IgA- mediated autoimmune disease triggered by gluten (wheat, barley, rye) in genetically susceptible subjects (HLA-DQ2/DQ8). Rousset 2004 , Salmi 2020.

In the intestine: immune response against gliadins → IgA anti-TG2 (tissue transglutaminase) autoantibodies and inflammatory response with villous atrophy or lymphocytic enteropathy. Collin 2003 , Ingen-Housz-Oro 2011.

In skin: granular deposit of IgA directed against TG3 (epidermal transglutaminase) in dermal papillae and basement membrane, considered pathognomonic. Salmi 2020 , Ingen-Housz-Oro 2011.

Strong familial aggregation with a pattern compatible with autosomal dominant inheritance and a high percentage of relatives with DH or celiac disease. Reunala 1996.

• Tense papules and vesicles of 1–3 mm, occasionally larger blisters; very pruritic, frequently excoriated and covered with crusts. Psalms 2020, Ingen-Housz-Oro 2011.

• Classic and almost constant pattern:
  • Extensor surfaces of elbows and knees.
  • Glutes and lumbosacral region.
  • Upper back, shoulder girdle.
  • Scalp and frontal hairline in some patients.
    Psalms 2020, Collin 2003.

• Insidious onset with itching intense, burning, often disproportionate to the number of visible vesicles.
• Grouped lesions (“herpetiform”), often already excoriated and crusted at the time of consultation.
• Frequent history of worsening after gluten ingestion (not always obvious to the patient).
• In most cases, digestive involvement is minimal or absent (subclinical celiac disease) although duodenal biopsy usually shows enteropathy. Ingen-Housz-Oro 2011, Herrero-González 2010.

• Erythema, wheals, and urticarial plaques are common around the vesicles.
• Excoriations, post-inflammatory hyperpigmentation, and lichenification in chronic cases.
• Nail, oral and genital mucosa: generally spared; frank mucosal involvement should raise suspicion of another autoimmune blistering condition. Collin 2003, Rose 2010.

• Chronic course, with flare-ups and remissions; without treatment it persists for years.
• Spectacular response to dapsone: relief of itching within 24–72 h is almost pathognomonic. Caproni 2009.
• La strict gluten-free diet (SGD) It leads to skin remission and allows for the withdrawal of dapsone in most patients after months-years. Andersson 1992, Heading 1976, Marks 1969.

• Non-classical distribution (trunk, face, palms/soles).
• Predominantly urticarial or eczematous presentation.
• Generalized bullous dermatosis that may mimic bullous pemphigoid or linear IgA dermatosis. Collin 2003, Rose 2010.
• In children: more polymorphic outbreaks, with greater facial and scalp involvement. Ingen-Housz-Oro 2011.

• Neutrophilic subepidermal bullous dermatosis. Rose 2010, Collin 2003.

• Early injury:
  • Neutrophilic microabscesses in tip of dermal papillae ± eosinophils.
  • Edema in papillae with beginning of dermoepidermal separation.
• Stable/bullous lesion:
  • Subepidermal blister with intact epidermal roof.
  • Inside: predominantly neutrophils, mixed with eosinophils and fibrin.
  • Papillary dermis with superficial perivascular mixed lymphocytic-neutrophilic infiltrate.
    Rose 2010, Psalms 2020.

• Direct immunofluorescence (IFD) – key test
  • Skin biopsy perilesional (apparently healthy but close to injury).
    • Classic pattern: granular deposits of IgA in dermal papillae and/or at the dermoepidermal junction, often with a C3 as an accompaniment. Psalms 2020, Dmochowski 2019.
    • This granular pattern is pathognomonic of DH; its absence requires reviewing the technique and exploring alternative diagnoses (linear IgA dermatosis, pemphigoid, etc.). Dmochowski 2019.
• Indirect immunofluorescence / serum serology
  • IgA anti-tissue transglutaminase (TG2).
  • IgA anti-endomysium.
  • IgA anti-epidermal transglutaminase (TG3) – highly specific, available in specialized centers. Ingen-Housz-Oro 2011, Collin 2003.
• Immunohistochemistry (IHC)
  • IHC for IgA and C3 in paraffin sections can be useful when fresh IFD is not available; its performance in bullous diseases has been systematized. Kasperkiewicz 2021.
• Molecular studies
  • HLA-DQ2/DQ8 genotyping can support the diagnosis, especially in doubtful cases; its absence makes DH/celiac disease unlikely, but it is not a routine test. Ingen-Housz-Oro 2011, Reunala 1996.
  • No other specific molecular tests are required for routine diagnosis.

• To confirm underlying disease and rule out comorbidities:
  • Celiac disease serology:
    • Total IgA (to rule out deficiency).
    • IgA anti-TG2, IgA anti-endomysium; optionally IgA/IgG anti-TG3. Collin 2003, Herrero-González 2010.
  • Duodenal biopsy by upper endoscopy:
    • Partial or total villous atrophy or lymphocytic enteropathy in most cases. Ingen-Housz-Oro 2011.
  • Complete blood count, reticulocytes, liver profile, creatinine, urinalysis:
    • Baseline and monitoring for dapsone. Ghaoui 2020.
  • G6PD: required before starting dapsone. Ghaoui 2020.
  • Ferritin, serum iron, folate, vitamin B12, calcium, and vitamin D:
    • To document malabsorption associated with celiac disease. Collin 2003.
  • TSH and thyroid antibodies, blood glucose/HbA1c:
    • Search for associated autoimmune diseases (thyroiditis, DM1). Ingen-Housz-Oro 2011.
• Cabinet
  • Bone densitometry (DEXA) in patients with long-standing celiac disease, low bone mass, or risk factors.
  • Upper digestive endoscopy with multiple duodenal biopsies at diagnosis and according to gastroenterological indication.

• Ideal type of biopsy
  • They are recommended two skin biopsies: Caproni 2009, Herrero-González 2010.
    • For HE
      • Punch ≥4 mm (or incisional) of a recent vesicle or tense papule.
      • It must include epidermis and reticular dermis; subcutis is not essential but may be included.
    • For IFD
      • Punch ≥4 mm of intact perilesional skin (2–3 cm from the lesion, with no visible vesicles).
      • Key to demonstrating granular IgA deposits.
• special considerations
  • Avoid areas previously treated with potent topical corticosteroids or calcineurins in the last 1–2 weeks if possible, as these may decrease the intensity of IgA deposits. Dmochowski 2019.
  • Ideally, a biopsy should be taken. before many months of strict DSGIgA deposits may decrease with years of diet, although they usually persist for quite some time. Psalms 2020.
• Contraindications
  • The usual findings for any skin biopsy:
    • Severe uncorrected coagulation disorders.
    • Intensive anticoagulation without possibility of adjustment (individual assessment).
    • Severe local infection at the biopsy site.
  • Fixing and shipping
    • Biopsy for HE → 10% formalin.
    • Biopsy for IFD → Michel's medium or physiological saline (coordinate with the laboratory for immediate collection). Dmochowski 2019.

• Strict gluten-free diet (GFD) for life
  • The cornerstone of treatment: improves enteropathy, reduces the risk of lymphoma, and allows discontinuation of dapsone in most cases. Andersson 1992, Marks 1969, Psalms 2020.
  • It requires coordination with nutrition and gastroenterology.
• Dapsone (sulfone) oral
  • Drug of choice for rapid control of rash and itching.
  • Usual starting dose: 50–100 mg/dayadjusting according to response, up to 1–2 mg/kg/day. Caproni 2009, Herrero-González 2010
  • Response: marked improvement of pruritus in 24–72 days and partial clearance of lesions within days. Caproni 2009.
  • Always accompany with DSG; dapsone does not correct enteropathy or risk of systemic complications. Ingen-Housz-Oro 2011.
• Potent/very potent topical corticosteroids
  • Useful as adjuncts for pruritus, especially at the beginning or in localized areas. Herrero-González 2010.

• When dapsone is contraindicated or poorly tolerated, or in refractory disease:
  • Sulfonamides
    • Sulfapyridine 500–1000 mg/8–12 h.
    • Sulfasalazine as an alternative in some protocols. Caproni 2009, Ingen-Housz-Oro 2011.
  • Other immunomodulators (evidence limited to small series/cases):
    • Azathioprine, mycophenolate, cyclosporine, rituximab in exceptional refractory cases. Nguyen 2021.

• Before starting dapsone:
  • History of anemia, cardiorespiratory disease, liver disease, G6PD deficiency, use of other oxidants (nitrites, certain antibiotics).
  • Baseline laboratory tests: complete blood count, reticulocytes, bilirubin, ALT/AST, creatinine, G6PD. Ghaoui 2020. 
• Controls:
  • Complete blood count and reticulocytes every 1–2 weeks at the beginning, then every 3 months.
  • Periodic liver function tests.
  • Monitor for symptoms of methemoglobinemia (dyspnea, cyanosis with normal saturation on pulse oximeter). Ghaoui 2020.
• Important adverse effects of dapsone:
  • Hemolysis (universal to some extent, more severe in G6PD deficiency).
  • Methemoglobinemia.
  • Agranulocytosis (rare, potentially fatal).
  • Peripheral neuropathy, hepatotoxicity, hypersensitivity syndrome (DRESS). Ghaoui 2020.

• Dapsone
  • Absolute contraindications:
    • Significant G6PD deficiency.
    • Severe uncorrected anemia.
    • Severe prior hypersensitivity to sulfones.
    • Severe active liver disease.
  • Relative contraindications:
    • Significant heart or lung disease (risk if methemoglobinemia occurs).
    • Pregnancy: Use is possible with caution and multidisciplinary consensus, considering that DSG is safe and essential. Ghaoui 2020, Caproni 2009. 
• Sulfonamides
  • Caution is advised in late pregnancy, breastfeeding, and in patients with a history of allergy to sulfonamides.

Salmi T, Hervonen K. Current Concepts of Dermatitis Herpetiformis. Acta Derm Venereol. 2020;100(5):adv00056. DOI:10.2340/00015555-3401. PMID:32039457.
Contemporary review that synthesizes epidemiology, pathophysiology (role of TG3), relationship with celiac disease, diagnosis (IFD and serology) and management focused on gluten-free diet and dapsone, highlighting good long-term prognosis with appropriate treatment.
PubMed

Salmi TT, Hervonen K, Kautiainen H, Collin P, Reunala T. Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from Finland. Br J Dermatol. 2011;165(2):354-359. DOI:10.1111/j.1365-2133.2011.10385.x. PMID:21517799.
A prospective population study demonstrating a high prevalence of DH in Finland, with a decrease in incidence in recent decades despite the increase in celiac disease, and providing solid data on age, sex and temporal evolution.
PubMed

Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol. 2003;4(1):13-20. DOI:10.2165/00128071-200304010-00002. PMID:12477369.
This review positions DH as the main cutaneous manifestation of celiac disease, describes the typical clinical presentation, the gut-skin correlation, and proposes a practical diagnostic and therapeutic algorithm for dermatologists.
PubMed

Ingen-Housz-Oro S. Dermatitis herpetiformis: a review. Ann Dermatol Venereol. 2011;138(3):221-227. DOI:10.1016/j.annder.2011.01.005. PMID:21397152.
In-depth review of epidemiology, pathophysiology (TG2/TG3 autoantibodies), clinical presentation and treatment; discusses the risk of lymphomas associated with poor adherence to the DSG and summarizes the association with other autoimmune diseases.
PubMed

Caproni M, Antiga E, Melani L, Fabbri P; Italian Group for Cutaneous Immunopathology. Guidelines for the diagnosis and treatment of dermatitis herpetiformis. J Eur Acad Dermatol Venereol. 2009;23(6):633-638. DOI:10.1111/j.1468-3083.2009.03188.x. PMID:19470076.
Clinical practice guideline that standardizes diagnostic criteria (IgA granular IFD as gold standard), recommends DSG + dapsone as first line and addresses monitoring and therapeutic alternatives.
PubMed

Herrero-González JE. [Clinical guidelines for the diagnosis and treatment of dermatitis herpetiformis]. Actas Dermosifiliogr. 2010;101(10):820-826. PMID:21159258.
Spanish guide that adapts international recommendations to the Spanish-speaking context, emphasizing the need for double biopsies (HE and IFD), celiac serology and DSG along with dapsone and sulfonamides.
PubMed

Nguyen CN, Kim SJ. Dermatitis Herpetiformis: An Update on Diagnosis, Disease Monitoring, and Management. Medicine (Kaunas). 2021;57(8):843. DOI:10.3390/medicina57080843. PMID:34441049.
Recent update reviewing new serological tools (anti-TG3), activity monitoring and treatment strategies, and summarizing therapeutic options beyond dapsone in refractory disease.
PubMed

Rose C, Bröcker EB, Zillikens D. Clinical, histological and immunopathological findings in 32 patients with dermatitis herpetiformis Duhring. J Dtsch Dermatol Ges. 2010;8(4):265-270. DOI:10.1111/j.1610-0387.2009.07292.x. PMID:19878401.
Clinical series detailing clinicopathological and immunopathological (IFD) correlation in DH, highlighting the pattern of neutrophilic microabscesses and IgA granular deposits, and their diagnostic value.
PubMed

Reunala T. Incidence of familial dermatitis herpetiformis. Br J Dermatol. 1996;134(3):394-398. PMID:8731659.
Prospective study demonstrating significant familial aggregation of DH and/or celiac disease in first-degree relatives, supporting a strong genetic basis (HLA-DQ2/DQ8) and dominant mode of inheritance.
PubMed

Smith JB, Tulloch JE, Meyer LJ, Zone JJ. The incidence and prevalence of dermatitis herpetiformis in Utah. Arch Dermatol. 1992;128(12):1608-1610. PMID:1456754.
Epidemiological work that provides incidence and prevalence data in the American population, showing figures comparable to those in Europe and a slight male predominance.
PubMed

Andersson H, Mobacken H. Dietary treatment of dermatitis herpetiformis. Eur J Clin Nutr. 1992;46(5):309-315. PMID:1600929.
Review on DSG in DH: documents normalization of intestinal mucosa and progressive reduction or discontinuation of dapsone in most patients faithful to the diet, with clear immunological improvement.
PubMed

Heading RC, Paterson WD, McClelland DB, Barnetson RS, Murray MS. Clinical response of dermatitis herpetiformis skin lesions to a gluten-free diet. Br J Dermatol. 1976;94(5):509-514. DOI:10.1111/j.1365-2133.1976.tb05138.x. PMID:773406.
Early clinical trial demonstrating clinical improvement of the rash and progressive reduction in the requirement for dapsone after initiating a gluten-free diet.
PubMed

Marks R, Whittle MW. Results of treatment of dermatitis herpetiformis with a gluten-free diet after one year. Br Med J. 1969;4(5686):772-775. DOI:10.1136/bmj.4.5686.772. PMID:5359941.
Classic study showing intestinal histological improvement and skin control in patients with DH treated with DSG for approximately one year, supporting diet as a disease-modifying treatment.
PubMed

Ghaoui N, Hanna E, Abbas O, Kibbi AG, Kurban M. Update on the use of dapsone in dermatology. Int J Dermatol. 2020;59(7):787-795. DOI:10.1111/ijd.14761. PMID:31909480.
Comprehensive review of the pharmacology, indications and adverse effects of dapsone, including its role in DH and detailed recommendations for hematological, hepatic and methemoglobinemia monitoring.
PubMed

Dmochowski M, Gornowicz-Porowska J, Bowszyc-Dmochowska M. An update on direct immunofluorescence for diagnosing dermatitis herpetiformis. Postepy Dermatol Alergol. 2019;36(6):655-658. DOI:10.5114/ada.2019.91415. PMID:31997990.
Focused review on IFD that reinforces the granular IgA pattern in dermal papillae as a key diagnostic criterion, discusses common sampling errors and alternatives when fresh skin is not available.
PubMed

Kasperkiewicz M, Lai O, Kim G, et al. Immunoglobulin and Complement Immunohistochemistry on Paraffin Sections in Autoimmune Bullous Diseases: A Systematic Review and Meta-analysis. Am J Dermatopathol.2021;43(10):689-699. DOI:10.1097/DAD.0000000000001817. PMID:33055534.
Meta-analysis evaluating the performance of IHC for immunoglobulins and complement in paraffin-embedded skin in autoimmune blistering, showing that it may be useful as adjunctive therapy where IFD is not available, including DH.
PubMed

Handa S, Dabas G, De D, et al. A retrospective study of dermatitis herpetiformis from an immunobullous disease clinic in north India. Int J Dermatol. 2018;57(8):959-964. DOI:10.1111/ijd.14029. PMID:29752728.
Indian retrospective series describing clinical, histological and treatment characteristics in a non-Caucasian context, confirming the universal importance of IFD and DSG + dapsone.
PubMed

Bogenrieder T, Stolz W. [From the New World. Louis A. Duhring and dermatitis herpetiformis]. Hautarzt.2003;54(2):167-172. DOI:10.1007/s00105-002-0438-5. PMID:12590314.
Historical article that reviews the figure of Duhring and the original description of the disease, useful to contextualize DH and its classic synonyms.
PubMed