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Coexistence of dermatitis herpetiformis, gluten-sensitive enteropathy, and ulcerative colitis
1050 Briefcommunications
Journal of the American Academy of Dermatology December 1994
Coexistence of dermatitis herpetiformis, gluten-sensitive enteropathy, and ulcerative colitis Marcella Malrnusi, MD, Vania Manca, MD, and Giampiero Girolomoni, MD Modena, Italy Dermatitis herpetiformis (DR) occurs in a subset of patients affected by gluten-sensitive enteropathy (GSE). DH has also been described in association with several immune-mediated disorders, mainly rheumatoid arthritis, thyroiditis, and pernicious anemia.'- 2 DR has been rarely reported in association with ulcerative colitis (UC). We describe a patient with DR and Uc. CASE REPORT A 60-year-old white woman had a 2-year history of a relapsing, intensely pruritic and burning, erythematous, papulovesicular eruption on the neck, shoulders, elbows, knees, and lumbosacral area. A biopsyspecimenrevealed edema and neutrophils in the papillary dermis. Direct immunofluorescenceshowed granular IgA and C3 along the dermoepidermal junction, but it was more intense in the dermal papillae. IgA antiendomysial and IgG and IgA antigliadin antibodies were detected in the serum. Waaler-Rose test results were positive (1:160). Relevant negative results were as follows: rheumatoid factor and antinuclear, antigastric parietal cells, antithyroglobulin, antimicrosomal and antimitochondrial antibodies. Routine laboratory investigations were normal except for a mild hypochromic anemia. Serum folate and vitamin B12 levelswere normal. The patient's haplotype was A3 j A25, B7jB8, Bw6, DR2/DR3, DR52, DQljDQ2. A jejunal biopsy specimen showed discrete villous atrophy and a lymphocytic infiltrate in the lamina propria characteristic of GSE grade II. The patient also had intermittent mild abdominal pain, diarrhea, tenesmus, and rectal bleeding for 5 years. A colonic biopsyspecimen had previously confirmed the presence of UC limited to the rectosigmoid, and the patient was taking sulfasalazine. Treatment with dapsone, 150 rug/day, and vitamin E, 800 U jday,3 resulted in complete remissionof cutaneous symptoms within 1 week. A gluten-free diet was also started, and after 6 months the patient was able to discontinue dapsone. A jejunal biopsy specimenobtained From the Department ofDermatology, University ofModena. Reprint requests: Marcella Malmusi, MD, Clinica Dermatologica, Universita diModena, Via del Pozzo 71, 41100 Modena, Italy. JAM ACAD DERMATOL 1994;31:1050-1. Copyright @ 1994 by the American Academy ofDermatology, Inc. 0190-9622/94 $3.00 + 0 16/54/57253
1 year later showedmarked improvementof the GSE that paralleled the complete remission of the skin lesions, whereas the rectosigmoid DC lesions were substantially unchanged. The patient is still receiving intermittent therapy with sulfasalazine. DISCUSSION UC has been rarely reported in association with DH or celiac disease.v ' Table I summarizes the cases described in the literature in which coexistence of DR and UC has been sufficiently proved. Other reports mentioned similar cases, but no details were provided.f Although the limited number of patients does not allow statistical evaluation, all patients were adults (range, 17 to 58 years; mean age, 40 years), and women predominated (5:2); in contrast, both DR and UC are more common in men. In addition, in all patients symptoms of DC preceded those of DR by 1 to 10 years, with a mean interval of 4.8 years. It is likely that the occurrence of DH in patients with UC could be more than a chance association. In three series of patients with DR,7-9 3.3% had UC; the prevalence of UC in the general population is only 0.05%.10 The nature of the association between DR and UC is not known. The coexistence of autoimmune diseases can be explained on the basis of immunogenetics: DR occurs most frequently in patients with a RLA-B8, -DR3, -DQ2 haplotype. Therefore, the association of D H with celiac disease, thyroid disease, and pernicious anemia may be on the basis of major histocompatibility complex linkage. In contrast, a recent study of white patients with DC confirmed a positive association with the DR2 allele. I I Our patient expressed all B8, DQ2, DR3, and DR2 alleles. An immunologic abnormality common to celiac disease, D H, and DC is a prolonged clearance of immune complexes.l? although the relevance of this finding to the pathogenesis of the diseases is not clear. A potential mechanism is that UC may favor the onset of DR by altering intestine barrier function, thus allowing foreign antigen access to the immune system. However, Crohn's disease has never been reported to occur with DH. It is also notewor-
· Journal of the American Academy of Dermatology Volume 31, Number 6
Brief communications
1051
Table I. Reported cases of DR associated with DC Age at onset
Ageat onset
Case No.
Age1Jr)/sex
ofUC(yr)
oCDH(yr)
1 2 3
17jF 47jF
15 36
52/F
44
17 46 49
4
40/M 48/M 32/F 60/F
NA
Other diseases
Reference No.
Raynaud's phenomenon; seronegative
13 7 7
polyarthritis
5 6 Our patient
40 31
55
30 48 32 58
Hepatitis
8
14 9
NA, Data not available.
thy that in the pathogenesis of both DC and DR the role of a viral infection or other environmental stimuli in the activation of the immune system has been advocated. It is possible that salazopyrine may be of help in the therapy of DH; in fact, our patient and other patients's 13, 14 who were concurrently treated with salazopyrine appeared to have less stringent requirements for both dapsone and a gluten-free diet.
REFERENCES 1. Hall RP. Dermatitis herpetiformis. J Invest Dermatol 1992;99:873-81. 2. Kaplan RP, Callen JP. Dermatitis herpetiformis: autoimmune disease association. Clin DermatoI1992;9:341-6. 3. Prussick R, Ali MAM, Rosenthal D, et al. The protective effect of vitamin E on the hemolysis associatedwithdapsone treatment in patients with dermatitis herpetifonnis. Arch Dermatol1992;128:210-3. 4. Kitis G, Holmes JKT, Cooper BT, et al. Association of coeliac disease and inflammatory disease. Gut 1980;21:63641. 5. Kumar J, Gibson J, O'Donoghue DP, et al. The existence
of inflammatory bowel lesions in gluten-sensitive enteropathy. Postgrad Med J 1979;55:753-6. 6. ChristensenOB, Hindsen M , Svensson A. Natural history of dermatitis herpetifonnis in southern Sweden. Derrnatologica 1986;173:271-7. 7. Davies MG, Marks R, Nuki G. Dermatitis herpetiformis: a skin manifestationof a generalized disturbance in immunity. Q J Med 1978;47:221-48. 8. Stockbriigger R, Kastrup W , Lundqvist G, et al. Development of gastric dysfunction in dermatitis herpetiformis. Acta Derm Venereol(Stockh) 1978;58:343-8. 9. Lambert D, Collet E, Foucher JL , et al. Dermatitis herpetiformis associated with ulcerative colitis. Clin Exp DermatoI1991;16:458-9. 10. BaylessT. Ulcerative colitis. In: Gitnick G, ed. Principles and practice of gastroenterology and hepatology. New York: Elsevier, 1988:461-96. 11. Toyoda H, Wang S-J, Yang H-Y, et al. Distinct associations of HLA class II genes with inflammatory boweldisease. Gastroenterology 1993;104:741-8. 12. Lava B, Nilsson B, Loof L, et al. Fe receptor function and circulating immune complexesin gluten sensitiveenteropathy: possible significance of serum 19A. Gut 1991;32:87680. 13. Laugier P, Orosco M, Hunziker MN, et al. Dermatite herpetiforme de Duhring associee a une recto-colite hemorragique. Bull Soc Fr Dermatol Syphil1972;79:267-8. 14. Dodd HJ. Dermatitis herpetiformis and ulcerative colitis: report of a case. Clio Exp Dennatol 1984;9:99-101.
Journal of the American Academy of Dermatology December 1994
Coexistence of dermatitis herpetiformis, gluten-sensitive enteropathy, and ulcerative colitis Marcella Malrnusi, MD, Vania Manca, MD, and Giampiero Girolomoni, MD Modena, Italy Dermatitis herpetiformis (DR) occurs in a subset of patients affected by gluten-sensitive enteropathy (GSE). DH has also been described in association with several immune-mediated disorders, mainly rheumatoid arthritis, thyroiditis, and pernicious anemia.'- 2 DR has been rarely reported in association with ulcerative colitis (UC). We describe a patient with DR and Uc. CASE REPORT A 60-year-old white woman had a 2-year history of a relapsing, intensely pruritic and burning, erythematous, papulovesicular eruption on the neck, shoulders, elbows, knees, and lumbosacral area. A biopsyspecimenrevealed edema and neutrophils in the papillary dermis. Direct immunofluorescenceshowed granular IgA and C3 along the dermoepidermal junction, but it was more intense in the dermal papillae. IgA antiendomysial and IgG and IgA antigliadin antibodies were detected in the serum. Waaler-Rose test results were positive (1:160). Relevant negative results were as follows: rheumatoid factor and antinuclear, antigastric parietal cells, antithyroglobulin, antimicrosomal and antimitochondrial antibodies. Routine laboratory investigations were normal except for a mild hypochromic anemia. Serum folate and vitamin B12 levelswere normal. The patient's haplotype was A3 j A25, B7jB8, Bw6, DR2/DR3, DR52, DQljDQ2. A jejunal biopsy specimen showed discrete villous atrophy and a lymphocytic infiltrate in the lamina propria characteristic of GSE grade II. The patient also had intermittent mild abdominal pain, diarrhea, tenesmus, and rectal bleeding for 5 years. A colonic biopsyspecimen had previously confirmed the presence of UC limited to the rectosigmoid, and the patient was taking sulfasalazine. Treatment with dapsone, 150 rug/day, and vitamin E, 800 U jday,3 resulted in complete remissionof cutaneous symptoms within 1 week. A gluten-free diet was also started, and after 6 months the patient was able to discontinue dapsone. A jejunal biopsy specimenobtained From the Department ofDermatology, University ofModena. Reprint requests: Marcella Malmusi, MD, Clinica Dermatologica, Universita diModena, Via del Pozzo 71, 41100 Modena, Italy. JAM ACAD DERMATOL 1994;31:1050-1. Copyright @ 1994 by the American Academy ofDermatology, Inc. 0190-9622/94 $3.00 + 0 16/54/57253
1 year later showedmarked improvementof the GSE that paralleled the complete remission of the skin lesions, whereas the rectosigmoid DC lesions were substantially unchanged. The patient is still receiving intermittent therapy with sulfasalazine. DISCUSSION UC has been rarely reported in association with DH or celiac disease.v ' Table I summarizes the cases described in the literature in which coexistence of DR and UC has been sufficiently proved. Other reports mentioned similar cases, but no details were provided.f Although the limited number of patients does not allow statistical evaluation, all patients were adults (range, 17 to 58 years; mean age, 40 years), and women predominated (5:2); in contrast, both DR and UC are more common in men. In addition, in all patients symptoms of DC preceded those of DR by 1 to 10 years, with a mean interval of 4.8 years. It is likely that the occurrence of DH in patients with UC could be more than a chance association. In three series of patients with DR,7-9 3.3% had UC; the prevalence of UC in the general population is only 0.05%.10 The nature of the association between DR and UC is not known. The coexistence of autoimmune diseases can be explained on the basis of immunogenetics: DR occurs most frequently in patients with a RLA-B8, -DR3, -DQ2 haplotype. Therefore, the association of D H with celiac disease, thyroid disease, and pernicious anemia may be on the basis of major histocompatibility complex linkage. In contrast, a recent study of white patients with DC confirmed a positive association with the DR2 allele. I I Our patient expressed all B8, DQ2, DR3, and DR2 alleles. An immunologic abnormality common to celiac disease, D H, and DC is a prolonged clearance of immune complexes.l? although the relevance of this finding to the pathogenesis of the diseases is not clear. A potential mechanism is that UC may favor the onset of DR by altering intestine barrier function, thus allowing foreign antigen access to the immune system. However, Crohn's disease has never been reported to occur with DH. It is also notewor-
· Journal of the American Academy of Dermatology Volume 31, Number 6
Brief communications
1051
Table I. Reported cases of DR associated with DC Age at onset
Ageat onset
Case No.
Age1Jr)/sex
ofUC(yr)
oCDH(yr)
1 2 3
17jF 47jF
15 36
52/F
44
17 46 49
4
40/M 48/M 32/F 60/F
NA
Other diseases
Reference No.
Raynaud's phenomenon; seronegative
13 7 7
polyarthritis
5 6 Our patient
40 31
55
30 48 32 58
Hepatitis
8
14 9
NA, Data not available.
thy that in the pathogenesis of both DC and DR the role of a viral infection or other environmental stimuli in the activation of the immune system has been advocated. It is possible that salazopyrine may be of help in the therapy of DH; in fact, our patient and other patients's 13, 14 who were concurrently treated with salazopyrine appeared to have less stringent requirements for both dapsone and a gluten-free diet.
REFERENCES 1. Hall RP. Dermatitis herpetiformis. J Invest Dermatol 1992;99:873-81. 2. Kaplan RP, Callen JP. Dermatitis herpetiformis: autoimmune disease association. Clin DermatoI1992;9:341-6. 3. Prussick R, Ali MAM, Rosenthal D, et al. The protective effect of vitamin E on the hemolysis associatedwithdapsone treatment in patients with dermatitis herpetifonnis. Arch Dermatol1992;128:210-3. 4. Kitis G, Holmes JKT, Cooper BT, et al. Association of coeliac disease and inflammatory disease. Gut 1980;21:63641. 5. Kumar J, Gibson J, O'Donoghue DP, et al. The existence
of inflammatory bowel lesions in gluten-sensitive enteropathy. Postgrad Med J 1979;55:753-6. 6. ChristensenOB, Hindsen M , Svensson A. Natural history of dermatitis herpetifonnis in southern Sweden. Derrnatologica 1986;173:271-7. 7. Davies MG, Marks R, Nuki G. Dermatitis herpetiformis: a skin manifestationof a generalized disturbance in immunity. Q J Med 1978;47:221-48. 8. Stockbriigger R, Kastrup W , Lundqvist G, et al. Development of gastric dysfunction in dermatitis herpetiformis. Acta Derm Venereol(Stockh) 1978;58:343-8. 9. Lambert D, Collet E, Foucher JL , et al. Dermatitis herpetiformis associated with ulcerative colitis. Clin Exp DermatoI1991;16:458-9. 10. BaylessT. Ulcerative colitis. In: Gitnick G, ed. Principles and practice of gastroenterology and hepatology. New York: Elsevier, 1988:461-96. 11. Toyoda H, Wang S-J, Yang H-Y, et al. Distinct associations of HLA class II genes with inflammatory boweldisease. Gastroenterology 1993;104:741-8. 12. Lava B, Nilsson B, Loof L, et al. Fe receptor function and circulating immune complexesin gluten sensitiveenteropathy: possible significance of serum 19A. Gut 1991;32:87680. 13. Laugier P, Orosco M, Hunziker MN, et al. Dermatite herpetiforme de Duhring associee a une recto-colite hemorragique. Bull Soc Fr Dermatol Syphil1972;79:267-8. 14. Dodd HJ. Dermatitis herpetiformis and ulcerative colitis: report of a case. Clio Exp Dennatol 1984;9:99-101.