There have been several landmarks in our understanding

Transcription

1 GASTROENTEROLOGY 2005;128:S87 S91 Skin Manifestations of Celiac Disease JOHN J. ZONE Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah There have been several landmarks in our understanding of dermatitis herpetiformis. It was described and named in 1884 by Dr Louis Duhring, a dermatologist at the University of Pennsylvania. 1 It was the first skin disease described by an American dermatologist. Dr Janet Marks and coworkers are credited with first describing, in 1966, the association of dermatitis herpetiformis and enteropathy. 2 J. B. van der Meer in Holland described the presence of granular immunoglobulin (Ig) A in dermal papillary tips of skin from patients with dermatitis herpetiformis. 3 Granular IgA deposited in dermal papillary tips is now recognized as the hallmark of this disorder. Dr Lionel Fry and coworkers in England as well as Dr Timo Reunala and coworkers in Finland have undertaken multiple investigations of this disorder over the past 30 years. Their work has included definitive information on the presence of the associated gluten-sensitive enteropathy as well as definition of the prevalence and inheritance of this disorder Drs Mobacken and Kastrup and coworkers in Sweden have reported similar results in the Swedish population. In the United States, Dr Steven Katz, working at the National Institutes of Health, has had a long-term interest in dermatitis herpetiformis and is responsible for much of the interest in dermatitis herpetiformis in the United States in the late 1970s and early 1980s. 14 Dr Russell Hall has led a continuing program and study over the past 20 years at Duke University. 15 Dr V. Kumar at the University of Buffalo is credited with the discovery of the endomysial antibody in patients with dermatitis herpetiformis. 16,17 At the University of Utah, we have been working on studies of dermatitis herpetiformis since the late 1970s and have now evaluated more than 800 patients. 18 The information presented at the National Institutes of Health Consensus Conference is the synthesis of the work of many of the abovenoted investigators from both Europe and the United States. Questions The questions posed by the Consensus Conference on Celiac Disease as a whole are answered individually relative to patients with dermatitis herpetiformis. For this purpose, it is best to understand that dermatitis herpetiformis is a cutaneous manifestation of celiac disease that is best diagnosed by identifying granular IgA in dermal papillae. All patients with dermatitis herpetiformis have some degree of celiac disease, and these patients are very likely to reflect the entire spectrum of histologic and clinical celiac disease in adults. How Is Dermatitis Herpetiformis Diagnosed? Patients with dermatitis herpetiformis demonstrate intensely pruritic papulovesicles and excoriations on the elbows, knees, buttocks, and scalp. It is extremely rare to have cases without characteristic involvement of one of these areas. However, occasional cases of dermatitis herpetiformis have been reported involving the palms and other unusual locations. Although dermatitis herpetiformis is considered a blistering disease of the skin, blisters are frequently not present on initial clinical presentation. Because of the intense pruritus, the small grouped papulovesicles are rapidly scratched, leaving only excoriated papules clinically. Vesicles and bullae are seen when patients who have had the condition suppressed by dapsone discontinue therapy abruptly. The histopathologic hallmark of dermatitis herpetiformis is the presence of neutrophils in dermal papillae with eventual vesiculation. Although granules of IgA that are believed to be pathogenic are located in the dermal papillae, the vesicle formed at the basement membrane occurs in the lamina lucida of the trilaminar basement membrane. 19 This is believed to be the result of the degradation of the lamina lucida by neutrophil lysosomal enzymes. The presence of granular IgA in dermal papillary tips in perilesional skin is a sine qua non for the diagnosis of dermatitis herpetiformis. This is such a constant finding in patients with this disorder that its consistent absence (occurring in 1.0% of cases) results in these cases being reported in the medical literature. The rule is certainly that granular IgA must be present for a definitive diagnosis by the American Gastroenterological Association /05/$30.00 doi: /j.gastro

2 S88 JOHN J. ZONE GASTROENTEROLOGY Vol. 128, No. 4 False negatives may occur if a biopsy is performed on involved skin or if the immunopathologist is not experienced with the techniques and interpretation of direct immunofluorescence. We and others have studied the proper biopsy site for specimens to be evaluated by direct immunofluorescence. 20 Erythematous skin, which is inflamed, may yield a negative direct immunofluorescence and did produce a negative direct immunofluorescence in 3 of the 19 patients we studied. This is believed to be secondary to the destruction of immunoreactants by the intense inflammatory process in inflamed skin. When a biopsy is performed on perilesional skin (clinically normal-appearing skin immediately adjacent to an area of inflammation), the results of the biopsy are virtually always positive in patients with dermatitis herpetiformis. When a biopsy is performed on uninvolved skin (2 6 cm distant from a lesion), there is generally less intense deposition of IgA and occasional biopsy results may be negative. As one proceeds to very distant sites (never involved skin), biopsy results are negative in the majority of cases. Granular IgA may also be seen at the basement membrane in Henoch-Schönlein purpura and lupus erythematosus. These disorders are easily differentiated clinically and histopathologically. Who Should Be Tested for Dermatitis Dermatitis herpetiformis is a relatively rare cause of pruritic skin eruptions. Consequently, patients who should be tested by direct immunofluorescence are those with characteristic findings of involvement of the forearms, knees, buttocks, and scalp with intense pruritus. In addition, patients who have an unexplained pruritic eruption that is persistent may also benefit from direct immunofluorescent testing. Lastly, patients with known symptoms of celiac disease who also have dermatitis warrant testing for dermatitis herpetiformis, because treatment of their condition with dapsone is likely to produce significant rapid improvement in their symptoms. What Is the Prevalence of Dermatitis The prevalence of dermatitis herpetiformis has been reported to be as low as 1.2 per 100,000 population in a postal survey in Great Britain in and as high as 39.2 per 100,000 population in central Sweden in Only one study has been performed in the United States of the prevalence of dermatitis herpetiformis, and this was reported in 1992 from the University of Utah. At that time, we established the prevalence in Utah to be 11.2 per 100,000 population. This is approximately the median range for incidence of the reports from northern Europe. 23 It should be recognized that the Utah population is predominantly white and of northern European descent. This is of significance to the understanding of the prevalence of dermatitis herpetiformis, because this disorder is much less common in black and Asian populations. It would therefore be expected that the prevalence of dermatitis herpetiformis in parts of the United States with higher black and Asian populations would be lower. Celiac disease and dermatitis herpetiformis are known to be genetic diseases. Utah has a predominant Mormon population, and one might question whether intermarriage influences the incidence and prevalence of these diseases in Utah. It must be understood, however, that the Mormon population does not have a higher rate of intermarriage than any other population in the United States. Consequently, it is our strong belief that the prevalence of dermatitis herpetiformis in Utah reflects the true prevalence in a northern European population and is not a reflection of genetic selection. We reported the incidence of dermatitis herpetiformis in Utah to be 0.98 per 100,000 population. 23 The direct immunofluorescence testing laboratory at the University of Utah is responsible for 95% of the diagnoses of dermatitis herpetiformis in Utah, and this prevalence of 1 per 100,000 population per year has continued in our laboratory since Because the HLA locus is extremely important in the pathogenesis of celiac disease, it is worthwhile reviewing HLA in dermatitis herpetiformis. The prevalence of HLA-DQ2 and -DQ8 is the same as in celiac disease, supporting the concept that dermatitis herpetiformis is a manifestation of celiac disease. Approximately 90% of patients with dermatitis herpetiformis express HLA- DQ2, which is found in 20% of controls. Non HLA- DQ2 patients usually express HLA-DQ8. Patients without these 2 predisposing HLA types are extremely rare. 24 Dermatitis herpetiformis, like celiac disease, is familial. Approximately 10% 15% of first-degree relatives of patients with dermatitis herpetiformis have celiac disease or dermatitis herpetiformis. The familial nature of dermatitis herpetiformis has been established in both the population in Utah and the population reported in Finland. 13,25 However, dermatitis herpetiformis does not segregate separately in celiac disease affected families but is interspersed with celiac disease throughout the kindreds. The mean age of onset of symptoms of dermatitis herpetiformis is 40.1 years for men and 36.2 years for women in our Utah population. Dermatitis herpetiformis has a later age of onset than celiac disease. There is

3 April Supplement 2005 SKIN MANIFESTATIONS OF CELIAC DISEASE S89 not an early childhood increase in incidence of dermatitis herpetiformis as there is in celiac disease. Also, there is a male/female predominance of 1.4:1 in dermatitis herpetiformis. This male/female ratio is reversed in celiac disease. What Are the Manifestations and Longterm Consequences of Dermatitis Virtually all patients with dermatitis herpetiformis have an associated enteropathy. This enteropathy ranges from no atrophy of the villi of the proximal small intestine with increased intraepithelial lymphocytes to blunted villi and in 20% of cases complete flattening of the villi. 5,8,12,26,27 As such, it is likely that the spectrum of intestinal abnormality in dermatitis herpetiformis reflects the true spectrum of histologic intestinal abnormality in celiac disease. The skin disease and the intestinal abnormality respond in weeks to months to gluten restriction. Both the skin disease and the intestinal disease recur with reinstitution of diet containing gluten. This strongly supports the belief that dermatitis herpetiformis is an intestinal manifestation of celiac disease. The severity of the skin disease and responsiveness to gluten restriction do not correlate with the severity of the intestinal inflammation. 27 The skin disease instead seems to be arbitrarily superimposed on all degrees of severity of histologic celiac disease in adults. In the University of Utah Clinical Research Center, we have had the opportunity to perform intestinal biopsies on patients with dermatitis herpetiformis. It is clear that some patients with very minimal intestinal disease may have severe dermatitis herpetiformis. In addition, patients with very severe villus atrophy in intestinal biopsy specimens may have severe skin disease. Clinically, one finds that 10% 20% of patients with dermatitis herpetiformis have classic symptoms of malabsorption and another 20% are estimated to have atypical symptoms, but at least 60% of patients have silent celiac disease. Complications of malabsorption, such as iron deficiency, occur in 10% of patients with dermatitis herpetiformis. The clinical associations of dermatitis herpetiformis include thyroid abnormalities, which occur in 15% 20% of patients. 28 This is predominantly hypothyroidism, but acute autoimmune thyroiditis and hyperthyroidism may occur. Pernicious anemia and Addison s disease are uncommon but do occur in association with dermatitis herpetiformis, as they do in celiac disease. 29,30 The incidence of T-cell lymphoma is increased, and there is some information to suggest that this prevalence of T-cell lymphoma is reversed by gluten restriction. 31 The prevalence of complications such as osteoporosis is unknown. IgA endomysial antibodies were initially described in the sera of patients with dermatitis herpetiformis. They have been found in 70% 90% of patients with dermatitis herpetiformis on a diet containing gluten. This means that 10% 30% of patients with dermatitis herpetiformis are IgA endomysial antibody negative and IgA tissue transglutaminase negative. 17,32 Because 10% 30% of cases of dermatitis herpetiformis would be missed on serologic screening, it seems likely that a similar percentage of the population of patients with celiac disease would be likewise missed. This makes it likely that the true prevalence of celiac disease is significantly higher than currently indicated by serologic testing. With the exception of the finding of granular IgA in dermal papillae of patients with dermatitis herpetiformis, no consistent serologic or immunologic difference between patients with dermatitis herpetiformis and patients with celiac disease has ever been identified. Recently, Sardy et al identified epidermal transglutaminase as the antigen in dermatitis herpetiformis skin. 33 The same investigators have evaluated sera of patients with dermatitis herpetiformis and celiac disease for the presence of epidermal transglutaminase antibodies. They found that the epidermal transglutaminase antibodies in sera of patients with dermatitis herpetiformis had higher avidity for the transglutaminase antigen than did sera of patients with celiac disease. The significance of this finding has not yet been determined. What Other Diseases Are Associated With Celiac Disease? Some immune-mediated cutaneous diseases other than dermatitis herpetiformis have been reported to reverse with gluten restriction. These include alopecia areata, psoriasis, and aphthous stomatitis. It is likely that chronic stimulation of the immune system by gluten may be a cause of these immune disorders in some patients. Approximately 5% of patients with idiopathic aphthous stomatitis have been found to have positive endomysial antibody tests and celiac disease on small bowel biopsy. Stomatitis in such patients clears on a gluten-free diet. 34 Patients with alopecia areata have also been reported to respond to gluten restriction. Fessatou et al reported 2 patients with alopecia areata who were endomysial antibody positive and had celiac disease on small bowel biopsy. Both patients regrew hair with a gluten-free diet. It is believed that 1% 2% of patients with alopecia

4 S90 JOHN J. ZONE GASTROENTEROLOGY Vol. 128, No. 4 areata are endomysial antibody positive and have celiac disease. However, not all patients with celiac disease and alopecia areata regrow their hair with gluten restriction. 35,36 Psoriasis is a T-cell mediated disorder of the skin. Occasional patients with psoriasis have been reported to improve with gluten restriction. Patients with psoriasis with positive gliadin antibody have also improved on a gluten-free diet. However, the prevalence of a positive endomysial antibody and a positive epidermal transglutaminase antibody in patients with psoriasis is uncertain. It is likely that gluten may be a source of chronic antigen stimulation in these patients with psoriasis. 24,37 What Is the Management of Dermatitis Unlike patients with celiac disease alone, patients with dermatitis herpetiformis have an alternative therapy. The cutaneous disease in dermatitis herpetiformis clears rapidly on treatment with dapsone (diaminodiphenylsulfone). The cutaneous disease, however, recurs rapidly if dapsone is discontinued. Dapsone suppresses the inflammation in the skin but has no influence on the intestinal abnormality. Many patients with dermatitis herpetiformis choose to take dapsone chronically and not restrict gluten intake, despite knowing that gluten is the causative agent for their eruption. This offers an opportunity for study of the long-term metabolic and immunologic effects of celiac disease in the absence of gluten restriction. What Are the Recommendations for Future Research on Dermatitis The presence of dermatitis herpetiformis is a marker of celiac disease that is independent of the severity of histologic celiac disease or the intestinal symptoms. The complications and course of dermatitis herpetiformis are a reflection of complications and course of the entire spectrum of celiac disease. As such, patients with dermatitis herpetiformis offer a unique opportunity for investigation of the complications and long-term consequence of celiac disease. A study of a large cohort of patients with dermatitis herpetiformis over a long time should produce further insights into the serologic and clinical implications of the entire spectrum of patients with long-term celiac disease. References 1. Duhring L. Dermatitis herpetiformis. JAMA 1884;3: Marks J, Shuster S, Watson AJ. Small-bowel changes in dermatitis herpetiformis. Lancet 1966;2: van der Meer JB. Granular deposits of immunoglobulins in the skin of patients with dermatitis herpetiformis. An immunofluorescent study. Br J Dermatol 1969;81: Reunala TL. Dermatitis herpetiformis. Clin Dermatol 2001;19: Fry L, McMinn RM, Cowan JD, Hoffbrand AV. Gluten-free diet and reintroduction of gluten in dermatitis herpetiformis. Arch Dermatol 1969;100: Fry L, Seah PP, Riches DJ, Hoffbrand AV. Clearance of skin lesions in dermatitis herpetiformis after gluten withdrawal. Lancet 1973;1: Fry L, Haffenden G, Wojnarowska F, Thompson BR, Seah PP. IgA and C3 complement in the uninvolved skin in dermatitis herpetiformis after gluten withdrawal. Br J Dermatol 1978;99: Fry L, Leonard JN, Swain F, Tucker WF, Haffenden G, Ring N, McMinn RM. Long term follow-up of dermatitis herpetiformis with and without dietary gluten withdrawal. Br J Dermatol 1982;107: Leonard J, Haffenden G, Tucker W, Unsworth J, Swain F, McMinn R, Holborow J, Fry L. Gluten challenge in dermatitis herpetiformis. N Engl J Med 1983;308: Reunala T, Salo OP, Tiilikainen A, Selroos O, Kuitunen P. Family studies in dermatitis herpetiformis. Ann Clin Res 1976;8: Reunala T. Dermatitis herpetiformis: genetic aspects and glutenfree diet treatment Reunala T, Kosnai I, Karpati S, Kuitunen P, Torok E, Savilahti E. Dermatitis herpetiformis: jejunal findings and skin response to a gluten free diet. Arch Dis Child 1984;59: Reunala T. Incidence of familial dermatitis herpetiformis. Br J Dermatol 1996;134: Katz SI, Strober W. The pathogenesis of dermatitis herpetiformis. J Invest Dermatol 1978;70: Hall RP. Dermatitis herpetiformis. Prog Dermatol 1992;26: Chorzelski TP, Beutner EH, Sulej J, Tchorzewska H, Jablonska S, Kumar V, Kapuscinska A. IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and coeliac disease. Br J Dermatol 1984;111: Kumar V, Beutner EH, Chorzelski TP. Distribution of monkey esophagus antigens reactive with IgA-class antibodies in the sera of dermatitis herpetiformis patients. Arch Dermatol Res 1984; 276: Herron MD, Zone JJ. Dermatitis herpetiformis and linear IgA bullous dermatosis. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. London; Mosby, 2003: Smith JB, Taylor TB, Zone JJ. The site of blister formation in dermatitis herpetiformis is within the lamina lucida. J Am Acad Dermatol 1992;27: Zone JJ, Meyer LJ, Petersen MJ. Deposition of granular IgA relative to clinical lesions in dermatitis herpetiformis. Arch Dermatol 1996;132: Wyatt E, Shuster S, Marks J. A postal survey of patients with dermatitis herpetiformis. Br J Dermatol 1971;85: Moi H. Incidence and prevalence of dermatitis herpetiformis in a country in central Sweden, with comments on the course of the disease and IgA deposits as diagnostic criterion. Acta Derm Venereol (Stockh) 1984;64: Smith JB, Tulloch JE, Meyer LJ, Zone JJ. The incidence and prevalence of dermatitis herpetiformis in Utah. Arch Dermatol 1992;128: Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol 2003;4: Meyer LJ, Zone JJ. Familial incidence of dermatitis herpetiformis. J Am Acad Dermatol 1987;17:

5 April Supplement 2005 SKIN MANIFESTATIONS OF CELIAC DISEASE S Fry L, McMinn RM, Cowan JD, Hoffbrand AV. Effect of gluten-free diet on dermatological, intestinal, and haematological manifestations of dermatitis herpetiformis. Lancet 1968;1: Shuster S, Watson AJ, Marks J. Coeliac syndrome in dermatitis herpetiformis. Lancet 1968: Cunningham MJ, Zone JJ. Thyroid abnormalities in dermatitis herpetiformis: prevalence of clinical thyroid disease and thyroid antibodies. Ann Intern Med 1985;102: Reunala T, Salmi J, Karvonen J. Dermatitis herpetiformis and celiac disease associated with Addison disease. Arch Dermatol 1987;123: Kastrup W, Mobacken H, Stockbrugger R, Swolin B, Westin J. Malabsorption of vitamin B12 in dermatitis herpetiformis and its association with pernicious anaemia. Acta Med Scand 1986; 220: Collin P, Pukkala E, Reunala T. Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease. Gut 1996;38: Koop I, Ilchmann R, Izzi L, Adragna A, Koop H, Barthelmes H. Detection of autoantibodies against tissue transglutaminase in patients with celiac disease and dermatitis herpetiformis. Am J Gastroenterol 2000;95: Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 2002;195: Jokinen J, Peters U, Maki M, Miettinen A, Collin P. Celiac sprue in patients with chronic oral mucosal symptoms. J Clin Gastroenterol 1998;26: Corazza GR, Andreani ML, Venturo N, Bernardi M, Tosti A, Gasbarrini G. Celiac disease and alopecia areata: report of a new association. Gastroenterology 1995;109: Fessatou S, Kostaki M, Karpathios T. Coeliac disease and alopecia areata in childhood. J Paediatr Child Health 2003;39: Michaelsson G, Gerden B, Hagforsen E, Nilsson B, Pihl-Lundin I, Kraaz W, Hjelmquist G, Loof L. Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet. Br J Dermatol 2000;142: Address requests for reprints to: John J. Zone, MD, Department of Dermatology, University of Utah School of Medicine, 4B454 SOM, 30 North 1900 East, Salt Lake City, Utah john.zone@hsc.utah.edu; fax: (801) Supported by a National Institutes of Health Research grant (RO1 DK50678) (to J.J.Z.).