Dermatitis Herpetiformis  

Dermatitis Herpetiformis – Introduction

• Dermatitis herpetiformis (DH) is an autoimmune blistering disease that is a cutaneous manifestation of celiac disease (CD).
• It is associated with gluten-sensitive enteropathy in nearly all cases, although only 20% of patients have gastrointestinal symptoms. ¹ 
• 15% to 25% of patients with CD will have DH. ²

Synonyms

Duhring disease

ICD-10CM CODE
L13.0	Dermatitis herpetiformis

Epidemiology & Demographics

Prevalence (In U.S.)

11 cases per 100,000 persons per yr ³ ; prevalence for CD is one in 133 adults

Predominant Gender

Male predominance (2:1) ³ ; however, female predominance in children ⁴

Predominant Age

Fourth decade of life, but can occur at any age ³

Predominant Race

Most common in Caucasians of northern European ancestry ³

Genetics

• Both CD and DH have a strong genetic component. 10% to 15% of patients with DH have a first-degree relative with either DH or CD. ⁵ 
• Specific HLA genes (involved in processing gliadin antigen in genetically susceptible individuals) have also been shown to predispose to developing DH (HLA-DQ2 in 90%, DQ8 in the remaining 10% ⁶ ).
• However, less than 50% of genetic predisposition is attributed to HLA genes.
• Autoimmune disorders associated with dermatitis herpetiformis are summarized in Table E1.

TABLE E1

Autoimmune Disorders Associated With Dermatitis Herpetiformis

From Bolognia J: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

Common
•Autoimmune thyroid disease (Hashimoto thyroiditis)•Insulin-dependent diabetes mellitus
Uncommon
•Pernicious anemia
Rare
•Addison disease•Autoimmune chronic active hepatitis•Alopecia areata•Myasthenia gravis•Sarcoidosis	•Systemic sclerosis (scleroderma)•Sjögren syndrome•Systemic lupus erythematosus•Vitiligo

Physical Findings & Clinical Presentation

• •Classically, the lesions of DH are small, grouped, “herpetiform” vesicles that are distributed symmetrically on extensor surfaces (elbows, knees, scalp, back, and buttocks). However, due to intense pruritus and scratching, pinpoint erosions and excoriations in the above distribution are often the most prominent findings on examination, with intact vesicles rarely seen.
• Spontaneous improvement with cyclic exacerbations is common.
• •Celiac-type enamel defects to permanent teeth, oral vesicles, or palmoplantar purpura have been reported as potential associated findings. ³
• Pathogenesis
• CD and DH are both autoimmune, mediated by immunoglobulin A (IgA) class autoantibodies. Dietary gluten is central to the pathogenesis in both. In genetically predisposed individuals, it is hypothesized that the gluten by-product, gliadin, complexes with tissue transglutaminase (tTG) in the gut, binding as an antigen to HLA-DQ2 on T cells, creating an immune response that results in anti-tTG IgA antibodies (i.e., antiendomysial antibodies) in the blood. ⁷ tTG cross-reacts with epidermal TG (eTG). The blood of CD patients with and without skin disease is found to have both skin and gut anti-TG IgA antibodies. ⁸ Yet, it is thought that the high-affinity IgA against eTG form complexes that are responsible for DH. ⁸ The deposition of IgA-eTG complexes in the papillary dermis triggers an immunologic cascade resulting in neutrophil recruitment and complement activation. ⁸
• Diagnosis
• Physical examination and routine histopathology are often suggestive of DH; however, direct immunofluorescence (DIF) of a perilesional skin biopsy has pathognomonic findings ⁹ and is the gold standard for diagnosis. 
• Differential Diagnosis
• •Clinically and histologically, the differential diagnosis includes ¹⁰ :
  • 1.Linear IgA dermatosis
  • 2.Bullous pemphigoid
  • 3.Bullous lupus
• These diagnoses can be differentiated by DIF on perilesional skin biopsy.
• •Other clinical diagnoses to consider ⁸⁹¹⁰ :
  • 1.Scabies (check for interdigital burrows and involvement of genitalia)
  • 2.Arthropod bite (urticarial papules, often in groups of three, over-exposed areas)
  • 3.Eczematous dermatitis (ill-defined, erythematous and xerotic plaques or deep seeded vesicles on hands)
  • 4.Herpes simplex or zoster infection (painful, not symmetric)
  • 5.Generalized pruritus (no blister history, not limited to extensor surfaces)
• Workup and Laboratory Tests
• •Evaluation for gastrointestinal symptoms, family history of DH or CD, and pruritus should be sought in patients with suspected DH.
• •Lesional skin biopsy: Will demonstrate a neutrophil-rich subepidermal bulla ¹⁰ and rule out many conditions.
• •DIF of normal-appearing perilesional skin biopsy: Will demonstrate pathognomonic IgA deposits localized to the dermal papillae and dermal-epidermal junction in a granular pattern. ¹⁰
• •Serology (enzyme-linked immunosorbent assay [ELISA]) for IgA tTG, ELISA for IgA eTG, if available, and indirect immunofluorescence for IgA endomysial antibodies (total IgA) can be used to aid in the diagnosis of DH in cases where the DIF is negative or equivocal, or for monitoring disease activity response to treatment. ⁹ Although these circulating antibodies in the blood exist, there is a high false-negative rate for anti-tTG and for antiendomysial antibodies (one third of DH patients are negative for antiendomysial antibodies ¹¹ ), and their absence does not exclude the diagnosis. Also, IgA-deficient DH patients may also have negative serologic results. ⁹ Those with the presence of circulating antibodies will have a reduction in levels in response to treatment adherence. ⁹
• Treatment
• A gluten-free diet (GFD) and dapsone are considered first-line therapy and are often started in conjunction. ⁹
• •GFD improves symptoms of both GI and skin disease, with GI responding quicker (skin responds after 2 mo). ⁹ A retrospective study showed remission (2 yr without symptoms) in 12%. ¹²
• •Dapsone results in improvement of skin manifestations within days but does not treat GI manifestations. ^9 , 13 Dapsone is typically tapered over time, while lifelong gluten avoidance is often necessary. ⁹
• •One study demonstrated GFD alone was comparable to GFD plus dapsone in the treatment of DH; hence GFD is an essential component in the treatment of DH.
• Nonpharmacologic Therapy
• •First line: GFD:
  • 1.Avoid barley, rye, wheat (can consume rice, corn, and oats).
  • 2.Consultation with a dietitian is recommended.
  • 3.Most patients need to follow diet indefinitely; however, cases of spontaneous remission have been reported. ¹⁴
• •Second line: Elemental diet (controversial):
  • 1.Can consider elemental diet (avoidance of whole proteins) in those patients who do not adequately respond to a strict GFD ⁸ ; however, data are limited.
• Acute General Rx
• •First line: Dapsone:
  • 1.Initial dose 25 to 50 mg PO daily with gradual increase to an average maintenance dose of 0.5 to 1 mg/kg daily (often maintenance dose of 100 mg daily). ^9 , 13
  • 2.Clinical monitoring weekly is recommended to optimize dose (optimal dose is when one to two new lesions/wk). ^9 , 13
  • 3.Caution: Dapsone may produce hemolysis (especially if G6PD deficiency), agranulocytosis, methemoglobinemia, systemic drug hypersensitivity reaction (DRESS), and long-term, a peripheral neuropathy.
  • 4.Baseline labs: CBC, liver function tests (LFTs), G6PD levels. After the initiation of therapy, monitor CBC every wk ×1 mo, then every other wk ×2 mo, monthly ×3 mo, then every 3 to 4 mo. Monitor LFTs every 3 to 4 mo.
• •Second-line alternatives:
  • 1.Sulfapyridine (500 to 1500 mg/day, compounded medication) or sulfasalazine (500 to 1000 mg bid) may be substituted in cases of dapsone intolerance or in the rare case that neuropathy develops. ⁹ Sulfapyridine must be compounded.
  • 2.Case reports of efficacy using topical dapsone 5% twice daily in patients who do not tolerate oral dapsone; also reported to be efficacious as an adjuvant to oral dapsone. ¹⁵
  • 3.Uncontrolled studies and case reports have suggested efficacy with tetracyclines, nicotinamide, cyclosporine, colchicine, and heparin. ^9 , 16
  • 4.Case reports have documented the use of Janus kinase (JAK) inhibitors in clearing DH lesions in those unable to tolerate oral dapsone. ¹⁷
• •Symptomatic relief for pruritus:
  • 1.Potent and superpotent topical corticosteroids (atrophy with prolonged use, limit to 14 days per mo), nonsedating antihistamines twice daily, sedating antihistamines at bedtime, mentholated lotion. ⁹
• Chronic Rx
• •As DH is considered to represent the cutaneous manifestations of CD, lifelong avoidance of gluten is typically recommended. Information about educational resources, such as national and local support groups, should be provided ( http://www.celiac.org/ ).
• •Patients with DH and CD have an increased risk of developing Hashimoto thyroiditis (50% with thyroid disease), non-Hodgkin lymphoma, and GI lymphomas. ³ An increased incidence of other autoimmune disorders (type 1 diabetes mellitus, pernicious anemia, Addison disease, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome) and osteoporosis have also been reported. ^3, 8, 18.
  • 1.Screening for thyroid disease (thyroid stimulating hormone [TSH], antithyroid peroxidase antibody titers) is typically recommended. ³
  • 2.Screening for autoimmune connective tissue diseases should be considered if there are suspicious signs or symptoms. ³
  • 3.Routine screening for GI lymphomas is controversial. ¹⁹
• Referral
• •Dermatologist for skin biopsy and management of cutaneous disease
• •Gastroenterologist for evaluation of CD
• •Nutritionist to educate patients about gluten-free diet
• •National support groups ( http://www.celiac.org/ ) and local support groups
• Pearls & Considerations
• •Classic areas involved are those that are exposed if in a “fetal position.”
• •Lesions may be worsened by iodides and certain NSAIDs; systemic steroids ineffective. ^9 , 19
• •Location of biopsies is IMPORTANT: False-negative DIF can result if biopsies are taken from lesional skin (should be taken from normal-appearing skin adjacent to lesion) as diagnostic IgA deposits are usually destroyed by the blistering process.
• •GFD results in reduced IgA in skin on DIF (with eventual disappearance) and reduced antiendomysial antibodies in the blood. Hence, serologies (e.g., antiendomysial antibodies) can be used to monitor degree of compliance to dietary gluten restriction.
• •Some studies have suggested a possible protective effect of GFD against intestinal lymphoma. ⁹ First-degree relatives do not appear to be at increased risk for GI or systemic lymphomas in the absence of DH or CD. ³
• References
• 1.Holtmeier W., et al.: Distinct TCR d repertoires are present in the cutaneous lesions and inflamed duodenum of patients with dermatitis herpetiformis . Exp Dermatol 2002; 11 (6): pp. 527-531.
• 2.Koop I., et al.: Detection of autoantibodies against tissue transglutaminase in patients with celiac disease and dermatitis herpetiformis, Am . J Gastroenterol 2000; 95 (8): pp. 2009-2014.
• 3.Bolotin D., Petronic-Rosic V.: Dermatitis herpetiformis: part I. Epidemiology, pathogenesis, and clinical presentation . J Am Acad Dermatol 2011; 64 (6): pp. 1017-1024.
• 4.Wong CL, Lara-Corrales I: Childhood dermatitis herpetiformis. In Harper’s textbook of pediatric dermatology; Hoboken, 2019, Wiley-Blackwell, pp 898-906.
• 5.Hervonen K., et al.: First-degree relatives are frequently affected in coeliac disease and dermatitis herpetiformis . Scand J Gastroenterol 2002; 37 (1): pp. 51-55.
• 6.Spurkland A., et al.: Dermatitis herpetiformis and celiac disease are both primarily associated with the HLA-DQ (a1∗ 0501,(ß1∗ 02) or the HLA-DQ (a1∗ 03,(ß1∗ 0302) heterodimers . Tissue Antigens 1997; 49 (1): pp. 29-34.
• 7.Di Sabatino A., et al.: The function of tissue transglutaminase in celiac disease . Autoimmun Rev 2012; 11 (10): pp. 746-753.
• 8.Stoj V., Lu J.: Nutrition and bullous diseases . Clin Dermatol 2021;
• 9.Bolotin D., Petronic-Rosic V.: Dermatitis herpetiformis: part II. Diagnosis, management, and prognosis . J Am Acad Dermatol 2011; 64 (6): pp. 1027-1033.
• 10.Caproni M., et al.: Guidelines for the diagnosis and treatment of dermatitis herpetiformis . J Eur Acad Dermatol Venereol 2009; 23 (6): pp. 633-638.
• 11.Alonso-Llamazares J., et al.: Clinical, pathologic, and immunopathologic features of dermatitis herpetiformis: review of the Mayo Clinic experience . Int J Dermatol 2007; 46 (9): pp. 910-919.
• 12.Paek S.Y., et al.: Remission in dermatitis herpetiformis: a cohort study . Arch Dermatol 2011; 147 (3): pp. 301-305.
• 13.Cardones A.R.G., Hall R.P.: Management of dermatitis herpetiformis . Dermatol Clin 2011; 29 (4): pp. 631-635.
• 14.Mobacken H., et al.: Spontaneous remission of dermatitis herpetiformis: dietary and gastrointestinal studies . Acta Derm Venereol 1986; 66 (3): pp. 245-250.
• 15.Burbidge T., Haber R.M.: Topical dapsone 5% gel as an effective therapy in dermatitis herpetiformis . J Cutan Med Surg 2016; 20 (6): pp. 600-601.
• 16.Wang Y et al: Two cases of dermatitis herpetiformis successfully treated with tetracycline and niacinamide, Acta Dermatovenerol Croat 26(3):273-273, 2018.
• 17.Kalantari Y., et al.: A literature review on Janus kinase (JAK) inhibitors for the treatment of immunobullous disorders . Int Immunopharmacol 2022; 110: pp. 108923.
• 18.Kárpáti S., et al.: Dermatitis herpetiformis . Clin Dermatol 2012; 30 (1): pp. 56-59.
• 19.Görög A., et al.: S2k guidelines (consensus statement) for diagnosis and therapy of dermatitis herpetiformis initiated by the European Academy of Dermatology and Venereology (EADV) . J Eur Acad Dermatol Venereol 2021; 35 (6): pp. 1251-1277.
• Suggested Readings
• Bolotin D., Rosic V.: Dermatitis herpetiformis part I: epidemiology, pathogenesis, and clinical presentation . J Am Acad Dermatol 2011; 64 (6): pp. 1017-1024.
• Bolotin D., Rosic V.: Dermatitis herpetiformis part II: diagnosis, management, and prognosis . J Am Acad Dermatol 2011; 64 (6): pp. 1027-1033.
• Burbidge T., Haber R.M.: Topical dapsone 5% gel as an effective therapy in dermatitis herpetiformis . J Cutan Med Surg 2016; 20: pp. 600-601.
• Cardones A.R., Hall R.P.: Management of dermatitis herpetiformis . Dermatol Clin 2011; 29: pp. 631-636.
• Paek S.Y., et al.: Remission in dermatitis herpetiformis: a cohort study . Arch Dermatol 2011; 147 (3): pp. 301-305.
• Salmi T.T., et al.: Dermatitis herpetiformis . Clin Exp Dermatol 2019; 44 (7): pp. 728-731.