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Medical Pearl: Using tissue transglutaminase antibodies to diagnose dermatitis herpetiformis
PEARLS Stuart J. Salasche, MD Surgical Pearls Editor
Mark G. Lebwohl, MD Medical Pearls Editor
Medical Pearl: Using tissue transglutaminase antibodies to diagnose dermatitis herpetiformis Anupam M. Desai, MD, Ravi S. Krishnan, MD, and Sylvia Hsu, MD Houston, Texas
D
ermatitis herpetiformis (DH) is an autoimmune blistering disease characterized by granular IgA deposits in the papillary dermis. DH is known to be associated with celiac disease, and with recent research showing that the two have a similar pathophysiology, it is now considered the cutaneous manifestation of celiac disease.1 DH is also associated with clinical or serologic thyroid abnormalities in about 50% of patients.2 DH typically presents with grouped vesicles or papules on the face (Fig 1) and extensor surfaces of the knees, elbows, and buttocks. However, given the extreme pruritus associated with this condition, it is not uncommon for patients to present with only erosions in these areas secondary to scratching. The standard for diagnosis of DH is direct immunofluorescence (DIF). The characteristic pattern of IgA deposition along the basement membrane with accentuation in the dermal papillae is highly specific for DH.3 Although DIF can usually confirm the diagnosis, there are a number of reported cases of DIF-negative DH. Up to 10% of cases have been found to be DIF negative, yielding a sensitivity of 90%.4-6 Furthermore, DIF requires skin biopsy for examination, exposing the patient to the associated risks and discomforts, and a permanent scar (albeit a small one). A serologic test based on assessing the autoantibodies found in DH would provide a quicker and less invasive alternative. Serum titers of antiendomysial antibodies have been studied in this capacity and have been found to be highly specific (96%) and sensitive (79%) markers for celiac disease.5 However, antiendomysial antibodies have the drawback of being determined by indirect
From the Department of Dermatology, Baylor College of Medicine. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Sylvia Hsu, MD, Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. J Am Acad Dermatol 2005;53:867-8. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.06.014
Fig 1. A 1-mm vesicle in moustache area. Patient is 41year-old Asian woman with 8-year history of intensely pruritic vesicles on face and elbows that would resolve spontaneously. Her medical history included hypothyroidism. She also had frequent problems with bloating. Her tissue transglutaminase (tTG) antibody level was strongly positive at 168 U (negative: \20; weak positive: 20-30; strong positive: [30). Patient was then placed on gluten-free diet. After patient had been on gluten-free diet for 6 months, tTG antibody level became negative (\20 U).
immunofluorescence on sections of monkey esophagus, making this test both time-consuming and subjective. Recently, the specific endomysial antigen has been identified as tissue transglutaminase (tTG).7 Patients with DH have been shown to have circulating anti-tTG IgA antibodies, and most have small bowel villous blunting on biopsy specimen, even if they do not have clinical signs of celiac disease.8,9 tTG antibodies are measured using an enzyme-linked immunosorbent assay (ELISA). This method has higher specificity and sensitivity compared with the endomysial antibodies immunofluorescent-based assay. Several studies have looked at ELISA detection of serum tTG antibodies to diagnose DH. In a study of 40 patients with DH, Caproni et al10 showed detection of serum tTG antibodies to have a specificity of 92.3% and sensitivity of 94.4% for patients with normal diets. Dieterich et al8 report similar results in a study of 61 patients with DH on normal diets. Furthermore, anti-tTG antibodies frequently decrease to normal levels for patients on a gluten-free 867
868 Pearls
J AM ACAD DERMATOL NOVEMBER 2005
diet, rendering this test an effective means of monitoring dietary compliance. The specificity and sensitivity of using tTG antibodies to diagnose DH compares favorably with that of skin biopsy with DIF. Furthermore, ELISA detection of tTG antibodies is quantitative, objective, and minimally invasive. In addition, because patients are likely to traumatize and scratch lesions significantly before presentation, often there are no fresh lesions available for skin biopsy. This may make the interpretation of the histology more difficult for the dermatopathologist. ELISA studies are also significantly more costeffective for the diagnosis of DH than skin biopsy for histopathology and DIF. In our practice, a tTG antibody test costs $117 (Quest Diagnostics, Teterboro, NJ) whereas skin biopsy for histopathology and DIF costs $643 (Dermpath Diagnostics, Cockerell and Associates, Dallas, Tex). This latter number does not include the cost of performing the skin biopsy. AntitTG serology is a practical and reliable first step in the diagnosis of DH. REFERENCES 1. Sa´rdy M, Ka´rpa´ti S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (Tgase 3) is the autoantigen
2.
3.
4.
5.
6.
7.
8.
9.
10.
of dermatitis herpetiformis. J Exp Med 2002;195: 747-57. Cunningham MJ, Zone JJ. Thyroid abnormalities in DH: prevalence of clinical thyroid disease and thyroid abnormalities. Ann Intern Med 1985;102:194-6. Warren SJ, Cockerell CJ. Characterization of a subgroup of patients with dermatitis herpetiformis with nonclassical histologic features. Am J Dermatopathol 2002;24:305-8. Beutner EH, Baughman RD, Austin BM, Plunkett RW, Binder WL. A case of dermatitis herpetiformis with IgA endomysial antibodies but negative direct immunofluorescence findings. J Am Acad Dermatol 2000;43:329-32. Peters MS, McEvoy MT. IgA antiendomysial antibodies in dermatitis herpetiformis. J Am Acad Dermatol 1989;21: 1225-31. Sousa L, Bajanca R, Cabral J, Fiadeiro T. Dermatitis herpetiformis: should direct immunofluorescence be the only diagnostic criterion? Pediatr Dermatol 2002;19:336-9. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3:797-801. Dieterich W, Laag E, Bruckner-Tuderman L, Reunala T, Karpati S, Zagoni T, et al. Antibodies to tissue transglutaminase as serologic markers in patients with dermatitis herpetiformis. J Invest Dermatol 1999;113:133-6. Gawkrodger DJ, Blackwell JN, Gilmour HM, Rifkind EA, Heading RC, Barnetson RS. Dermatitis herpetiformis: diagnosis, diet and demography. Gut 1984;25:151-7. Caproni M, Cardinali C, Renzi D, Calabro A, Fabbri P. Tissue transglutaminase antibody assessment in dermatitis herpetiformis. Br J Dermatol 2001;144:196-7.
Medical Pearl: Interpretation of tuberculin skin tests in patients who have received the BCG vaccine Anupam M. Desai, MD, and Sylvia Hsu, MD Houston, Texas
T
he introduction of biologic agents, such as tumor necrosis factor (TNF)-a inhibitors, has provided a valuable treatment option for patients with psoriasis and other autoimmune rheumatic conditions. However, the immunosuppression caused by these agents puts them at risk for side effects, such as reactivation of latent tuberculosis.1
From the Department of Dermatology, Baylor College of Medicine. Funding sources: None. Conflicts of interest: None. Reprint requests: Sylvia Hsu, MD, Professor of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. J Am Acad Dermatol 2005;53:868-9. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.05.034
Tuberculin skin tests are routinely placed before treatment to reduce this risk. There is often confusion among physicians as to how to interpret this test, particularly in patients who have received the BCG vaccine. The tuberculin skin test should be placed by using 5 tuberculin U (0.1 mL) of purified protein derivative injected intradermally (not subcutaneously), usually on the volar aspect of the forearm. The test should be read in 48 to 72 hours, and the diameter of induration (not erythema) should be recorded in millimeters.2 The degree of induration interpreted as a positive skin test depends on the risk factors for a given patient. For HIV-positive patients, close contacts of someone with active tuberculosis, patients with
Mark G. Lebwohl, MD Medical Pearls Editor
Medical Pearl: Using tissue transglutaminase antibodies to diagnose dermatitis herpetiformis Anupam M. Desai, MD, Ravi S. Krishnan, MD, and Sylvia Hsu, MD Houston, Texas
D
ermatitis herpetiformis (DH) is an autoimmune blistering disease characterized by granular IgA deposits in the papillary dermis. DH is known to be associated with celiac disease, and with recent research showing that the two have a similar pathophysiology, it is now considered the cutaneous manifestation of celiac disease.1 DH is also associated with clinical or serologic thyroid abnormalities in about 50% of patients.2 DH typically presents with grouped vesicles or papules on the face (Fig 1) and extensor surfaces of the knees, elbows, and buttocks. However, given the extreme pruritus associated with this condition, it is not uncommon for patients to present with only erosions in these areas secondary to scratching. The standard for diagnosis of DH is direct immunofluorescence (DIF). The characteristic pattern of IgA deposition along the basement membrane with accentuation in the dermal papillae is highly specific for DH.3 Although DIF can usually confirm the diagnosis, there are a number of reported cases of DIF-negative DH. Up to 10% of cases have been found to be DIF negative, yielding a sensitivity of 90%.4-6 Furthermore, DIF requires skin biopsy for examination, exposing the patient to the associated risks and discomforts, and a permanent scar (albeit a small one). A serologic test based on assessing the autoantibodies found in DH would provide a quicker and less invasive alternative. Serum titers of antiendomysial antibodies have been studied in this capacity and have been found to be highly specific (96%) and sensitive (79%) markers for celiac disease.5 However, antiendomysial antibodies have the drawback of being determined by indirect
From the Department of Dermatology, Baylor College of Medicine. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Sylvia Hsu, MD, Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. J Am Acad Dermatol 2005;53:867-8. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.06.014
Fig 1. A 1-mm vesicle in moustache area. Patient is 41year-old Asian woman with 8-year history of intensely pruritic vesicles on face and elbows that would resolve spontaneously. Her medical history included hypothyroidism. She also had frequent problems with bloating. Her tissue transglutaminase (tTG) antibody level was strongly positive at 168 U (negative: \20; weak positive: 20-30; strong positive: [30). Patient was then placed on gluten-free diet. After patient had been on gluten-free diet for 6 months, tTG antibody level became negative (\20 U).
immunofluorescence on sections of monkey esophagus, making this test both time-consuming and subjective. Recently, the specific endomysial antigen has been identified as tissue transglutaminase (tTG).7 Patients with DH have been shown to have circulating anti-tTG IgA antibodies, and most have small bowel villous blunting on biopsy specimen, even if they do not have clinical signs of celiac disease.8,9 tTG antibodies are measured using an enzyme-linked immunosorbent assay (ELISA). This method has higher specificity and sensitivity compared with the endomysial antibodies immunofluorescent-based assay. Several studies have looked at ELISA detection of serum tTG antibodies to diagnose DH. In a study of 40 patients with DH, Caproni et al10 showed detection of serum tTG antibodies to have a specificity of 92.3% and sensitivity of 94.4% for patients with normal diets. Dieterich et al8 report similar results in a study of 61 patients with DH on normal diets. Furthermore, anti-tTG antibodies frequently decrease to normal levels for patients on a gluten-free 867
868 Pearls
J AM ACAD DERMATOL NOVEMBER 2005
diet, rendering this test an effective means of monitoring dietary compliance. The specificity and sensitivity of using tTG antibodies to diagnose DH compares favorably with that of skin biopsy with DIF. Furthermore, ELISA detection of tTG antibodies is quantitative, objective, and minimally invasive. In addition, because patients are likely to traumatize and scratch lesions significantly before presentation, often there are no fresh lesions available for skin biopsy. This may make the interpretation of the histology more difficult for the dermatopathologist. ELISA studies are also significantly more costeffective for the diagnosis of DH than skin biopsy for histopathology and DIF. In our practice, a tTG antibody test costs $117 (Quest Diagnostics, Teterboro, NJ) whereas skin biopsy for histopathology and DIF costs $643 (Dermpath Diagnostics, Cockerell and Associates, Dallas, Tex). This latter number does not include the cost of performing the skin biopsy. AntitTG serology is a practical and reliable first step in the diagnosis of DH. REFERENCES 1. Sa´rdy M, Ka´rpa´ti S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (Tgase 3) is the autoantigen
2.
3.
4.
5.
6.
7.
8.
9.
10.
of dermatitis herpetiformis. J Exp Med 2002;195: 747-57. Cunningham MJ, Zone JJ. Thyroid abnormalities in DH: prevalence of clinical thyroid disease and thyroid abnormalities. Ann Intern Med 1985;102:194-6. Warren SJ, Cockerell CJ. Characterization of a subgroup of patients with dermatitis herpetiformis with nonclassical histologic features. Am J Dermatopathol 2002;24:305-8. Beutner EH, Baughman RD, Austin BM, Plunkett RW, Binder WL. A case of dermatitis herpetiformis with IgA endomysial antibodies but negative direct immunofluorescence findings. J Am Acad Dermatol 2000;43:329-32. Peters MS, McEvoy MT. IgA antiendomysial antibodies in dermatitis herpetiformis. J Am Acad Dermatol 1989;21: 1225-31. Sousa L, Bajanca R, Cabral J, Fiadeiro T. Dermatitis herpetiformis: should direct immunofluorescence be the only diagnostic criterion? Pediatr Dermatol 2002;19:336-9. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3:797-801. Dieterich W, Laag E, Bruckner-Tuderman L, Reunala T, Karpati S, Zagoni T, et al. Antibodies to tissue transglutaminase as serologic markers in patients with dermatitis herpetiformis. J Invest Dermatol 1999;113:133-6. Gawkrodger DJ, Blackwell JN, Gilmour HM, Rifkind EA, Heading RC, Barnetson RS. Dermatitis herpetiformis: diagnosis, diet and demography. Gut 1984;25:151-7. Caproni M, Cardinali C, Renzi D, Calabro A, Fabbri P. Tissue transglutaminase antibody assessment in dermatitis herpetiformis. Br J Dermatol 2001;144:196-7.
Medical Pearl: Interpretation of tuberculin skin tests in patients who have received the BCG vaccine Anupam M. Desai, MD, and Sylvia Hsu, MD Houston, Texas
T
he introduction of biologic agents, such as tumor necrosis factor (TNF)-a inhibitors, has provided a valuable treatment option for patients with psoriasis and other autoimmune rheumatic conditions. However, the immunosuppression caused by these agents puts them at risk for side effects, such as reactivation of latent tuberculosis.1
From the Department of Dermatology, Baylor College of Medicine. Funding sources: None. Conflicts of interest: None. Reprint requests: Sylvia Hsu, MD, Professor of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. J Am Acad Dermatol 2005;53:868-9. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.05.034
Tuberculin skin tests are routinely placed before treatment to reduce this risk. There is often confusion among physicians as to how to interpret this test, particularly in patients who have received the BCG vaccine. The tuberculin skin test should be placed by using 5 tuberculin U (0.1 mL) of purified protein derivative injected intradermally (not subcutaneously), usually on the volar aspect of the forearm. The test should be read in 48 to 72 hours, and the diameter of induration (not erythema) should be recorded in millimeters.2 The degree of induration interpreted as a positive skin test depends on the risk factors for a given patient. For HIV-positive patients, close contacts of someone with active tuberculosis, patients with