- Email: [email protected]
Long-term follow-up of dermatitis herpetiformis in children
Journal of the
American Academy of Dermatology
Cowan et al
14. Moynahan EJ: Acquired albinism with intraocular depigmentation. Proc R Soc Med 54:696-697, 1961. 15. Cowan CL, Grimes PE, Chakrabarti SG, et al: Retinitis pigmentosa associated with hearing loss, thyroid disease, vitiligo, and alopecia areata. Retina 2:84-88, 1982. 16. Jones IS: Pigmented tumors, in Reese AS, editor: Tumors of the eye, ed. 3. Hagerstown, MD, 1976, Harper & Row, Publisher, p. 185. 17. Wagoner HP, Wellbrock WL: Benign melanomas and melanoepithelioma of the choriod. Arch Ophthalmol 4:509-515, 1930.
18. Alberts EC: Benign melanomas of the choroid and their malignant transformation. Am J Ophthalmo123:779-783, 1940. 19. Gass JDM: Differentia/diagnosis of intraocular tumors: A stereoscopic presentation. St. Louis, 1974, The C. V. Mosby Co., p. 21. 20. Lerner AB: On the etiology of vitiligo and gray hair. Am J Med 51:141-147, 1971.
Long-term follow-up of dermatitis herpetiformis in children Elisa Ermacora, M . D . , * Luigia Prampolini, M.D. ,** Giuliana Tribbia, M.D. ,*** Gabriella Pezzoli, M . D . , * Carlo Gelmetti, M.D.,* Gabriella Cucchi, M . D . , * * Alberto Tettamanti, M.D.,** Annamaria Giunta, M.D.,** and Ferdinando Gianotti, M.D.* Milan and Bergamo, Italy Dermatitis herpetiformis was diagnosed in seventy-six children by its clinical features and by detection of granular IgA deposits in the papillary dermis of perilesional skin. Enteric alterations demonstrated by measurement of Dxylose absorption and by small intestinal biopsies were detected in over 90% of all patients. A complete follow-up was obtained for all children who were followed for 3 to 10 years. Treatment with a gluten-free diet alone led to a reversal of the intestinal abnormality in 100% of our children and to the disappearance of cutaneous lesions in 82% of reported cases. This suggests that a complete remission of symptoms can be obtained with a gluten-free diet alone. Dapsone alone is effective therapy for the rash but does not affect the intestinal alterations. Furthermore, the lack of side effects to dietetic therapy for a long period of time makes the diet the treatment of choice in this disease. (J AM ACAD DERMATOL15:24-30, 1986.)
Dermatitis herpetiformis is a chronic disease characterized by a very pruritic eruption of small From the Department of Dermatology and Pediatric Dermatology* and the Department of Pediatrics,** University of Milan, and Tribbia,*** Ospedall Riuniti di Bergamo. Accepted for publication Jan. 28, 1986. Reprint requests to: Dr. Elisa Ermacora, Instituto di Clinica Dermatologiea I e Dermatologia Pediatrica, Via Pace 9-20123 MILANO-Italy.
24
erythematous and edematous papules, and sometimes vesicles, distributed in a herpeslike or figurate pattern. These cutaneous lesions are symmetrically located on the extensor aspects of the limbs, on the shoulders, on the nape of the neck, on the sacral area, and, occasionally, on the face and palms. A single eruption lasts from a few days to weeks, with continuous recurrences for years
Volume 15 Number 1 July, 1986
Dermatitis herpetiformis in children
25
Fig. 1. Dermatitis herpetiformis. Small erythematous-edematous papules in figurate pattern on a shoulder mixed with small crusts and hypochromic areas. Fig. 2. Dermatitis herpetiformis. Edematous lesions on the sacral area and buttocks. Fig. 3. Linear IgA dermatosis. Large, tense bullae in a "rosette" pattern in the pelvic region. (Figs. 1 and 2). Histologic preparations show marked polymorphonuclear leukocyte infiltration filling the top of the papillary dermis and forming microabscesses with fibrin that are overlaid with subepidermal vesicles. 2 Under the electron microscope, these vesicles are seen to be situated between the basal lamina and the dermis. Granular deposits of IgA in the papillary dermis are pathognomonic. 3 A gluten-dependent enteropathy has been observed in 85% to 95% of cases. 1.4 The lesions are
histologically similar to the intestinal lesions of celiac disease, 5'6 but in dermatitis herpetiformis the clinical symptoms are mild and are seen in only a few patients. Biochemically the nutritional and malabsorption patterns are rarely abnormal, 7 probably because the intestinal mucosa is only partially affected as demonstrated by multiple biopsies. 8,9 In children, human lymphocyte antigens (HLA) B 8, and Dr 3, and Dr 7 are detected, as they are in celiac disease in 60% to 80% of cases.l,m,II Oral admin-
26
Journal of the American Academy of Dermatology
Errhacora et al
Table I. Differential diagnosis: Dermatitis herpetiformis versus linear IgA dermatosis in childhood Characteristics
Dermatitis herpetiformis Small erythematous-edematous papules in figurate pattern Extensor aspects of the limbs, shoulders, nape of the neck, sacral area
Skin lesions Skin regions
[
Linear IgA dermatosis Large, tense bullae in a "rosette" pattern Perioral region, lower part of trunk, pelvic region, extremities Spontaneous healing in years or at puberty Rarely present
Chronic
Course
Almost always present
Gluten-dependent enteropa'-
Subepidermal vesicles, PMN infiltration, and fibrin in the papillary dermis Granular deposits of IgA in the papillary dermis Negative Deposits of IgA on dermal microfibrillae Effective in most of cases Excellent Modest
Histology
Subepidermal blisters
DIF
Linear deposits of IgA at BMZ
IIF Immune electron microscopy
Circulating IgA anti-BMZ (70%) Deposits of IgA in lamina lucida
Skin response to GFD Dapsone Corticosteroids
Effective in a few cases Modest Excellent if associated to Dapsone
thy
BMZ: Basementmembranezone; DIF: direct immunofluorescence;IIF: indirect immunofiuoreseence;PMN: polymorphonuclear. istration o f dapsone rapidly heals both the cutaneous lesions and relieves the pruritus. When it is stopped, there is a prompt relapse. Linear IgA dermatosis (Fig. 3) can be clearly differentiated by clinical and immunopathologic pattems as summarized in Table I. Our children with IgA linear dermatosis will be discussed in a separate paper. SUBJECTS AND METHODS Between 1974 and 1983, dermatitis herpetiformis was diagnosed in seventy-six children (36% boys), confirmed by detection of granular IgA in the papillary dermis of perilesional skin by direct immunofluoreseence tests. All the tests were performed in the same laboratory using fluorescein-conjugated Fab2 fragment antisera against IgA, IgG, IgM, and fluorescein-conjugated antibodies to C3 fraction of complement and fibrinogen (Istituto Behring, Milan, Italy). A detailed history was taken for each child, with special attention to gastrointestinal symptoms, age at their onset and their relationship to the introduction of gluten into the diet, and time since weaning. Intestinal biopsy specimens from the duodenojejunal flexure were taken from all the children with a Watson capsule. Xylosemia, measured 60 minutes after oral administration
of 5 gm of D-xylose (method of Roe and Rice~2), was used as an index of absorption. All the children with mucosal changes were immediately placed on a glutenfree diet. Dapsone (diaminodiphenylsulfone; Neosulfonazina Farmitalia) was added to the diet at doses of 0.5-1 mg/ kg/day if there were diffuse cutaneous lesions or distm'bing pruritus. Children without mucosal changes were treated with dapsone only at variable doses (0.52 mg/kg/day). The parents of children who were on a gluten-free diet were followed with periodic information and came to meetings to obtain strict dietary collaboration. The gluten sensitivity of the disease was demonstrated in a group of twenty-six children who were allowed to resume a normal diet. Follow-ups (clinical, biochemical, and histotogic) were complete for all the children. RESULTS No skin lesions were detected in children younger than 10 months of age. The most frequent ages of onset of dermatitis herpetiformis were between the second and the seventh years of life (75%), as shown in Fig. 4. From the histories, thirty children (38%) had had a chronic or relapsing diarrhea dur-
Volume 15 Number 1 July, 1986
Dermatitis herpetiformis in children
27
Number of oase~ 14
12 10
0 I
2
3
4
5
6
7
B
9
I0
11
12
13
Years
Fig. 4, Age of onset of dermatitis herpetiformis in Milan area. ing the first 2 years of life, but only eight patients had established diagnoses of malabsorption before the onset of dermatitis herpetiformis. At the time when the diagnosis of dermatitis herpetiformis was made, the weights of eleven children (15%) were below the tenth percentile, while the lengths of ten (13%) were below the tenth percentile. The D-xylose load test gave abnormal results in 32% of the patients. Biopsy specimens of the small intestine showed affected jejunal mucosa in sixtysix of seventy-six cases (85%), subtotal atrophy in thirty-seven cases, and partial atrophy in twentynine. Of ten subjects with normal intestinal mucosa, six had repeat biopsies done after 1 to 3 years on normal diets. Biopsy specimens from three of them showed altered mucosa, and the other three had remained normal. Finally, changes in the small intestine were detected in over 90% of cases.
Children on gluten-free diet therapy In thirty-three of forty-one children treated with a gluten-free diet only, all cutaneous manifestations disappeared within 1 to 6 months. The remaining eight children showed only reduction of the rash. Probably four of these did not always follow the diet.
Children on gluten-free diet plus dapsone therapy Of twenty-eight children treated with glutenfree diet plus dapsone, eighteen were able to dis-
continue dapsone therapy within 2 to 18 months (mean, 13 months). The other ten were s611 being treated at the time of writing, but with a lower dose of the drug (0.125-0.5 mg/kg/day).
Children on flapsone therapy Of seven children treated with dapSone alone, four were able to discontinue the drug within 1 to 4 years. The other three remained on therapy:
Side effects The side effects of dapsone therapy m our patients were decreases in hemoglobin of more than 2 gm in 50% of the children giVen 2 mglkg/day of dapsone and in 10% of the children given 1.5 to 2 mg/kg/day. Lower doses of dapsone never induced this side effect. Methemoglobinemia was also observed during the first week of treatment but never required interruption of the therapy. One child with a glucose-6-phosphate dehydirogenase (G-6-PD) deficiency had to stop taking the drug because of severe hemolysis. (Thus a screening test for G-6-PD activity should be performed prior to the administration of dapsone.) This child continued on a gluten-free diet alone and the rash cleared in 4 months.
Demonstration of gluten sensitivity of dermatitis herpetiformis In order to prove the gluten sensitivity of the disease, twenty-six children with gut lesions were submitted to a second jejunal biopsy after 12 to
Joumal of the American Academy of Dermatology
Ermacora et al
28
Table
II. Patients free o f cutaneous and intestinal symptoms after discontinuing therapy [
Case ,,,,,,,
,
1
[
,,2
[
3
4
5
6
,
7
10 N +
1 PA +
6 N +
+
-
+
,,
Onset of DH (age in years) Jejunum Dapsone GFD Age at stop-therapy Follow-up after stop-therapy (years) IgA after stop-therapy (years) Jejunum i n stop-therapy
3 N +
2 N +
3 TA +
_
_
+
7 3
4 4
5 5
10, 5 7
5 6
7 6
4 3
+ 1 N
+ 1 ND
+ 2 N
-1,5 ND
_ 6 N
_ 2.5 ND
+ 2 N
-
2 PA
DH: Dermatitis herpetiformis; GFD: gluten-free diet; N: normal mucosa; ND: not done; PA: partial atrophy; TA: total atrophy. 18 months on the gluten-free diet. At the time of this biopsy all the patients had normal results in the I>xylose test and had been without skin lesions for more than 6 months. These biopsy specimens showed normal mucosa and the children were allowed to return to a normal diet. All twenty-six had recurrences of skin rash 1 to 26 weeks after return to a normal diet arid all twenty-six had abnormal mucosa at the time of a third jejunal biopsy performed 2 to 6 months after resuming a normal diet. At the same time results of the xylose tests were abnormal in seven children (27%). All twenty-six children were again placed on a gluten-free diet.
abnormalities of either biochemical or clinical parameters are difficult to explain. The intestinal lesions may involve only the proximal area of the intestinal tract rather than the entire length? -8 In some of the eight children diagnosed previously as having celiac disease, the cutaneous symptoms appeared when gluten was reintroduced. In the others the symptoms were present even when they were on the gluten-free diet. On this basis, two different explanations can be proposed:
DISCUSSION
1, These children had dermatitis herpetiformis with marked intestinal symptoms and ~ere misdiagnosed as having celiac disease. The early removal of gluten from their diets could have delayed the appearance of t h e skin lesions until gluten was reintroduced. 2. These children actually did have celiac disease, with the dermatitis herpetiformis I'epresenting a different manifestation in an additional organ. The small number of patients with celiac disease who develop dermatitis herpetiformis 6,~5goes against this second proposal, as does the fact that in our region the frequencies of the two diseases are quite similar.
In agreement with data in the a,~ailable literature, 7'13 only thirty children of seventy-six (38%) had clinical hlstories of intestinal symptoms and only eight had a diagnosis of celiac disease. The I>xylose test results and growth percentiles were abnormal for only a small number of subjects. 7 The jejunal biopsy, however, showed mucosal alterations in over 90% of the cases, i4 The lack of Correlation between the high frequency of histologic lesions and the only slight
Treatment with gluten-free diet alone led to a return to normal intestinal mucosa in 100% of our children and also to disappearance of cutaneous lesions in 82% of the cases reported. This suggests that complete disappearance of both cutaneous and intestinal symptoms can be obtained with glutenfree diet alone if it is properly followed over a long period of time (more than 6 monthst6'aT). Dapsone given alone is rapidly effective against eruption but is not effective against the intestinal al-
Children
in stop-therapy
At the time of writing, 2 to 7 years after discontinuing therapy, only seven of the seventy-six children had no cutaneous symptoms. These seven have had additional skin and intestinal biopsies. The findings are summarized in Table II.
Volume 15 Number 1 July, 1986
terations. ~s We demonstrated this in three children treated with dapsone alone. Although the skin lesions disappeared, the intestinal mucosa remained altered even after 1 to 3 years of this therapy. In our group of twenty-six children, involvement of gluten in both the intestinal and skin lesions of dermatitis herpetiformis was fully confirmed. In children exposed to gluten after a period on gluten-free diet, no intestinal symptoms were observed even when mucosal alterations (as confirmed by biopsy) were present. Cutaneous relapses occurred when normal diets were resumed; they ranged widely in their severity, in their time of appearance, and they were apparently independent o f the duration of the preceding treatment? In some cases of severe relapses, an additional treatment with dapsone had to be added during the waiting period prior to the third biopsy. On reintroduction of the gluten-free diet, two different skin responses were observed: 1. Subjects who had only slight rashes after the reintroduction of the gluten, and therefore were not given dapsone, showed prompt clearing of the lesions on the gluten-free diet (8-30 days). 2. Patients who, in addition to gluten-free diet also required dapsone, were able to discontinue this drug only after many months (9-27) on the gluten-free diet. Some were still in therapy with dapsone plus glutenfree diet at the time of writing. At present, a relationship between celiac disease and dermatitis herpetiformis cannot be established. ~9 The gluten seems to be responsible for the intestinal symptoms in both diseases, ~7 although in dermatitis herpetiformis the clinical s y m p t o m s are slight. Gluten-free diet leads to normalization of intestinal mucosa in both diseases and in dermatitis herpetitbrmis, specifically, it clears the cutaneous eruption. 4'~6'~7 Cutaneous deposits of IgA have never been observed in celiac disease. 6,~9 In addition, while there is familial ten' dency in first-degree relatives with different frequencies in celiac disease, no first-degree relatives with dermatitis herpetiformis were detected in our cases of dermatitis herpetiformis nor have any been reported in the literature. Furthermore, the monozygotic twin of an affected female child never had any cutaneous eruption and had a negative skin biopsy. Moreover, some parents of chil-
Dermatitis herpetiformis in children
29
dren with dermatitis herpetiformis had skin biopsies and no IgA could be seen by direct immunofluorescence tests. In both diseases there is a high percentage of HLA B8, Dr 3, and Dr 7. ~°,~ None of these findings serve to show whether celiac disease and dermatitis herpetiformis are two different diseases or are different expressions of the same disease. This would be of particular importance for the prognosis of dermatitis herpetiformis. It is known that in celiac disease patients the diet must be continued indefinitely. The studies by Leonard et aP 7 conceming the reintroduction of gluten into the diets of adults with dermatitis herpetiformis who had been on a gluten-free diet and free of skin symptoms for years show that the gluten sensitivity can persist indefinitely. Of all our patients, only four had reached puberty at the time of writing, and they still had dermatitis herpetiformis. This observation is in contrast with the experience in adults, in whom the beginning of the disease was not clearly established in childhood. Because of the small number of patients who have been cured or have reached puberty and are still ill, we are unable to establish a prognosis for dermatitis herpetiformis in children. In our experience, the response to dietetic therapy alone has been excellent. In contrast to dapsone therapy, gluten-free diet has no side effects even after a prolonged period of time, and we consider it the treatment of choice. REFERENCES
1. Katz SJ, Hall RP, Lawley TJ, Strober W: Dermatitis herpetiformis: The skin and the gut. Ann Intern Med 93:857-874, 1980. 2. Katz SJ, Strober W: The pathogenesis of dermatitis herpetiformis. J Invest Dermatol 70:63-75, 1978. 3. Fry L, Seah PP: Dermatitis herpetiformis: An evaluation of diagnostic criteria. Br J Dermatol 90:137-146, 1974, 4. Fry L, Leonard J, Swain F, et al: Long term follow-up of dermatitis herpetiformis with and without dietary gluten withdrawaI. Br J Dermatol 107:631-640, 1982, 5. Brown JR, Parker F, Weinstein WM, Rubin CE: The small intestinal mucosa in dermatitis herpetiformis. Severity and distribution of small intestinal lesions and associated malabsorption. Gastroenterology 60:355-361, 1971. 6. Scott BB, Young S, Raja SM, et al: Coeliac disease and dermatitis herpetiformis. Further studies of their relationship. Gut 17:759-762, 1976. 7. Fry L, Keir P, McMinn RMH, et al: Small intestine structure and function and haematological changes in dermatitis herpetiformis. Lancet 2:729-734, 1967.
Journal of the American Academy of Dermatology
Ermacora et al
8. Scott BB, Losowsky MS: Patchiness and duodenal-jejunal variation of the mucosal abnormality in eoeliae disease and dermatitis herpetiformis. Gut 17:984-992, 1976. 9. Weinstein WM, Brown JR, Parker F, Rubin CE: The small intestinal mueosa in dermatitis herpetiformis. II. Relationship of the small intestinal lesions to gluten. Gastroenterology 60'362-369, 1971. 10. Pehamberger H, Holubar K, Mayr WR: HLA-DR3 in dermatitis herpetiformis. Br J Dermatol 104:321-324, 1981. 11. Richiardi P, Borelli I, Malavasi F, et al: HLA antigens in juvenile dermatitis herpetiformis. Acta Derm Venereol (Stockh) 61:241-244, 1981. 12. Roe JH, Rice EW: A photometric method for the determination to free pentose in animal tissues. J Biol Chem 173:507, 1948. 13. Ljunghail K, Loof L, Grimelius L, et al: Dermatitis herpefiformis: Relation between circulating antibodies against reticulin and gluten, small intestinal mucosa
14. 15. 16.
17. 18. 19.
status and absorptive capacity. Acta Derm Venereoi (Stockh) 63:27-34, 1983. Gawkrodger DJ, Blackwell JN, Gilmour HM, et al: Dermatitis herpetiformis: Diagnosis, diet and demography. Gut 25:151-157, 1984. Shuster S, Watson AJ, Marks J: Coeliac syndrome in dermatitis herpetiformis. Lancet 1:1101-1106, 1968. Frodin T, Gotthard R, Hed J, et al: Gluten-free diet for dermatitis herpetiformis: The long-term effect on cutaneous, immunological and jejunal manifestations. Aeta Derm Venereol (Stockh) 61:405-411, 1981. Leonard J, Haffenden G, Tucker W, et al: Gluten challenge in dermatitis herpctiformis. N Engl J Med 308-'816819, 1983. Reunala T, Blomquist K, Tarpila S: Gluten-free diet in dermatitis herpetiformis. Clinical response of skin lesions in 81 patients. Br J Dermatol 4:287-289, 1977. Leonard JN, Haffenden G, Tucker W, et al: Skin biopsies in relatives of patients with dermatitis herpetiformis. Acta Derm Venereol (Stockh) 63:252-254, 1983.
I !
I
Dose-response study of topical minoxidil in male pattern baldness* Elise A. Olsen, M . D . , Elizabeth R. D e L o n g , P h . D . , and Madeline S. Weiner, R . N . , B . S . N . Durham, NC Eighty-nine healthy men with male pattern baldness completed a 6-month double-blind, placebo-controlled study of 0.01%, 0.1%, 1%, and 2% topical minoxidil. Subjects on 2% topical minoxidil had a statistically significant increase in mean total target area hair count over baseline compared to the placebo, 0.01%, and 0.1% topical minoxidil groups (p = 0.04). Changes from baseline were more impressive with the 2% topical minoxidil group but not significantly different from the 1% topical minoxidil group in all parameters of objective response to treatment. The investigator, however, rated more subjects as having at least a moderate cosmetic response to treatment in the 2% versus 1% topical minoxidil treatment group. These results indicate that 1% topical minoxidil is the lowest effective concentration o f topical minoxidil for male pattern baldness of those tested. Because o f the more impressive changes in hair counts and the cosmetic preference for the 2% versus 1% topical minoxidil, 2% topical minoxidil may be the standard preferred treatment for male pattern baldness. (J AM ACAD DERMXrOL 15:3037, 1986.)
From the Division of Dermatology,Department of Medicine, Duke University Medical Centerand Health Services Research, Veterans Administration Hospital. Supported in part by a grant from The Upjohn Company, Kalamazoo, ML 30
Accepted for publication Feb. 7, 1986. Reprint requests to: Dr. Elise A. Olsen, Box 3294, Duke University Medical Center, Durham, NC 27710/919-684-6844. *This is Publication No. 144 from the Dermatologic Research Laboratories at Duke University Medical Center.
American Academy of Dermatology
Cowan et al
14. Moynahan EJ: Acquired albinism with intraocular depigmentation. Proc R Soc Med 54:696-697, 1961. 15. Cowan CL, Grimes PE, Chakrabarti SG, et al: Retinitis pigmentosa associated with hearing loss, thyroid disease, vitiligo, and alopecia areata. Retina 2:84-88, 1982. 16. Jones IS: Pigmented tumors, in Reese AS, editor: Tumors of the eye, ed. 3. Hagerstown, MD, 1976, Harper & Row, Publisher, p. 185. 17. Wagoner HP, Wellbrock WL: Benign melanomas and melanoepithelioma of the choriod. Arch Ophthalmol 4:509-515, 1930.
18. Alberts EC: Benign melanomas of the choroid and their malignant transformation. Am J Ophthalmo123:779-783, 1940. 19. Gass JDM: Differentia/diagnosis of intraocular tumors: A stereoscopic presentation. St. Louis, 1974, The C. V. Mosby Co., p. 21. 20. Lerner AB: On the etiology of vitiligo and gray hair. Am J Med 51:141-147, 1971.
Long-term follow-up of dermatitis herpetiformis in children Elisa Ermacora, M . D . , * Luigia Prampolini, M.D. ,** Giuliana Tribbia, M.D. ,*** Gabriella Pezzoli, M . D . , * Carlo Gelmetti, M.D.,* Gabriella Cucchi, M . D . , * * Alberto Tettamanti, M.D.,** Annamaria Giunta, M.D.,** and Ferdinando Gianotti, M.D.* Milan and Bergamo, Italy Dermatitis herpetiformis was diagnosed in seventy-six children by its clinical features and by detection of granular IgA deposits in the papillary dermis of perilesional skin. Enteric alterations demonstrated by measurement of Dxylose absorption and by small intestinal biopsies were detected in over 90% of all patients. A complete follow-up was obtained for all children who were followed for 3 to 10 years. Treatment with a gluten-free diet alone led to a reversal of the intestinal abnormality in 100% of our children and to the disappearance of cutaneous lesions in 82% of reported cases. This suggests that a complete remission of symptoms can be obtained with a gluten-free diet alone. Dapsone alone is effective therapy for the rash but does not affect the intestinal alterations. Furthermore, the lack of side effects to dietetic therapy for a long period of time makes the diet the treatment of choice in this disease. (J AM ACAD DERMATOL15:24-30, 1986.)
Dermatitis herpetiformis is a chronic disease characterized by a very pruritic eruption of small From the Department of Dermatology and Pediatric Dermatology* and the Department of Pediatrics,** University of Milan, and Tribbia,*** Ospedall Riuniti di Bergamo. Accepted for publication Jan. 28, 1986. Reprint requests to: Dr. Elisa Ermacora, Instituto di Clinica Dermatologiea I e Dermatologia Pediatrica, Via Pace 9-20123 MILANO-Italy.
24
erythematous and edematous papules, and sometimes vesicles, distributed in a herpeslike or figurate pattern. These cutaneous lesions are symmetrically located on the extensor aspects of the limbs, on the shoulders, on the nape of the neck, on the sacral area, and, occasionally, on the face and palms. A single eruption lasts from a few days to weeks, with continuous recurrences for years
Volume 15 Number 1 July, 1986
Dermatitis herpetiformis in children
25
Fig. 1. Dermatitis herpetiformis. Small erythematous-edematous papules in figurate pattern on a shoulder mixed with small crusts and hypochromic areas. Fig. 2. Dermatitis herpetiformis. Edematous lesions on the sacral area and buttocks. Fig. 3. Linear IgA dermatosis. Large, tense bullae in a "rosette" pattern in the pelvic region. (Figs. 1 and 2). Histologic preparations show marked polymorphonuclear leukocyte infiltration filling the top of the papillary dermis and forming microabscesses with fibrin that are overlaid with subepidermal vesicles. 2 Under the electron microscope, these vesicles are seen to be situated between the basal lamina and the dermis. Granular deposits of IgA in the papillary dermis are pathognomonic. 3 A gluten-dependent enteropathy has been observed in 85% to 95% of cases. 1.4 The lesions are
histologically similar to the intestinal lesions of celiac disease, 5'6 but in dermatitis herpetiformis the clinical symptoms are mild and are seen in only a few patients. Biochemically the nutritional and malabsorption patterns are rarely abnormal, 7 probably because the intestinal mucosa is only partially affected as demonstrated by multiple biopsies. 8,9 In children, human lymphocyte antigens (HLA) B 8, and Dr 3, and Dr 7 are detected, as they are in celiac disease in 60% to 80% of cases.l,m,II Oral admin-
26
Journal of the American Academy of Dermatology
Errhacora et al
Table I. Differential diagnosis: Dermatitis herpetiformis versus linear IgA dermatosis in childhood Characteristics
Dermatitis herpetiformis Small erythematous-edematous papules in figurate pattern Extensor aspects of the limbs, shoulders, nape of the neck, sacral area
Skin lesions Skin regions
[
Linear IgA dermatosis Large, tense bullae in a "rosette" pattern Perioral region, lower part of trunk, pelvic region, extremities Spontaneous healing in years or at puberty Rarely present
Chronic
Course
Almost always present
Gluten-dependent enteropa'-
Subepidermal vesicles, PMN infiltration, and fibrin in the papillary dermis Granular deposits of IgA in the papillary dermis Negative Deposits of IgA on dermal microfibrillae Effective in most of cases Excellent Modest
Histology
Subepidermal blisters
DIF
Linear deposits of IgA at BMZ
IIF Immune electron microscopy
Circulating IgA anti-BMZ (70%) Deposits of IgA in lamina lucida
Skin response to GFD Dapsone Corticosteroids
Effective in a few cases Modest Excellent if associated to Dapsone
thy
BMZ: Basementmembranezone; DIF: direct immunofluorescence;IIF: indirect immunofiuoreseence;PMN: polymorphonuclear. istration o f dapsone rapidly heals both the cutaneous lesions and relieves the pruritus. When it is stopped, there is a prompt relapse. Linear IgA dermatosis (Fig. 3) can be clearly differentiated by clinical and immunopathologic pattems as summarized in Table I. Our children with IgA linear dermatosis will be discussed in a separate paper. SUBJECTS AND METHODS Between 1974 and 1983, dermatitis herpetiformis was diagnosed in seventy-six children (36% boys), confirmed by detection of granular IgA in the papillary dermis of perilesional skin by direct immunofluoreseence tests. All the tests were performed in the same laboratory using fluorescein-conjugated Fab2 fragment antisera against IgA, IgG, IgM, and fluorescein-conjugated antibodies to C3 fraction of complement and fibrinogen (Istituto Behring, Milan, Italy). A detailed history was taken for each child, with special attention to gastrointestinal symptoms, age at their onset and their relationship to the introduction of gluten into the diet, and time since weaning. Intestinal biopsy specimens from the duodenojejunal flexure were taken from all the children with a Watson capsule. Xylosemia, measured 60 minutes after oral administration
of 5 gm of D-xylose (method of Roe and Rice~2), was used as an index of absorption. All the children with mucosal changes were immediately placed on a glutenfree diet. Dapsone (diaminodiphenylsulfone; Neosulfonazina Farmitalia) was added to the diet at doses of 0.5-1 mg/ kg/day if there were diffuse cutaneous lesions or distm'bing pruritus. Children without mucosal changes were treated with dapsone only at variable doses (0.52 mg/kg/day). The parents of children who were on a gluten-free diet were followed with periodic information and came to meetings to obtain strict dietary collaboration. The gluten sensitivity of the disease was demonstrated in a group of twenty-six children who were allowed to resume a normal diet. Follow-ups (clinical, biochemical, and histotogic) were complete for all the children. RESULTS No skin lesions were detected in children younger than 10 months of age. The most frequent ages of onset of dermatitis herpetiformis were between the second and the seventh years of life (75%), as shown in Fig. 4. From the histories, thirty children (38%) had had a chronic or relapsing diarrhea dur-
Volume 15 Number 1 July, 1986
Dermatitis herpetiformis in children
27
Number of oase~ 14
12 10
0 I
2
3
4
5
6
7
B
9
I0
11
12
13
Years
Fig. 4, Age of onset of dermatitis herpetiformis in Milan area. ing the first 2 years of life, but only eight patients had established diagnoses of malabsorption before the onset of dermatitis herpetiformis. At the time when the diagnosis of dermatitis herpetiformis was made, the weights of eleven children (15%) were below the tenth percentile, while the lengths of ten (13%) were below the tenth percentile. The D-xylose load test gave abnormal results in 32% of the patients. Biopsy specimens of the small intestine showed affected jejunal mucosa in sixtysix of seventy-six cases (85%), subtotal atrophy in thirty-seven cases, and partial atrophy in twentynine. Of ten subjects with normal intestinal mucosa, six had repeat biopsies done after 1 to 3 years on normal diets. Biopsy specimens from three of them showed altered mucosa, and the other three had remained normal. Finally, changes in the small intestine were detected in over 90% of cases.
Children on gluten-free diet therapy In thirty-three of forty-one children treated with a gluten-free diet only, all cutaneous manifestations disappeared within 1 to 6 months. The remaining eight children showed only reduction of the rash. Probably four of these did not always follow the diet.
Children on gluten-free diet plus dapsone therapy Of twenty-eight children treated with glutenfree diet plus dapsone, eighteen were able to dis-
continue dapsone therapy within 2 to 18 months (mean, 13 months). The other ten were s611 being treated at the time of writing, but with a lower dose of the drug (0.125-0.5 mg/kg/day).
Children on flapsone therapy Of seven children treated with dapSone alone, four were able to discontinue the drug within 1 to 4 years. The other three remained on therapy:
Side effects The side effects of dapsone therapy m our patients were decreases in hemoglobin of more than 2 gm in 50% of the children giVen 2 mglkg/day of dapsone and in 10% of the children given 1.5 to 2 mg/kg/day. Lower doses of dapsone never induced this side effect. Methemoglobinemia was also observed during the first week of treatment but never required interruption of the therapy. One child with a glucose-6-phosphate dehydirogenase (G-6-PD) deficiency had to stop taking the drug because of severe hemolysis. (Thus a screening test for G-6-PD activity should be performed prior to the administration of dapsone.) This child continued on a gluten-free diet alone and the rash cleared in 4 months.
Demonstration of gluten sensitivity of dermatitis herpetiformis In order to prove the gluten sensitivity of the disease, twenty-six children with gut lesions were submitted to a second jejunal biopsy after 12 to
Joumal of the American Academy of Dermatology
Ermacora et al
28
Table
II. Patients free o f cutaneous and intestinal symptoms after discontinuing therapy [
Case ,,,,,,,
,
1
[
,,2
[
3
4
5
6
,
7
10 N +
1 PA +
6 N +
+
-
+
,,
Onset of DH (age in years) Jejunum Dapsone GFD Age at stop-therapy Follow-up after stop-therapy (years) IgA after stop-therapy (years) Jejunum i n stop-therapy
3 N +
2 N +
3 TA +
_
_
+
7 3
4 4
5 5
10, 5 7
5 6
7 6
4 3
+ 1 N
+ 1 ND
+ 2 N
-1,5 ND
_ 6 N
_ 2.5 ND
+ 2 N
-
2 PA
DH: Dermatitis herpetiformis; GFD: gluten-free diet; N: normal mucosa; ND: not done; PA: partial atrophy; TA: total atrophy. 18 months on the gluten-free diet. At the time of this biopsy all the patients had normal results in the I>xylose test and had been without skin lesions for more than 6 months. These biopsy specimens showed normal mucosa and the children were allowed to return to a normal diet. All twenty-six had recurrences of skin rash 1 to 26 weeks after return to a normal diet arid all twenty-six had abnormal mucosa at the time of a third jejunal biopsy performed 2 to 6 months after resuming a normal diet. At the same time results of the xylose tests were abnormal in seven children (27%). All twenty-six children were again placed on a gluten-free diet.
abnormalities of either biochemical or clinical parameters are difficult to explain. The intestinal lesions may involve only the proximal area of the intestinal tract rather than the entire length? -8 In some of the eight children diagnosed previously as having celiac disease, the cutaneous symptoms appeared when gluten was reintroduced. In the others the symptoms were present even when they were on the gluten-free diet. On this basis, two different explanations can be proposed:
DISCUSSION
1, These children had dermatitis herpetiformis with marked intestinal symptoms and ~ere misdiagnosed as having celiac disease. The early removal of gluten from their diets could have delayed the appearance of t h e skin lesions until gluten was reintroduced. 2. These children actually did have celiac disease, with the dermatitis herpetiformis I'epresenting a different manifestation in an additional organ. The small number of patients with celiac disease who develop dermatitis herpetiformis 6,~5goes against this second proposal, as does the fact that in our region the frequencies of the two diseases are quite similar.
In agreement with data in the a,~ailable literature, 7'13 only thirty children of seventy-six (38%) had clinical hlstories of intestinal symptoms and only eight had a diagnosis of celiac disease. The I>xylose test results and growth percentiles were abnormal for only a small number of subjects. 7 The jejunal biopsy, however, showed mucosal alterations in over 90% of the cases, i4 The lack of Correlation between the high frequency of histologic lesions and the only slight
Treatment with gluten-free diet alone led to a return to normal intestinal mucosa in 100% of our children and also to disappearance of cutaneous lesions in 82% of the cases reported. This suggests that complete disappearance of both cutaneous and intestinal symptoms can be obtained with glutenfree diet alone if it is properly followed over a long period of time (more than 6 monthst6'aT). Dapsone given alone is rapidly effective against eruption but is not effective against the intestinal al-
Children
in stop-therapy
At the time of writing, 2 to 7 years after discontinuing therapy, only seven of the seventy-six children had no cutaneous symptoms. These seven have had additional skin and intestinal biopsies. The findings are summarized in Table II.
Volume 15 Number 1 July, 1986
terations. ~s We demonstrated this in three children treated with dapsone alone. Although the skin lesions disappeared, the intestinal mucosa remained altered even after 1 to 3 years of this therapy. In our group of twenty-six children, involvement of gluten in both the intestinal and skin lesions of dermatitis herpetiformis was fully confirmed. In children exposed to gluten after a period on gluten-free diet, no intestinal symptoms were observed even when mucosal alterations (as confirmed by biopsy) were present. Cutaneous relapses occurred when normal diets were resumed; they ranged widely in their severity, in their time of appearance, and they were apparently independent o f the duration of the preceding treatment? In some cases of severe relapses, an additional treatment with dapsone had to be added during the waiting period prior to the third biopsy. On reintroduction of the gluten-free diet, two different skin responses were observed: 1. Subjects who had only slight rashes after the reintroduction of the gluten, and therefore were not given dapsone, showed prompt clearing of the lesions on the gluten-free diet (8-30 days). 2. Patients who, in addition to gluten-free diet also required dapsone, were able to discontinue this drug only after many months (9-27) on the gluten-free diet. Some were still in therapy with dapsone plus glutenfree diet at the time of writing. At present, a relationship between celiac disease and dermatitis herpetiformis cannot be established. ~9 The gluten seems to be responsible for the intestinal symptoms in both diseases, ~7 although in dermatitis herpetiformis the clinical s y m p t o m s are slight. Gluten-free diet leads to normalization of intestinal mucosa in both diseases and in dermatitis herpetitbrmis, specifically, it clears the cutaneous eruption. 4'~6'~7 Cutaneous deposits of IgA have never been observed in celiac disease. 6,~9 In addition, while there is familial ten' dency in first-degree relatives with different frequencies in celiac disease, no first-degree relatives with dermatitis herpetiformis were detected in our cases of dermatitis herpetiformis nor have any been reported in the literature. Furthermore, the monozygotic twin of an affected female child never had any cutaneous eruption and had a negative skin biopsy. Moreover, some parents of chil-
Dermatitis herpetiformis in children
29
dren with dermatitis herpetiformis had skin biopsies and no IgA could be seen by direct immunofluorescence tests. In both diseases there is a high percentage of HLA B8, Dr 3, and Dr 7. ~°,~ None of these findings serve to show whether celiac disease and dermatitis herpetiformis are two different diseases or are different expressions of the same disease. This would be of particular importance for the prognosis of dermatitis herpetiformis. It is known that in celiac disease patients the diet must be continued indefinitely. The studies by Leonard et aP 7 conceming the reintroduction of gluten into the diets of adults with dermatitis herpetiformis who had been on a gluten-free diet and free of skin symptoms for years show that the gluten sensitivity can persist indefinitely. Of all our patients, only four had reached puberty at the time of writing, and they still had dermatitis herpetiformis. This observation is in contrast with the experience in adults, in whom the beginning of the disease was not clearly established in childhood. Because of the small number of patients who have been cured or have reached puberty and are still ill, we are unable to establish a prognosis for dermatitis herpetiformis in children. In our experience, the response to dietetic therapy alone has been excellent. In contrast to dapsone therapy, gluten-free diet has no side effects even after a prolonged period of time, and we consider it the treatment of choice. REFERENCES
1. Katz SJ, Hall RP, Lawley TJ, Strober W: Dermatitis herpetiformis: The skin and the gut. Ann Intern Med 93:857-874, 1980. 2. Katz SJ, Strober W: The pathogenesis of dermatitis herpetiformis. J Invest Dermatol 70:63-75, 1978. 3. Fry L, Seah PP: Dermatitis herpetiformis: An evaluation of diagnostic criteria. Br J Dermatol 90:137-146, 1974, 4. Fry L, Leonard J, Swain F, et al: Long term follow-up of dermatitis herpetiformis with and without dietary gluten withdrawaI. Br J Dermatol 107:631-640, 1982, 5. Brown JR, Parker F, Weinstein WM, Rubin CE: The small intestinal mucosa in dermatitis herpetiformis. Severity and distribution of small intestinal lesions and associated malabsorption. Gastroenterology 60:355-361, 1971. 6. Scott BB, Young S, Raja SM, et al: Coeliac disease and dermatitis herpetiformis. Further studies of their relationship. Gut 17:759-762, 1976. 7. Fry L, Keir P, McMinn RMH, et al: Small intestine structure and function and haematological changes in dermatitis herpetiformis. Lancet 2:729-734, 1967.
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8. Scott BB, Losowsky MS: Patchiness and duodenal-jejunal variation of the mucosal abnormality in eoeliae disease and dermatitis herpetiformis. Gut 17:984-992, 1976. 9. Weinstein WM, Brown JR, Parker F, Rubin CE: The small intestinal mueosa in dermatitis herpetiformis. II. Relationship of the small intestinal lesions to gluten. Gastroenterology 60'362-369, 1971. 10. Pehamberger H, Holubar K, Mayr WR: HLA-DR3 in dermatitis herpetiformis. Br J Dermatol 104:321-324, 1981. 11. Richiardi P, Borelli I, Malavasi F, et al: HLA antigens in juvenile dermatitis herpetiformis. Acta Derm Venereol (Stockh) 61:241-244, 1981. 12. Roe JH, Rice EW: A photometric method for the determination to free pentose in animal tissues. J Biol Chem 173:507, 1948. 13. Ljunghail K, Loof L, Grimelius L, et al: Dermatitis herpefiformis: Relation between circulating antibodies against reticulin and gluten, small intestinal mucosa
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17. 18. 19.
status and absorptive capacity. Acta Derm Venereoi (Stockh) 63:27-34, 1983. Gawkrodger DJ, Blackwell JN, Gilmour HM, et al: Dermatitis herpetiformis: Diagnosis, diet and demography. Gut 25:151-157, 1984. Shuster S, Watson AJ, Marks J: Coeliac syndrome in dermatitis herpetiformis. Lancet 1:1101-1106, 1968. Frodin T, Gotthard R, Hed J, et al: Gluten-free diet for dermatitis herpetiformis: The long-term effect on cutaneous, immunological and jejunal manifestations. Aeta Derm Venereol (Stockh) 61:405-411, 1981. Leonard J, Haffenden G, Tucker W, et al: Gluten challenge in dermatitis herpctiformis. N Engl J Med 308-'816819, 1983. Reunala T, Blomquist K, Tarpila S: Gluten-free diet in dermatitis herpetiformis. Clinical response of skin lesions in 81 patients. Br J Dermatol 4:287-289, 1977. Leonard JN, Haffenden G, Tucker W, et al: Skin biopsies in relatives of patients with dermatitis herpetiformis. Acta Derm Venereol (Stockh) 63:252-254, 1983.
I !
I
Dose-response study of topical minoxidil in male pattern baldness* Elise A. Olsen, M . D . , Elizabeth R. D e L o n g , P h . D . , and Madeline S. Weiner, R . N . , B . S . N . Durham, NC Eighty-nine healthy men with male pattern baldness completed a 6-month double-blind, placebo-controlled study of 0.01%, 0.1%, 1%, and 2% topical minoxidil. Subjects on 2% topical minoxidil had a statistically significant increase in mean total target area hair count over baseline compared to the placebo, 0.01%, and 0.1% topical minoxidil groups (p = 0.04). Changes from baseline were more impressive with the 2% topical minoxidil group but not significantly different from the 1% topical minoxidil group in all parameters of objective response to treatment. The investigator, however, rated more subjects as having at least a moderate cosmetic response to treatment in the 2% versus 1% topical minoxidil treatment group. These results indicate that 1% topical minoxidil is the lowest effective concentration o f topical minoxidil for male pattern baldness of those tested. Because o f the more impressive changes in hair counts and the cosmetic preference for the 2% versus 1% topical minoxidil, 2% topical minoxidil may be the standard preferred treatment for male pattern baldness. (J AM ACAD DERMXrOL 15:3037, 1986.)
From the Division of Dermatology,Department of Medicine, Duke University Medical Centerand Health Services Research, Veterans Administration Hospital. Supported in part by a grant from The Upjohn Company, Kalamazoo, ML 30
Accepted for publication Feb. 7, 1986. Reprint requests to: Dr. Elise A. Olsen, Box 3294, Duke University Medical Center, Durham, NC 27710/919-684-6844. *This is Publication No. 144 from the Dermatologic Research Laboratories at Duke University Medical Center.