TG2 (tissue transglutaminase) is more prominent in classical coeliac disease. Both conditions carry the same long-term risks including lymphoma, which is reduced by strict gluten-free diet."

3. "How do you manage a patient newly diagnosed with dermatitis herpetiformis?"

   Model Answer: "Management involves dual therapy addressing both skin manifestations and underlying enteropathy:

   Immediate:

   • Screen for G6PD deficiency (essential before dapsone)
   • Initiate dapsone 50mg daily (dramatic response within 24-72 hours confirms diagnosis)
   • Begin strict gluten-free diet immediately
   • Refer to specialist dietitian for GFD education

   Investigations:

   • Coeliac serology (anti-TG2, EMA, anti-TG3)
   • Consider small bowel biopsy to assess enteropathy
   • Nutritional screen (FBC, iron, B12, folate, calcium, vitamin D)
   • Thyroid function (10-15% have autoimmune thyroid disease)
   • Baseline DEXA scan

   Follow-up:

   • Monitor CBC weekly for 4 weeks, then monthly for 3 months, then 3-monthly
   • Titrate dapsone to minimum effective dose (usually 50-150mg daily)
   • After 12-18 months of strict GFD, attempt gradual dapsone reduction
   • Annual review with serology, nutritional screening, dietary compliance assessment
   • Long-term: Many patients discontinue dapsone after 2-5 years on strict GFD; lifelong GFD essential to prevent complications including lymphoma."

Viva Points

Viva Point: Opening Statement: "Dermatitis herpetiformis is a chronic autoimmune blistering disease representing the cutaneous manifestation of gluten-sensitive enteropathy. It is characterized by intensely pruritic grouped vesicles on extensor surfaces and is pathognomonic for coeliac disease, though gastrointestinal symptoms are often minimal."

Key Facts to Mention:

• Pathognomonic DIF finding: Granular IgA in dermal papillae [3]
• 100% of patients have gluten-sensitive enteropathy on biopsy [22]
• Male predominance (M:F ratio 1.5-2:1) unlike most autoimmune diseases [8]
• Dramatic response to dapsone within 24-72 hours [35]
• Strict lifelong gluten-free diet prevents complications including lymphoma (1-3% risk without GFD) [4]
• Associated with HLA-DQ2 (90-95%) and DQ8 (5-10%) [12]

Management Priorities:

1. Confirm diagnosis: DIF of perilesional skin (gold standard)
2. G6PD screening mandatory before dapsone
3. Initiate dual therapy: Dapsone (rapid control) + GFD (definitive treatment)
4. Screen for complications: Enteropathy, nutritional deficiencies, thyroid disease
5. Long-term: GFD adherence monitoring, malignancy surveillance

Common Mistakes

❌ Mistakes that Fail Candidates:

1. Biopsy Error: Taking DIF from lesional skin rather than perilesional skin (yields false negatives)

2. Missing G6PD Screening: Starting dapsone without checking G6PD (life-threatening haemolysis in deficient patients)

3. Dapsone Monotherapy: Using dapsone alone without emphasizing lifelong gluten-free diet (fails to address underlying disease and prevent complications)

4. Confusing Immunofluorescence Patterns:

   • DH = granular IgA
   • Linear IgA disease = linear IgA (different disease)
   • Bullous pemphigoid = linear IgG and C3

5. Neglecting Enteropathy: Focusing only on skin without addressing coeliac disease and its complications

6. Inadequate Monitoring: Failing to monitor for dapsone haematological toxicity (especially first 4 weeks)

7. Missing Lymphoma Risk: Not discussing the 1-3% lifetime risk of EATL and importance of GFD in risk reduction

High-Yield Facts for Vivas

• Classic triad: Intense pruritus + extensor distribution + grouped vesicles
• Diagnostic test: DIF showing granular IgA in dermal papillae (sensitivity ~100%)
• Speed of dapsone response: 24-72 hours (diagnostic feature)
• GFD response timeline: Skin lesions improve over 6-24 months; IgA deposits clear over 2-5 years
• Dapsone mechanism: Anti-neutrophil (blocks chemotaxis and myeloperoxidase)
• Most serious complication: Enteropathy-associated T-cell lymphoma (1-3% lifetime risk)
• Sex ratio: Male predominance (unusual for autoimmune disease)
• HLA association: 95% carry HLA-DQ2 or DQ8
• Antibody: Anti-TG3 (epidermal transglutaminase) most specific for DH

Clinical Cases for Exam Preparation

Clinical Pearl: Case 1: Classic Presentation

History: A 42-year-old male presents with a 6-month history of intensely itchy rash on his elbows and knees. The itch is worse at night and he describes it as "unbearable burning." He scratches until bleeding. He denies gastrointestinal symptoms but mentions occasional bloating. No significant medical history.

Examination: Symmetrical excoriations over both elbows with scattered 2-3mm vesicles on erythematous base. Similar lesions on both knees and scattered lesions on buttocks. Multiple crusts and post-inflammatory hyperpigmentation. No oral lesions.

Investigations:

• DIF (perilesional elbow skin): Granular IgA deposits in dermal papillae (pathognomonic)
• Histology (knee vesicle): Papillary microabscesses, subepidermal cleft with neutrophils
• Serology: Anti-TG2 IgA 85 U/mL (positive), anti-TG3 IgA positive, EMA positive
• FBC: Hb 11.2 g/dL (mild anaemia), MCV 78 fL (microcytic)
• Iron studies: Ferritin 15 ng/mL, low serum iron (iron deficiency)
• Duodenal biopsy: Marsh 2 enteropathy (crypt hyperplasia with increased IELs)
• HLA typing: HLA-DQ2 positive

Management:

1. Immediate:

   • Dapsone 50mg daily initiated (after G6PD screen negative)
   • Pruritus resolved within 48 hours
   • No new lesions after 5 days

2. Ongoing:

   • Strict gluten-free diet commenced immediately
   • Specialist coeliac dietitian referral
   • Iron supplementation: Ferrous sulfate 200mg daily
   • Calcium + vitamin D supplementation

3. Monitoring:

   • CBC weekly × 4, then monthly × 3, then 3-monthly
   • Dapsone maintained at 50mg daily
   • Repeat anti-TG2 at 6 months: Declined to 35 U/mL (improving GFD compliance)
   • At 18 months: Dapsone reduced to 25mg daily
   • At 30 months: Dapsone discontinued, remained controlled on GFD alone

Learning Points:

• Classic demographic (middle-aged male) and distribution (elbows, knees, buttocks)
• Dramatic dapsone response within 48-72 hours confirms diagnosis
• Iron deficiency common due to enteropathy despite minimal GI symptoms
• Successful dapsone withdrawal after 2.5 years of strict GFD demonstrates definitive role of dietary treatment

Clinical Pearl: Case 2: Diagnostic Challenge - Atypical Presentation

History: A 28-year-old female presents with 3-month history of intensely itchy papular rash on shoulders and lower back. She has scratched so severely that "there are hardly any bumps left, just scratches." She has type 1 diabetes mellitus diagnosed at age 12. Her sister has coeliac disease. No GI symptoms.

Initial Examination: Extensive linear excoriations over shoulders and sacral area. Few intact 2mm papules. No obvious vesicles. Differential diagnosis considered: neurotic excoriations, scabies, papular urticaria.

Initial Investigations:

• Skin biopsy from papule: Non-specific dermal inflammation with eosinophils
• Scabies microscopy: Negative

Clinical Course:

• Treated empirically for scabies (permethrin) - no improvement
• Referred to dermatology 2 months later
• New vesicles appeared on elbow extensors

Dermatology Assessment:

• High clinical suspicion for DH given:
  • Intense pruritus disproportionate to visible lesions
  • Type 1 diabetes (associated autoimmune condition)
  • Family history of coeliac disease
  • Extensor surface involvement (new elbow lesions)

Definitive Investigations:

• DIF from perilesional elbow skin: Granular IgA deposits in dermal papillae - DIAGNOSTIC
• Serology: Anti-TG2 IgA 128 U/mL (strongly positive), anti-TG3 IgA positive
• Gastroscopy with duodenal biopsies: Marsh 3a (partial villous atrophy)
• HLA-DQ2 positive

Management and Outcome:

• Dapsone 50mg daily: Pruritus resolved within 36 hours
• Strict GFD initiated
• Patient reported dramatic quality of life improvement
• Dapsone tapered over 18 months and discontinued
• Remained controlled on GFD alone at 3-year follow-up

Learning Points:

• DH may present with predominantly excoriated lesions with few intact vesicles
• High index of suspicion needed in patients with:
  • Unexplained intense pruritus
  • Associated autoimmune disease (Type 1 DM)
  • Family history of coeliac disease
• DIF from appropriate site (perilesional skin) is crucial - earlier non-diagnostic biopsy was likely from wrong site
• Speed of dapsone response (36 hours) is diagnostically valuable

Clinical Pearl: Case 3: Complication - Dapsone Hypersensitivity Syndrome

History: A 55-year-old male with recently diagnosed DH (confirmed by DIF showing granular IgA). G6PD screen was normal. Started dapsone 50mg daily with excellent initial response (pruritus resolved within 48 hours). Also commenced gluten-free diet.

Presenting Complaint: Three weeks after starting dapsone, develops fever (39.2°C), malaise, and new widespread rash.

Examination:

• Temperature 39.2°C
• Extensive morbilliform erythematous rash over trunk and limbs (different from original DH rash)
• Facial oedema
• Cervical and axillary lymphadenopathy (2-3cm nodes, tender)
• Mild hepatomegaly

Investigations:

• FBC: WCC 15.2 × 10⁹/L with eosinophilia (3.8 × 10⁹/L, 25%)
• LFTs: ALT 256 U/L, AST 198 U/L, ALP 178 U/L (hepatitis)
• CRP: 78 mg/L
• Viral serology (EBV, CMV, hepatitis): Negative
• Atypical lymphocytes on blood film

Diagnosis: Dapsone Hypersensitivity Syndrome (DHS) - also known as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

Management:

1. Immediate:

   • STOP dapsone immediately (NEVER rechallenge)
   • Hospital admission for monitoring

2. Treatment:

   • Prednisolone 60mg daily (1mg/kg)
   • Supportive care: IV fluids, antipyretics
   • Monitor liver function closely

3. Monitoring:

   • Daily LFTs for first week
   • CBC monitoring (eosinophil count)
   • Gradual steroid taper over 6-8 weeks (rapid taper risks relapse)

4. Alternative DH Management:

   • Strict gluten-free diet alone initially
   • After DHS resolved, commenced sulfasalazine 1g BD as dapsone alternative
   • Adequate DH control achieved

Outcome:

• Fever resolved within 48 hours of stopping dapsone
• Rash improved over 7 days
• LFTs normalized over 3 weeks
• Complete recovery
• DH controlled with sulfasalazine + GFD

Learning Points:

• DHS is rare (less than 1%) but potentially fatal (mortality 10% if untreated)
• Typical onset: 2-6 weeks after starting dapsone
• Classic triad: Fever, rash, lymphadenopathy
• Key features: Eosinophilia, hepatitis, systemic involvement
• Management: Immediate dapsone cessation, systemic corticosteroids
• NEVER rechallenge with dapsone
• Alternatives: Sulfasalazine, sulfapyridine, or GFD alone

Clinical Pearl: Case 4: Refractory Disease - Diagnostic Re-evaluation

History: A 38-year-old female diagnosed with DH 18 months ago based on clinical presentation and positive anti-TG2 serology. DIF was reported as "positive for IgA." Started dapsone with initial good response, but disease has been difficult to control despite escalating dapsone to 200mg daily. Now on strict gluten-free diet for 12 months with good serology response (anti-TG2 normalized), yet skin disease persists.

Re-evaluation Findings:

• Review of original DIF slides requested
• Revised DIF interpretation: LINEAR (not granular) IgA deposition at basement membrane zone
• Corrected diagnosis: Linear IgA Disease (LAD), NOT dermatitis herpetiformis

Key Distinctions:

Management After Correct Diagnosis:

• Patient educated about correct diagnosis
• GFD discontinued (not beneficial in LAD)
• Dapsone continued at 100mg daily (adequate control)
• No need for enteropathy monitoring
• No increased malignancy risk

Learning Points:

• Critical importance of correct DIF pattern interpretation: Granular vs. Linear
• DH refractory to dapsone + GFD should prompt diagnostic re-evaluation
• Request slide review if disease behavior inconsistent with diagnosis
• LAD may have positive anti-TG2 antibodies as false positive (lower specificity than anti-TG3)
• Experienced dermatopathologist essential for accurate DIF interpretation

Differential Diagnosis Pearls

How to Distinguish DH from Linear IgA Disease Clinically:

While DIF is definitive, clinical clues may suggest one diagnosis over the other:

When to Suspect Alternative Diagnoses:

1. Bullous Pemphigoid:

   • Elderly patients (> 70 years)
   • Large tense bullae (not tiny vesicles)
   • Flexural distribution
   • DIF: Linear IgG and C3 (not IgA)

2. Pemphigus (Foliaceus/Vulgaris):

   • Flaccid blisters (not tense)
   • Positive Nikolsky sign
   • Mucosal involvement (vulgaris)
   • DIF: Intercellular IgG (not basement membrane)

3. Scabies:

   • Interdigital web involvement
   • Linear burrows
   • Family/close contacts affected
   • Dermoscopy/microscopy confirms mites

4. Eczema (Dyshidrotic):

   • Palmoplantar vesicles
   • Seasonal variation
   • Negative DIF
   • May coexist with DH

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