- Email: [email protected]
Acute generalized exanthematous pustulosis induced by itraconazole
794
Brief communications
mones and pregnancy have been reported to either improve or exacerbate autoimmune diseases. Autoimmune bttllous diseases also are modulated b y pregnancy. Herpes gestations occurs during pregnancy and puerperium, and pemphigus vulgaris can develop or be exacerbated during pregnancy or immediately postpartum. 9 On the other hand, patients with linear IgA disease improve during pregnancy. 10 Although one patient has been discussed in w h o m E B A developed on the second day after her third delivery, 11 there are few observations on the influence of pregnancy on EBA. In our patient, the onset o f E B A in connection with systemic estrogen and progesterone treatment and the exacerbation in her first month o f gestation and during the luteal phase o f her menstrual cycle implicate progesterone as a key factor. Another possibility is that hormonal factors accelerate not the autoimmune response but bulla formation through, for example, augmentation o f protease activity. REFERENCES
1. Woodley DT, Gammon WR, Briggaman RA. Epidermolysis bullosa acqnisita: autoimmunity to type VII collagen. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, editors. Derruatology in general medicine. New York: McGraw-Hill, 1993:630-5.
Journal of the American Academy of Dermatology May 1997
2. Sugi T, Hashimoto T, Hibi T, et al. Production of human monoclonal anti-basement membrane zone (BMZ) antibodies from a patient with bullous pemphigoid (BP) by Epstein-Barr virus transformation: analyses of the heterogeneity of anti-BMZ antibodies in BP sera using them. J Clin Invest 1989;84:1050-5. 3. Dmochowski M, Hashimoto T, Bhogal BS, et al. lmmunoblotting studies of linear IgA disease. J Dermatol Sci 1993;6:194-200. 4. Stem R, Fishman J, Brusman H, et al. Systemic lupus erythematosus associated with Klinefelter's syndrome. AnJaritis Rheum 1977;20:18-22. 5. Jungers P, Dougados M, Pellissier C, et al. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum 1982;25:618-23. 6. Mackworth-Young CG, Parke AL, Morley KD, et al. Sex hormones in male patients with systemic lupus erythematosus: a comparison with other disease groups. Eur J Rheumatol Inflamm 1983;6:228-32. 7. Luster MI, Hayes HT, Korach K, et al. Estrogen immunosuppression is regulated through estrogenic responses in the thymus. J Immunol 1984;133:110-6. 8. Billingham RE, Beer AE. Reproductive immunology: past, present, and future. Perspect Biol Med 1984;27:259-75. 9. Goldberg NS, DeFeo C, Kirshenbaum N. Pemphigus ~xtlgaffs and pregnancy: risk factors and recommendations. J Am Acad Dermatol 1993;28:877-9. 10. Collier PM, Kelly SE, Wojnarowska F. Linear IgA disease and pregnancy. J Am Acad Dermatol 1994;30:40711. 11. Kero M, Niemi KM, Kanerva L. Pregnancy as a trigger of epidermolysis bullosa acquisita. Acta Derm Venereol (Stockh) 1983;63:353-6.
Acute generalized exanthematous pustulosis induced by itraconazole Young Min Park, MD, Jin W o u Kim, MD, and Chung W o n Kim, M D Seoul, Korea Only one case o f acute generalized exanthematous pustulosis (AGEP) induced b y itraconazole has been reported in the English-language literature. 1 W e report a case of A G E P induced by itraconazole in a 27-year-old w o m a n with a 15-year history o f psoriasis vulgaris.
From the Department of Dermatology, Catholic University Medical College. Reprint requests: Jin Wou Kim, MD, Deparlment of Dermatology, St. Paul's Hospital, Catholic University Medical College, 620-56, Jeonnong-dong, Dongdaemoon-ku, Seoul, 130-022, Korea. J Am Acad Dermatol 1997;36:794-6. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/54/79670
CASE REPORT
A 27-year-old Korean woman had a generalized, pmritic, erythematous, maculopapular, and pusmlar eruption accompanied by a low-grade fever, edema of the face and legs, and malaise. She had a 15-year history of psoriasis on the scalp, knees, and elbows, which had been treated with topical corticosteroids. Two weeks earlier, she began taking itraconazole, 100 mg twice daily. One week later fever and pmritic, multiple, symmetric, erythematous papules developed, some of which became confluent, producing plaques on her face, trunk, and limbs (Fig. 1, A). Her palms and soles were spared; her mucous membranes were not involved. Overlying these papules and plaques were multiple minute pustules (Fig. 1, B). She continued to take itraconazole for the next 5 days. Laboratory studies showed leukocytosis (16,200/mm3),
Journal of the American Academy of Dermatology Volume 36, Number 5, Part 1
Brief cormnunications
795
Fig. 2. Subcomeal pustule composed of neutrophils in the upper stratum malpighium and a diffuse perivascular infiltrate with numerous neutrophils and several eosinophils in the papillary dermis. (Hematoxylin-eosin stain; original magnification x40.)
Fig. 1. A, Symmetrically distributed erythematous plaques and desquamation on the trunk. B, Some minute pustules on the erythematous plaques on the thigh. hypoalbuminemia (2.9 mg/dl), and hypocalcemia (8.1 mg/dl). The erythrocyte sedimentation rate was elevated (35 mm/br). Cultures for bacteria and fungi were negative. A skin biopsy specimen revealed a subcomeal pustule containing many neutrophils, and a diffuse perivascular infiltrate in the papillary dermis composed of mononuclear cells, many neutrophils, arid a few eosinophils (Fig. 2). A diagnosis of generalized pustular psoriasis was made, and treatment was started with etretinate, 30 mg daily. One day later, etretinate was stopped and treatment of symptoms with oral hydroxyzine and topical 1% hydrocortisone lotion resulted in clearing of her eruption within 10 days. One month later we perfolaned scratch/patch tests with saline- or alcohol-diluted (100 rag/10 ml) itraconazole and other drugs. All were negative. With the patient's permission, an oral provocation test done with itraconazole (33.3 mg) resulted in pustule formation within 2 hours in a few erythematous plaques on her trunk. There has been no recurrence of pustular lesions for 2 years.
DISCUSSION Generalized pustular psoriasis (GPP) induced by drugs is a well-described phenomenon, whereas a
generalized pustular drug eruption is uncommon. It is often difficult to differentiate between them, especially in a patient with a previous history of psoriasis. In 1980, Beylot, Bionlac, and Doutre 2 introduced the term acute generalized exanthematous pustulosis (AGEP) to describe a pustular drag-induced eruption characterized by numerous, small, nonfollicular pustules arising on a widespread edematous erytbematous bed resembling GPP, associated with high fever and neutrophilia. In 1991, Roujeau et al. 3 retrospectively analyzed 63 patients with AGEP, including 11 patients with a history of psoriasis. AGEP appeared distinct from pustular psoriasis based on several slight pathologic differences, drug induction in most cases, a more acute course of fever and pustulosis, and rapid spontaneous heating. Therefore they suggested that AGEP is a reaction pattern, perhaps favored by a "psoriatic background." We believe that the characteristics of our patient are consistent with those described by Roujeau et al. 3 The most frequent causes of AGEP appear to be drugs, although acute infections with enterovimses and hypersensitivity to mercury may be involved. 3 Drugs implicated include amoxicillin, ampicillin, spiramycin, erythromycin, cyclins, nadoxolol, carbamazepine and nifedipine. 3 Reports of pustular drug eruption induced by other drugs such as cephalexin,4, 5 cephradine,6 cefazolin,7 diltiazem,8 naproxen, 9 norfloxacin, l° and trimethoprim-sulfamethoxazole 11 have been described. We believe that in our patient a pustular eruption developed from the use of itraconazole. In our patient there was no
796
Journal of the American Academy of Dermatology May 1997
Brief communications
history o f recent infection or contact to mercury. Recently, H e y m a n n and Manders I described a case o f A G E P induced b y the administration o f itraconazole for onychomycosis. However, the patient had no family history o f psoriasis, and challenge with itraconazole was not performed. W e propose that itraconazole should be added to the list o f drugs causing A G E P and that physicians should be cautious in the use of itraconazole in a patient with psoriasis.
4. 5. 6. 7. 8.
REFERENCES 1. Heymann WR, Manders SM. Itraconazole-induced acute generalized exanthemic pustulosis. J Am Acad Dermatol 1995;33:130-1. 2. Beylot C, Bioulac P, Doutre MS. Pustuloses exanth6matiques aigu~s g6n6ralis6es: h propos de 4 cas. Ann Dermatol Venereol 1980;107:37-48. 3. Roujeau J-C, Bioulac P, Bourseau C, et al. Acute general-
9. 10. 11.
ized exanthematous pusmlosis: analysis of 63 cases. Arch Dermatol 1991;127:1333-8. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drag exposure: Is it pustular psoriasis or a pusmlar drag eruption? Br J Dermatol 1994;130:514-9. Jackson H, Vion B, Levy PM. Generalized eruptive pustular drag rash due to cephalexin. Dermatologica 1988; 177:292-4. Kalb RE, Grossman ME. Pustular eruption following administration of cephradine. Curls 1986;38:58-60. Fayol J, Bernard P, Bonnetblanc JM. Pustular eruption following administration of cefazolin: a second case report [letter]. J Am Acad Dermatol 1988;19:571. Lambert DG, Dalac S, Beer F, et al. Acute generalized exanthematous pustular dermatitis induced by diltiazem. Br J Dermatol 1988;118:308-9. Grattan CE. Generalized eruptive pustular drug rash due to naproxen. Dermatologica 1989; 179:57-8. Shelley ED, Shelley WB. The subcomeal pustular drug eruption: an example induced by norfloxacin. Cuffs 1988; 42:24-7. MacDonald KJS, Green CM, Kenicer KJA. Pustular dermatosis induced by co-trimoxazole. Br Med J 1986;293: 1279-80.
Efficacy of cyclosporine on mucocutaneous manifestations of Behget's disease Oktay A v o , M D , Nalan Gtirler, M D , and Ali Tahsin Gtine~, M D Behqet' s disease (BD) is a chronic multisystemic disorder whose m a i n manifestations include m u c o cutaneous, ocular, and vascular abnormalities. Therapy includes corticosteroids, immunosuppressants, interferons, and colchicine. 1-4 Recently several reports have indicated that cyclospofine is effective in the treatment o f BD. 2' 5-8 T h e dermatology literature includes only a f e w case reports about the effects o f cyclosporine on m u c o cutaneous manifestations o f the disease. 9' 10 W e evaluated cyclosporine therapy in the treatment o f mucocutaneous manifestations of B D in an open clinical study.
From the Departmentof Dermatology,Dokuz Eylul University. Reprintrequests: OktayAvcl,MD, DokuzEylulUniversity,Facultyof Medicine, Departmentof Dermatology,35340 Inciralti,Izmir,Turkey. J Am Acad Dermatol 1997;36:796-7. Copyright © 1997 by the American Academyof Dermatology,Inc. 0190-9622/97/$5.00 + 0 16/54/79672
Izmir, Turkey
MATERIAL AND METHODS Patients with BD who have a positive pathergy test, diagnosed by the criteria of the International Study Group for Behqet's Disease, u were studied. Baseline clinical characteristics were recorded. Baseline laboratory measurements included hemoglobin; erythrocyte and leukocyte counts; blood potassium and magnesium levels; fasting blood sugar; urea and uric acid; serum levels of creatinine, lipids, proteins; fiver function tests and urinalysis were also done. The patients were treated with cyclosporine, 5 mg/kg daily. Whole blood trough drug levels of cyclosporine were investigated early in the treatment. Patients were clinically examined at monthly intervals and blood pressure levels were recorded. Laboratory tests and pathergy tests were also performed at monthly intervals. Adverse effects were monitored and treatment was continued unless a nephrotoxic or hepatotoxic adverse effect appeared. If the semm creatinine level exceeded 30% of baseline during treatment, the dose of cyclosporine was reduced to 2.5 mg/kg daily, and if the increase of serum creatinine level continued, cyclosporine was discontinued.
Brief communications
mones and pregnancy have been reported to either improve or exacerbate autoimmune diseases. Autoimmune bttllous diseases also are modulated b y pregnancy. Herpes gestations occurs during pregnancy and puerperium, and pemphigus vulgaris can develop or be exacerbated during pregnancy or immediately postpartum. 9 On the other hand, patients with linear IgA disease improve during pregnancy. 10 Although one patient has been discussed in w h o m E B A developed on the second day after her third delivery, 11 there are few observations on the influence of pregnancy on EBA. In our patient, the onset o f E B A in connection with systemic estrogen and progesterone treatment and the exacerbation in her first month o f gestation and during the luteal phase o f her menstrual cycle implicate progesterone as a key factor. Another possibility is that hormonal factors accelerate not the autoimmune response but bulla formation through, for example, augmentation o f protease activity. REFERENCES
1. Woodley DT, Gammon WR, Briggaman RA. Epidermolysis bullosa acqnisita: autoimmunity to type VII collagen. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, editors. Derruatology in general medicine. New York: McGraw-Hill, 1993:630-5.
Journal of the American Academy of Dermatology May 1997
2. Sugi T, Hashimoto T, Hibi T, et al. Production of human monoclonal anti-basement membrane zone (BMZ) antibodies from a patient with bullous pemphigoid (BP) by Epstein-Barr virus transformation: analyses of the heterogeneity of anti-BMZ antibodies in BP sera using them. J Clin Invest 1989;84:1050-5. 3. Dmochowski M, Hashimoto T, Bhogal BS, et al. lmmunoblotting studies of linear IgA disease. J Dermatol Sci 1993;6:194-200. 4. Stem R, Fishman J, Brusman H, et al. Systemic lupus erythematosus associated with Klinefelter's syndrome. AnJaritis Rheum 1977;20:18-22. 5. Jungers P, Dougados M, Pellissier C, et al. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum 1982;25:618-23. 6. Mackworth-Young CG, Parke AL, Morley KD, et al. Sex hormones in male patients with systemic lupus erythematosus: a comparison with other disease groups. Eur J Rheumatol Inflamm 1983;6:228-32. 7. Luster MI, Hayes HT, Korach K, et al. Estrogen immunosuppression is regulated through estrogenic responses in the thymus. J Immunol 1984;133:110-6. 8. Billingham RE, Beer AE. Reproductive immunology: past, present, and future. Perspect Biol Med 1984;27:259-75. 9. Goldberg NS, DeFeo C, Kirshenbaum N. Pemphigus ~xtlgaffs and pregnancy: risk factors and recommendations. J Am Acad Dermatol 1993;28:877-9. 10. Collier PM, Kelly SE, Wojnarowska F. Linear IgA disease and pregnancy. J Am Acad Dermatol 1994;30:40711. 11. Kero M, Niemi KM, Kanerva L. Pregnancy as a trigger of epidermolysis bullosa acquisita. Acta Derm Venereol (Stockh) 1983;63:353-6.
Acute generalized exanthematous pustulosis induced by itraconazole Young Min Park, MD, Jin W o u Kim, MD, and Chung W o n Kim, M D Seoul, Korea Only one case o f acute generalized exanthematous pustulosis (AGEP) induced b y itraconazole has been reported in the English-language literature. 1 W e report a case of A G E P induced by itraconazole in a 27-year-old w o m a n with a 15-year history o f psoriasis vulgaris.
From the Department of Dermatology, Catholic University Medical College. Reprint requests: Jin Wou Kim, MD, Deparlment of Dermatology, St. Paul's Hospital, Catholic University Medical College, 620-56, Jeonnong-dong, Dongdaemoon-ku, Seoul, 130-022, Korea. J Am Acad Dermatol 1997;36:794-6. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/54/79670
CASE REPORT
A 27-year-old Korean woman had a generalized, pmritic, erythematous, maculopapular, and pusmlar eruption accompanied by a low-grade fever, edema of the face and legs, and malaise. She had a 15-year history of psoriasis on the scalp, knees, and elbows, which had been treated with topical corticosteroids. Two weeks earlier, she began taking itraconazole, 100 mg twice daily. One week later fever and pmritic, multiple, symmetric, erythematous papules developed, some of which became confluent, producing plaques on her face, trunk, and limbs (Fig. 1, A). Her palms and soles were spared; her mucous membranes were not involved. Overlying these papules and plaques were multiple minute pustules (Fig. 1, B). She continued to take itraconazole for the next 5 days. Laboratory studies showed leukocytosis (16,200/mm3),
Journal of the American Academy of Dermatology Volume 36, Number 5, Part 1
Brief cormnunications
795
Fig. 2. Subcomeal pustule composed of neutrophils in the upper stratum malpighium and a diffuse perivascular infiltrate with numerous neutrophils and several eosinophils in the papillary dermis. (Hematoxylin-eosin stain; original magnification x40.)
Fig. 1. A, Symmetrically distributed erythematous plaques and desquamation on the trunk. B, Some minute pustules on the erythematous plaques on the thigh. hypoalbuminemia (2.9 mg/dl), and hypocalcemia (8.1 mg/dl). The erythrocyte sedimentation rate was elevated (35 mm/br). Cultures for bacteria and fungi were negative. A skin biopsy specimen revealed a subcomeal pustule containing many neutrophils, and a diffuse perivascular infiltrate in the papillary dermis composed of mononuclear cells, many neutrophils, arid a few eosinophils (Fig. 2). A diagnosis of generalized pustular psoriasis was made, and treatment was started with etretinate, 30 mg daily. One day later, etretinate was stopped and treatment of symptoms with oral hydroxyzine and topical 1% hydrocortisone lotion resulted in clearing of her eruption within 10 days. One month later we perfolaned scratch/patch tests with saline- or alcohol-diluted (100 rag/10 ml) itraconazole and other drugs. All were negative. With the patient's permission, an oral provocation test done with itraconazole (33.3 mg) resulted in pustule formation within 2 hours in a few erythematous plaques on her trunk. There has been no recurrence of pustular lesions for 2 years.
DISCUSSION Generalized pustular psoriasis (GPP) induced by drugs is a well-described phenomenon, whereas a
generalized pustular drug eruption is uncommon. It is often difficult to differentiate between them, especially in a patient with a previous history of psoriasis. In 1980, Beylot, Bionlac, and Doutre 2 introduced the term acute generalized exanthematous pustulosis (AGEP) to describe a pustular drag-induced eruption characterized by numerous, small, nonfollicular pustules arising on a widespread edematous erytbematous bed resembling GPP, associated with high fever and neutrophilia. In 1991, Roujeau et al. 3 retrospectively analyzed 63 patients with AGEP, including 11 patients with a history of psoriasis. AGEP appeared distinct from pustular psoriasis based on several slight pathologic differences, drug induction in most cases, a more acute course of fever and pustulosis, and rapid spontaneous heating. Therefore they suggested that AGEP is a reaction pattern, perhaps favored by a "psoriatic background." We believe that the characteristics of our patient are consistent with those described by Roujeau et al. 3 The most frequent causes of AGEP appear to be drugs, although acute infections with enterovimses and hypersensitivity to mercury may be involved. 3 Drugs implicated include amoxicillin, ampicillin, spiramycin, erythromycin, cyclins, nadoxolol, carbamazepine and nifedipine. 3 Reports of pustular drug eruption induced by other drugs such as cephalexin,4, 5 cephradine,6 cefazolin,7 diltiazem,8 naproxen, 9 norfloxacin, l° and trimethoprim-sulfamethoxazole 11 have been described. We believe that in our patient a pustular eruption developed from the use of itraconazole. In our patient there was no
796
Journal of the American Academy of Dermatology May 1997
Brief communications
history o f recent infection or contact to mercury. Recently, H e y m a n n and Manders I described a case o f A G E P induced b y the administration o f itraconazole for onychomycosis. However, the patient had no family history o f psoriasis, and challenge with itraconazole was not performed. W e propose that itraconazole should be added to the list o f drugs causing A G E P and that physicians should be cautious in the use of itraconazole in a patient with psoriasis.
4. 5. 6. 7. 8.
REFERENCES 1. Heymann WR, Manders SM. Itraconazole-induced acute generalized exanthemic pustulosis. J Am Acad Dermatol 1995;33:130-1. 2. Beylot C, Bioulac P, Doutre MS. Pustuloses exanth6matiques aigu~s g6n6ralis6es: h propos de 4 cas. Ann Dermatol Venereol 1980;107:37-48. 3. Roujeau J-C, Bioulac P, Bourseau C, et al. Acute general-
9. 10. 11.
ized exanthematous pusmlosis: analysis of 63 cases. Arch Dermatol 1991;127:1333-8. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drag exposure: Is it pustular psoriasis or a pusmlar drag eruption? Br J Dermatol 1994;130:514-9. Jackson H, Vion B, Levy PM. Generalized eruptive pustular drag rash due to cephalexin. Dermatologica 1988; 177:292-4. Kalb RE, Grossman ME. Pustular eruption following administration of cephradine. Curls 1986;38:58-60. Fayol J, Bernard P, Bonnetblanc JM. Pustular eruption following administration of cefazolin: a second case report [letter]. J Am Acad Dermatol 1988;19:571. Lambert DG, Dalac S, Beer F, et al. Acute generalized exanthematous pustular dermatitis induced by diltiazem. Br J Dermatol 1988;118:308-9. Grattan CE. Generalized eruptive pustular drug rash due to naproxen. Dermatologica 1989; 179:57-8. Shelley ED, Shelley WB. The subcomeal pustular drug eruption: an example induced by norfloxacin. Cuffs 1988; 42:24-7. MacDonald KJS, Green CM, Kenicer KJA. Pustular dermatosis induced by co-trimoxazole. Br Med J 1986;293: 1279-80.
Efficacy of cyclosporine on mucocutaneous manifestations of Behget's disease Oktay A v o , M D , Nalan Gtirler, M D , and Ali Tahsin Gtine~, M D Behqet' s disease (BD) is a chronic multisystemic disorder whose m a i n manifestations include m u c o cutaneous, ocular, and vascular abnormalities. Therapy includes corticosteroids, immunosuppressants, interferons, and colchicine. 1-4 Recently several reports have indicated that cyclospofine is effective in the treatment o f BD. 2' 5-8 T h e dermatology literature includes only a f e w case reports about the effects o f cyclosporine on m u c o cutaneous manifestations o f the disease. 9' 10 W e evaluated cyclosporine therapy in the treatment o f mucocutaneous manifestations of B D in an open clinical study.
From the Departmentof Dermatology,Dokuz Eylul University. Reprintrequests: OktayAvcl,MD, DokuzEylulUniversity,Facultyof Medicine, Departmentof Dermatology,35340 Inciralti,Izmir,Turkey. J Am Acad Dermatol 1997;36:796-7. Copyright © 1997 by the American Academyof Dermatology,Inc. 0190-9622/97/$5.00 + 0 16/54/79672
Izmir, Turkey
MATERIAL AND METHODS Patients with BD who have a positive pathergy test, diagnosed by the criteria of the International Study Group for Behqet's Disease, u were studied. Baseline clinical characteristics were recorded. Baseline laboratory measurements included hemoglobin; erythrocyte and leukocyte counts; blood potassium and magnesium levels; fasting blood sugar; urea and uric acid; serum levels of creatinine, lipids, proteins; fiver function tests and urinalysis were also done. The patients were treated with cyclosporine, 5 mg/kg daily. Whole blood trough drug levels of cyclosporine were investigated early in the treatment. Patients were clinically examined at monthly intervals and blood pressure levels were recorded. Laboratory tests and pathergy tests were also performed at monthly intervals. Adverse effects were monitored and treatment was continued unless a nephrotoxic or hepatotoxic adverse effect appeared. If the semm creatinine level exceeded 30% of baseline during treatment, the dose of cyclosporine was reduced to 2.5 mg/kg daily, and if the increase of serum creatinine level continued, cyclosporine was discontinued.