Laboratory Studies

The diagnosis of dermatitis herpetiformis (DH) is made on the basis of skin biopsy results. However, other tests should be performed depending on the presence of symptoms of associated syndromes. Serum markers, such as IgA endomysial antibodies, are negative in as many as 10-37% of patients with dermatitis herpetiformis.^{[37, 38]}Arguments have been made in favor of testing for tissue transglutaminase for diagnosis,^[39]but tissue transglutaminase enzyme-linked immunosorbent assay positivity can occur in many autoimmune diseases because of impurities and cross-reactivity.^[40]

Procedures

The diagnosis is made after observing characteristic findings from skin biopsy specimens. The biopsy sample should be taken from the edge of a lesion for hematoxylin and eosin staining and from normal-appearing perilesional skin for direct immunofluorescence staining.

Results of direct immunofluorescence of lesional skin are often falsely negative. The vigorous immune response degrades the IgA antibody at the site. Therefore, biopsy specimens for the direct immunofluorescence studies should be taken from healthy-appearing skin.

See the image below.

Immunofluorescence showing immunoglobulin A at the dermoepidermal junction (direct immunofluorescence stain).

View Media Gallery

Histologic Findings

Biopsy specimens of lesional skin reveal neutrophils in the dermal papillae, with fibrin deposition, neutrophil fragments, and edema. Eosinophils may be present. Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation. Vesicles form in the lamina lucida, the weakest portion of the dermoepidermal junction, due to neutrophil lysosomal enzymes.^[41]See the image below.

Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation in the lamina lucida, the weakest portion of the dermoepidermal junction (hematoxylin and eosin stain).

View Media Gallery

The histologic differential diagnosis of early skin lesions includes bullous lupus erythematosus, bullous pemphigoid, epidermolysis bullosa acquisita, and linear IgA disease.^[42]The histologic differential diagnosis of late skin lesions includes bullous drug eruption, bullous pemphigoid, erythema multiforme, and herpes gestationis.

Granular IgA deposits in dermal papillae of perilesional skin observed by direct immunofluorescence is the criterion standard of diagnosis. However, the presence of both granular and linear IgA deposits has been reported on direct immunofluorescence testing in a patient with dermatitis herpetiformis.^{[43, 44]}

Inflammation in lesional skin degrades the immunoreactants and is usually negative for the diagnostic granular pattern. Because deposits are found more reliably in the surrounding normal-appearing skin, the standard practice is to obtain biopsy specimens from normal-appearing perilesional skin for direct immunofluorescent staining.

Treatment & Management

Duhring L. Dermatitis herpetiformis. JAMA. 1884. 3:225.
Losurdo G, Principi M, Iannone A, Amoruso A, Ierardi E, Di Leo A, et al. Extra-intestinal manifestations of non-celiac gluten sensitivity: An expanding paradigm. World J Gastroenterol. 2018 Apr 14. 24 (14):1521-1530. [QxMD MEDLINE Link].
Lakoš Jukić I, Jerković Gulin S, Marinović B. Blistering diseases in the mature patient. Clin Dermatol. 2018 Mar - Apr. 36 (2):231-238. [QxMD MEDLINE Link].
Arbache ST, Nogueira TG, Delgado L, Miyamoto D, Aoki V. Immunofluorescence testing in the diagnosis of autoimmune blistering diseases: overview of 10-year experience. An Bras Dermatol. 2014 Nov-Dec. 89 (6):885-9. [QxMD MEDLINE Link].
Plotnikova N, Miller JL. Dermatitis herpetiformis. Skin Therapy Lett. 2013 Mar. 18(3):1-3. [QxMD MEDLINE Link].
Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med. 2002 Mar 18. 195(6):747-57. [QxMD MEDLINE Link].
Hull CM, Liddle M, Hansen N, et al. Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis. Br J Dermatol. 2008 Jul. 159(1):120-4. [QxMD MEDLINE Link].
Marietta EV, Camilleri MJ, Castro LA, Krause PK, Pittelkow MR, Murray JA. Transglutaminase autoantibodies in dermatitis herpetiformis and celiac sprue. J Invest Dermatol. 2008 Feb. 128(2):332-5. [QxMD MEDLINE Link].
Smecuol E, Sugai E, Niveloni S, et al. Permeability, zonulin production, and enteropathy in dermatitis herpetiformis. Clin Gastroenterol Hepatol. 2005 Apr. 3(4):335-41. [QxMD MEDLINE Link].
Cannistraci C, Lesnoni La Parola I, et al. Co-localization of IgA and TG3 on healthy skin of coeliac patients. J Eur Acad Dermatol Venereol. 2007 Apr. 21(4):509-14. [QxMD MEDLINE Link].
Samolitis NJ, Hull CM, Leiferman KM, Zone JJ. Dermatitis herpetiformis and partial IgA deficiency. J Am Acad Dermatol. 2006 May. 54(5 Suppl):S206-9. [QxMD MEDLINE Link].
Hall RP 3rd, Benbenisty KM, Mickle C, Streiien RD. Serum IL-8 in patients with dermatitis herpetiformis is produced in response to dietary gluten. J Invest Dermatol. 2007 Sept. 127(9):2158-67. [QxMD MEDLINE Link].
Antiga E, Quaglino P, Pierini I et al. Regulatory T cells as well as IL-10 are reduced in the skin of patients with dermatitis herpetiformis. J Dermatol Sci. Jan 2015. 77(1):54-62. [QxMD MEDLINE Link].
Hall RP 3rd, Takeuchi F, Benbenisty KM, Streilein RD. Cutaneous endothelial cell activation in normal skin of patients with dermatitis herpetiformis associated with increased serum levels of IL-8, sE-Selectin, and TNF-alpha. J Invest Dermatol. 2006 Jun. 126(6):1331-7. [QxMD MEDLINE Link].
Dahl MV, Falk RJ, Carpenter R, Michael AF. Membrane attack complex of complement in dermatitis herpetiformis. Arch Dermatol. 1985 Jan. 121(1):70-2. [QxMD MEDLINE Link].
Zebrowska A, Wagrowska-Danilewicz M, et al. Expression of selected ADAMs in bullous pemphigoid and dermatitis herpetiformis. Journal of Dermatological Science. 2009. 56:58-73.
Grimwood RE, Guevara A. Leuprolide acetate-induced dermatitis herpetiformis. Cutis. 2005 Jan. 75(1):49-52. [QxMD MEDLINE Link].
Caproni M, Torchia D, Antiga E, et al. The role of apoptosis in the pathogenesis of dermatitis herpetiformis. Int J Immunopathol Pharmacol. 2005 Oct-Dec. 18(4):691-9. [QxMD MEDLINE Link].
Ollague JE, Nousari CH. Expression of Elafin in Dermatitis Herpetiformis. Am J Dermatopathol. 2018 Jan. 40 (1):1-6. [QxMD MEDLINE Link].
Hardman CM, Garioch JJ, Leonard JN, et al. Absence of toxicity of oats in patients with dermatitis herpetiformis. N Engl J Med. 1997 Dec 25. 337(26):1884-7. [QxMD MEDLINE Link].
Garsed K, Scott BB. Can oats be taken in a gluten-free diet? A systematic review. Scand J Gastroenterol. 2007 Feb. 42(2):171-8. [QxMD MEDLINE Link].
Al-Niaimi F,Cox NH,Lewis-Jones S. Dermatitis herpetiformis exacerbated by cornstarch. JAAD. 2010. 62:510-511.
Jiminez A, Hull C, Zone, J. Dermatitis Herpetiformis resistant to dapsone due to dietary iodide. JAAD Case Rep. Aug 2019. 5(8):713-14. [QxMD MEDLINE Link].
Accetta P, Kumar V, Beutner EH, Chorzelski TP, Helm F. Anti-endomysial antibodies. A serologic marker of dermatitis herpetiformis. Arch Dermatol. 1986 Apr. 122(4):459-62. [QxMD MEDLINE Link].
Schulze F, van Beek N, Terheyden P, Zillikens D, Schmidt E. Concomitant Bullous Pemphigoid and Dermatitis Herpetiformis. Dermatology. 2013 Jun 14. [QxMD MEDLINE Link].
Gaspari AA, Huang CM, Davey RJ, Bondy C, Lawley TJ, Katz SI. Prevalence of thyroid abnormalities in patients with dermatitis herpetiformis and in control subjects with HLA-B8/-DR3. Am J Med. 1990 Feb. 88(2):145-50. [QxMD MEDLINE Link].
Helsing P, Froen H. Dermatitis herpetiformis presenting as ataxia in a child. Acta Derm Venereol. 2007. 87(2):163-5. [QxMD MEDLINE Link].
Sigurgeirsson B, Agnarsson BA, Lindelöf B. Risk of lymphoma in patients with dermatitis herpetiformis. BMJ. 1994 Jan 1. 308(6920):13-5. [QxMD MEDLINE Link]. [Full Text].
Hassan S, Dalle S, Descloux E, Balme B, Thomas L. [Dermatitis herpetiformis associated with progesterone contraception]. Ann Dermatol Venereol. 2007 Apr. 134(4 Pt 1):385-6. [QxMD MEDLINE Link].
Bardella MT, Fredella C, Saladino V, et al. Gluten intolerance: gender- and age-related differences in symptoms. Scand J Gastroenterol. 2005 Jan. 40(1):15-9. [QxMD MEDLINE Link].
Templet JT, Welsh JP, Cusack CA. Childhood dermatitis herpetiformis: a case report and review of the literature. Cutis. 2007 Dec. 80(6):473-6. [QxMD MEDLINE Link].
Swerdlow AJ, Whittaker S, Carpenter LM, English JS. Mortality and cancer incidence in patients with dermatitis herpetiformis: a cohort study. Br J Dermatol. 1993 Aug. 129(2):140-4. [QxMD MEDLINE Link].
Lewis NR, Logan RF, Hubbard RB, West J. No increase in risk of fracture, malignancy or mortality in dermatitis herpetiformis: a cohort study. Aliment Pharmacol Ther. 2008 Jun 1. 27(11):1140-7. [QxMD MEDLINE Link].
Viljamaa M, Kaukinen K, Pukkala E, Hervonen K, Reunala T, Collin P. Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: 30-year population-based study. Dig Liver Dis. 2006 Jun. 38(6):374-80. [QxMD MEDLINE Link].
Hervonen K, Vomanen M, Kaitiainen H, Collin P, Reunala T. Lymphoma in patients with dermatitis herpetiformis and their first-degree relatives. Br J Dermatol. 2005 Jan. 152(2):82-6. [QxMD MEDLINE Link].
George DE, Browning JC, Hsu S. Medical pearl: dermatitis herpetiformis--potential for confusion with eczema. J Am Acad Dermatol. 2006 Feb. 54(2):327-8. [QxMD MEDLINE Link].
Alonso-Llamazares J, Gibson LE, Rogers RS 3rd. Clinical, pathologic, and immunopathologic features of dermatitis herpetiformis: review of the Mayo Clinic experience. Int J Dermatol. 2007 Sep. 46(9):910-9. [QxMD MEDLINE Link].
Antiga E, Verdelli A, Calabrò A, Fabbri P, Caproni M. Clinical and immunopathological features of 159 patients with dermatitis herpetiformis: an Italian experience. G Ital Dermatol Venereol. 2013 Apr. 148(2):163-9. [QxMD MEDLINE Link].
Desai AM, Krishnan RS, Hsu S. Medical pearl: Using tissue transglutaminase antibodies to diagnose dermatitis herpetiformis. J Am Acad Dermatol. 2005 Nov. 53(5):867-8. [QxMD MEDLINE Link].
Sardy M, Csikos M, Geisen C, et al. Tissue transglutaminase ELISA positivity in autoimmune disease independent of gluten-sensitive disease. Clin Chim Acta. 2007 Feb. 376(1-2):126-35. [QxMD MEDLINE Link].
Smith JB, Taylor TB, Zone JJ. The site of blister formation in dermatitis herpetiformis is within the lamina lucida. J Am Acad Dermatol. 1992 Aug. 27(2 Pt 1):209-13. [QxMD MEDLINE Link].
Madan V, Jamieson LA, Bhogal BS, Wong CS. Inflammatory epidermolysis bullosa acquisita mimicking toxic epidermal necrolysis and dermatitis herpetiformis. Clin Exp Dermatol. 2009 Jul 29. [QxMD MEDLINE Link].
Van L, Browning JC, Krishnan RS, Kenner-Bell BM, Hsu S. Dermatitis herpetiformis: potential for confusion with linear IgA bullous dermatosis on direct immunofluorescence. Dermatol Online J. 2008 Jan 15. 14(1):21. [QxMD MEDLINE Link]. [Full Text].
Ko CJ, Colegio OR, Moss JE, McNiff JM. Fibrillar IgA deposition in dermatitis herpetiformis-an underreported pattern with potential clinical significance. Journal of cutaneous pathology. 2010. 37:475-477.
Ciacci C, Ciclitira P, Hadjivassiliou M, Kaukinen K, Ludvigsson JF, McGough N, et al. The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis. United European Gastroenterol J. 2015 Apr. 3 (2):121-35. [QxMD MEDLINE Link].
Koskinen O, Villanen M, Korponay-Szabo I, et al. Oats do not induce systemic or mucosal autoantibosy response in children with coeliac disease. Pediartic Gastroentol Nutr. 2009. 48:559-65.
Reunala T, Collin P, Holm K, et al. Tolerance to oats in Dermatitis Herpetiformis. Gut. 1998. 43:490-493.
Thompson, T, Lee AR, Grace T. Gluten Contamination of Grains, Seeds and Flours in the United States: A pilot study. American Diabetic Association. 2010. 110:967-940.
Thompson T, Dennis M, Higgins LA, Lee AR, Sharrett MK. Gluten free diet survey: are Americans with coeliac disease consuming recommended amounts of fiber, iron, calcium and grain foods. J Hum Nutr Diet. 2005. 18:163-9.
Paek SY, Steinberg SM, Katz SI. Remission in dermatitis herpetiformis: a cohort study. Arch Dermatol. 2011 Mar. 147(3):301-5. [QxMD MEDLINE Link].
Bevans SL, Sami N. Dapsone and sulfasalazine combination therapy in dermatitis herpetiformis. Int J Dermatol. 2017 May. 56 (5):e90-e92. [QxMD MEDLINE Link].
Albers LN, Zone JJ, Stoff BK, Feldman RJ. Rituximab Treatment for Recalcitrant Dermatitis Herpetiformis. JAMA Dermatol. 2017 Mar 1. 153 (3):315-318. [QxMD MEDLINE Link].
Sladden MJ, Johnston GA. Complete resolution of dermatitis herpetiformis with the Atkins' diet. Br J Dermatol. 2006 Mar. 154(3):565-6. [QxMD MEDLINE Link].
Smith JB, Fowler JB, Zone JJ. The effect of ibuprofen on serum dapsone levels and disease activity in dermatitis herpetiformis. Arch Dermatol. 1994 Feb. 130(2):257-9. [QxMD MEDLINE Link].
AGA Institute. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology. 2006 Dec. 131 (6):1977-80. [QxMD MEDLINE Link].
Kadunce DP, McMurry MP, Avots-Avotins A, Chandler JP, Meyer LJ, Zone JJ. The effect of an elemental diet with and without gluten on disease activity in dermatitis herpetiformis. J Invest Dermatol. 1991 Aug. 97(2):175-82. [QxMD MEDLINE Link].
Zeedijk N, van der Meer JB, Poen H, van der Putte SC. Dermatitis herpetiformis: consequences of elemental diet. Acta Derm Venereol. 1986. 66(4):316-20. [QxMD MEDLINE Link].
Nguyen KT, Gwinn CC, Vary JC Jr. Rituximab treatment for dermatitis herpetiformis in the setting of type 1 diabetes mellitus, celiac disease, vitiligo, autoimmune hemolytic anemia, and autoimmune thrombocytopenia. JAAD Case Rep. 2020 Feb. 6 (2):122-123. [QxMD MEDLINE Link]. [Full Text].
Silvers DN, Juhlin EA, Berczeller PH, McSorley J. Treatment of dermatitis herpetiformis with colchicine. Arch Dermatol. 1980 Dec. 116 (12):1373-84. [QxMD MEDLINE Link].
Wang Y, Yang B, Zhou G, Zhang F. Two Cases of Dermatitis Herpetiformis Successfully Treated with Tetracycline and Niacinamide. Acta Dermatovenerol Croat. 2018 Oct. 26 (3):273-275. [QxMD MEDLINE Link].
Shah SA, Ormerod AD. Dermatitis herpetiformis effectively treated with heparin, tetracycline and nicotinamide. Clin Exp Dermatol. 2000 May. 25 (3):204-5. [QxMD MEDLINE Link].
Zemtsov A, Neldner KH. Successful treatment of dermatitis herpetiformis with tetracycline and nicotinamide in a patient unable to tolerate dapsone. J Am Acad Dermatol. 1993 Mar. 28 (3):505-6. [QxMD MEDLINE Link].
Lahteenoja H, Irjala K, Viander M, Vainio E, Toivanen A, Syrjanen S. Oral mucosa is frequently affected in patients with dermatitis herpetiformis. Arch Dermatol. 1998 Jun. 134(6):756-8. [QxMD MEDLINE Link].

Media Gallery

Light micrograph shows neutrophils in the dermal papillae, with fibrin deposition, neutrophil fragments, and edema (hematoxylin and eosin stain).
Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation in the lamina lucida, the weakest portion of the dermoepidermal junction (hematoxylin and eosin stain).
Classic vesicles of dermatitis herpetiformis.
Immunofluorescence showing immunoglobulin A at the dermoepidermal junction (direct immunofluorescence stain).
Polymorphic lesions on extensor surface of arm.

of 5

Author

Jami L Miller, MD Associate Professor, Department of Dermatology, Vanderbilt University Medical School; Vice Chair for Education, Director of Phototherapy Unit, Medical Director of Dermatology Clinic at 100 Oaks, Vanderbilt University Medical Center

Jami L Miller, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Shehnaz Aysha K Zaman, MD Resident Physician, Department of Dermatology, Vanderbilt Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Julia R Nunley, MD Professor, Department of Dermatology, Virginia Commonwealth University Medical Center

Julia R Nunley, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Nephrology, International Society of Nephrology, Medical Dermatology Society, Medical Society of Virginia, National Kidney Foundation, Phi Beta Kappa, Women's Dermatologic Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Board of Dermatology<br/>Author for: Up-to-date.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Russell Hall, MD J Lamar Callaway Professor And Chair, Department of Dermatology, Duke University Medical Center, Duke University School of Medicine

Russell Hall, MD is a member of the following medical societies: American Academy of Dermatology, American Federation for Medical Research, American Society for Clinical Investigation, Society for Investigative Dermatology

Disclosure: Received consulting fee from Novan for consulting; Received consulting fee from Stieffel, a GSK company for consulting; Received salary from Society for Investigative Dermatology for board membership.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Kristina Collins, MD, and Hunter Sams, MD, to the development and writing of this article.

Dermatitis Herpetiformis Workup

Laboratory Studies

Procedures

Histologic Findings

References

Tables

Contributor Information and Disclosures

What would you like to print?