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Erythema multiforme after verapamil treatment
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lsotretinoin treatment of severe cystic acne in a heart transplant patient receiving cyciosporine: Consideration of drug interactions To the Editor." In their brief communication, "Isotretinoin Treatment of Severe Acne in Post-transplant Patients Taking Cyclosporine" (J AM ACAD DERMA'rOL 1990;22:693-4) Bunker et al. point out the concern that isotretinoin may enhance transplant rejection. This conclusion is based on experimental evidence with skin homografts treated with vitamin A acid. 1 We wish to bring to the authors' attention a similar case of a heart transplant recipient who responded to a 20-week course of isotretinoin therapy for severe cystic ache. 2This patient was also referred to in a recent review. 3 In 1986 O'Connell et al.2 conducted a study of 107 consecutive cases of heart transplantation at Stanford University Medical Center. Ache was a frequent cause of morbidity and was present in 59 of these patients. In most cases the acne was characteristic of steroid acne. However, one patient, a 27-year old man, had severe nodulocystic acne on the face, neck, upper chest, and back. Topical antibiotics and oral tetracycline failed to control his disease. Isotretinoin was therefore begun at a dose of 40 mg daily, increased to 80 mg at 2 months, and continued at that dose up to 20 weeks, then discontinued. Cephalexin (Keflex) was added because of the initial slow response to isotretinoin. The response to cephalexin was resolution of the cysts on the face and marked improvement of the inflammatory papular component. The aerie continued to improve after discontinuation of the isotretinoin. The patient's cyclosporine trough levels remained within the recommended therapeutic range. There was no evidence of graft rejection during the course of isotretinoin therapy, and the cardiac status remained stable. Potential drug interactions are of concern in patients receiving cyclosporine and must be considered when new therapies are initiated. Cyclosporine is metabolized in the liver by the cytochrome P-450 microsomal enzyme system. Two drugs commonly prescribed by dermatologists, erythromycin and ketoconazole, may increase cyclosporine concentrations in the blood by inhibiting hepatic microsomal enzymes. Other drugs that may similarly inhibit the excretion and/or metabolism of cyclosporine and thereby raise blood levels of the drug include the anabolic steroids danazol and norethindrone, oral contraceptives, and calcium-channel antagonists. Drugs that may increase hepatic clearance by hepatic enzyme induction and thereby decrease cyclosporine blood levels include phenytoin, phenobarbital, tuberculostatic therapy with rifampin and isoniazid. A third category of drugs can interact with cyclosporine by altering renal function. These in-
ll
III
I
II II
I
I I
clude aminoglycoside antibiotics, melphalan, amphotericin B, trimethoprim and trimethoprim-sulfamethoxazoie. When isotretinoin is given to patients receiving cyclospofine, attention must also be directed to the possible combined effect of both drugs on serum lipids. Hyperlipidemia is a well-known side effect of retinoid therapy.4 Cyclosporine therapy may also increase total cholesterol,s Acute pancreatitis is a common complication among transplant patients6and has also been reported in patients receiving isotretinoin for cystic ache. 7 Thus careful monitoring of serum cholesterol and triglycerides is essential in patients receiving both drugs. With the report of Bunker et al., there are now two cases of the safe and effective use of isotretinoin for severe cystic ache in heart transplant recipients, and there are additional reports of the use ofisotretinoin in patients with renal transplants. However, experience to date is limited, and such patients must be carefully monitored with regard to their increased risk of adverse side effects from potential drug interactions.
Elizabeth A. Abel, MD Stanford, California
REFERENCES 1. Floersheim GL, BollagW. Accelerated rejection of skin homografts by vitamin A acid. Transplantation 1972;14:564-7. 2. O'Connell BM, Abel EA, Nickoloff BJ, et al. Dermatological complications followingcardiac transplantation. Heart Transplant 1986;5:430-6. 3. Abel EA. Cutaneous manifestations of immunosuppression in organ transplant recipients. J AM ACAD DERMATOL 1989;21:167-79. 4. Bershad S, Rubinstein A, Paterniti JR, et al. Changes in plasma lipidsand lipoproteinsduring isotretinointherapy for acne. N Engl J Med 1985;313"981-5. 5. Ballantyne CM, Podet EJ, Patsch WP et ~1. Effects of cyclosporine therapy on plasma llpoprotein levels. JAMA 1989;262:53-6. 6. Kahan BD. Drug therapy---cyclo~porine.N Engl J Med 1989;321 : 1725-38. 7. Shalita AR, Cunningham W J, Leyden J J, et al. Isotretinoin treatnaent of ache and related disorders: an update. J AM ACADDERMATOL1983;9:629-38.
Erythema multiforme after verapamil treatment To the Editor: [n their article "Angioedema from Calcium Channel Blockers," Sadick et al. (J AM ACADDERMATOL1989;21:132-3) reported patients with periorbital angioedema after the use of calcium channel blockers and reviewed cutaneous side effects of these agents, which ineluded verapamil. Verapamil-induced skin reactions were alopecia, maculopapular eruptions, ecchymosis, purpuric vasculiticlesions, urticaria, and hyperkeratosis. Erythema multiforme, however, was not mentioned. We report the case of a hypertensive patient in whom 511
512
Journal of the American Academy of Dermatology
Correspondence
erythema mnltiforme developed during verapamil treatment in a dose of 240 mg once daily. After 7 days of the treatment, the patient noticed an itching macular eruption on the extremities. There was no history of a recent infection or any drug intake other than verapamil. Physical examination revealed erythematous macules with characteristic iris lesions located in a symmetric fashion on the extensor aspects of arms and legs. The mucosal surfaces were intact and systemic findings were normal. The results of routine laboratory investigations were within normal limits. Histopathologie examination of the specimen obtained from a skin lesion disclosed findings consistent with erythema multiforme. Verapamil was stopped and oral prednisolone, 40 mg daily, was started. The lesions subsided within a few days and disappeared in a week. Nazif Kf~rkq~o]lu, MD, and Ferda Alaybeyi, PhD, Turkish Health and Therapy Foundation Ahmet ~lrs, Hospital Emek, 06510, Ankara, Turkey
Reply To the Editor." The report of erythema multiforme after verapamil treatment is not surprising. Type IV delayed hypersensitivity eruptions have been reported with veraparnil, nifedipine, and diltiazem. In addition, the strong antigenicity of this class of drugs may manifest as type I urtiearia/angioedema as well as type III immune complex vasculitic disease. It is hoped that the case reported by Kfirkqiio~lu and Alaybeyi as well as our review will continue to make physicians aware of the wide spectrum of hypersensitivity reaction patterns that can occur in up to 14% of patients treated with this class of medications. ]Veil S. Sadick, MD 40 E. 72nd St. New York, N Y 10021
Dominant dystrophic epidermolysis bullosa with intraepidermal type VII collagen To the Editor: An article by Fine et al. (J AM ACAD DEP,MATOL 1990;22:188-95) described a new subset of dystrophic epidermolysis buUosa (EB) characterized by the presence at birth of extensive blisters, which regress during the first year of life. In addition, these patients demonstrate granular intracytoplasmic deposits of LH7:2 in the basilar keratinocytes. Two patients exhibited an autosomal dominant mode of transmission. We recently had the opportunity to examine a newborn with similar findings, also with a dominant inheritance pattern. Our patient is a white female term infant born Jan. 22, 1990 to an 18-year-old mother, gravida 2, para 2. The pregnancy and vaginal delivery were uncomplicated. The patient was born with blisters on the extremities, hands, feet, trunk, face, and oral mucosa. After 3 weeks of age, she also began to have nail involvement. The lesions
healed without scarring; when the patient was 9 weeks old bullae were smaller and fewer, sparing the oral mucosa and primarily involving the extremities. At 6 months of age, the patient developed only an occasional blister. The patient is gaining weight and developing normally. The mother stated that during her first 6 months of life, she also had blisters. These spontaneously resolved at 6 months of age, and she has no sequelae. Her first child is unaffected. Three saucerized excisions were performed on freshly induced blisters. One specimen was processed for light microscopy, which failed to reveal a blister; however, marked edema of the papillary dermis was noted. A portion of the second specimen was processed for transmission electron microscopy, which showed a bulla with the basement membrane attached to the epidermal side of the split. Immunofluorescence mapping performed by us and by Dr. Fine demonstrated bullous pemphigoid antigen, laminin, and type IV collagen on the roof of an obvious subepidermal cleavage plane. Additional monoclonal antibody studies performed by Dr. Fine revealed GB3 antigen in the normal linear array along the dermoepidermal junction. However, LH7:2 antigen was present in a granular array both along the dermoepidermal junction and in a perinuclear distribution within epidermal cytoplasm. This is the sixth reported ease of dystrophic epidermolysis buliosa demonstrating intraepidermal type VII collagen. The clinical features of this case and the four reported by Fine and colleagues suggest that this subset of dystrophic EB has a fairly good prognosis with marked improvement or resolution occurring during the first year of life. Our patient demonstrated a subset of dystrophic EB with an autosomal dominant inheritance characterized by widespread blisters present at birth that either completely cease or markedly diminish during the first year of life. These cases stress the importance of immunomapping and basement membrane-specific monoclonal antibody studies. The performance of these studies will allow early diagnosis of a form of dystrophic EB that may spontaneously resolve within the first year of life. Martha L. McCollough, MD, a Ronald E. Grimwood, MD, ~ and William J. Grabski, M D a Brooke Army Medical Center a and Wilford Hall Medical Center, b San Antonio, Texas
Small malignant melanomas To the Editor: I read with interest the article by Kamino et al. (J AM ACAD DERMATOL1990;22:1032-8). Among the eases reported in this article was a small melanoma developing in a patient with a history of a previous large melanoma. The second melanoma was aneuploid, where-
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lsotretinoin treatment of severe cystic acne in a heart transplant patient receiving cyciosporine: Consideration of drug interactions To the Editor." In their brief communication, "Isotretinoin Treatment of Severe Acne in Post-transplant Patients Taking Cyclosporine" (J AM ACAD DERMA'rOL 1990;22:693-4) Bunker et al. point out the concern that isotretinoin may enhance transplant rejection. This conclusion is based on experimental evidence with skin homografts treated with vitamin A acid. 1 We wish to bring to the authors' attention a similar case of a heart transplant recipient who responded to a 20-week course of isotretinoin therapy for severe cystic ache. 2This patient was also referred to in a recent review. 3 In 1986 O'Connell et al.2 conducted a study of 107 consecutive cases of heart transplantation at Stanford University Medical Center. Ache was a frequent cause of morbidity and was present in 59 of these patients. In most cases the acne was characteristic of steroid acne. However, one patient, a 27-year old man, had severe nodulocystic acne on the face, neck, upper chest, and back. Topical antibiotics and oral tetracycline failed to control his disease. Isotretinoin was therefore begun at a dose of 40 mg daily, increased to 80 mg at 2 months, and continued at that dose up to 20 weeks, then discontinued. Cephalexin (Keflex) was added because of the initial slow response to isotretinoin. The response to cephalexin was resolution of the cysts on the face and marked improvement of the inflammatory papular component. The aerie continued to improve after discontinuation of the isotretinoin. The patient's cyclosporine trough levels remained within the recommended therapeutic range. There was no evidence of graft rejection during the course of isotretinoin therapy, and the cardiac status remained stable. Potential drug interactions are of concern in patients receiving cyclosporine and must be considered when new therapies are initiated. Cyclosporine is metabolized in the liver by the cytochrome P-450 microsomal enzyme system. Two drugs commonly prescribed by dermatologists, erythromycin and ketoconazole, may increase cyclosporine concentrations in the blood by inhibiting hepatic microsomal enzymes. Other drugs that may similarly inhibit the excretion and/or metabolism of cyclosporine and thereby raise blood levels of the drug include the anabolic steroids danazol and norethindrone, oral contraceptives, and calcium-channel antagonists. Drugs that may increase hepatic clearance by hepatic enzyme induction and thereby decrease cyclosporine blood levels include phenytoin, phenobarbital, tuberculostatic therapy with rifampin and isoniazid. A third category of drugs can interact with cyclosporine by altering renal function. These in-
ll
III
I
II II
I
I I
clude aminoglycoside antibiotics, melphalan, amphotericin B, trimethoprim and trimethoprim-sulfamethoxazoie. When isotretinoin is given to patients receiving cyclospofine, attention must also be directed to the possible combined effect of both drugs on serum lipids. Hyperlipidemia is a well-known side effect of retinoid therapy.4 Cyclosporine therapy may also increase total cholesterol,s Acute pancreatitis is a common complication among transplant patients6and has also been reported in patients receiving isotretinoin for cystic ache. 7 Thus careful monitoring of serum cholesterol and triglycerides is essential in patients receiving both drugs. With the report of Bunker et al., there are now two cases of the safe and effective use of isotretinoin for severe cystic ache in heart transplant recipients, and there are additional reports of the use ofisotretinoin in patients with renal transplants. However, experience to date is limited, and such patients must be carefully monitored with regard to their increased risk of adverse side effects from potential drug interactions.
Elizabeth A. Abel, MD Stanford, California
REFERENCES 1. Floersheim GL, BollagW. Accelerated rejection of skin homografts by vitamin A acid. Transplantation 1972;14:564-7. 2. O'Connell BM, Abel EA, Nickoloff BJ, et al. Dermatological complications followingcardiac transplantation. Heart Transplant 1986;5:430-6. 3. Abel EA. Cutaneous manifestations of immunosuppression in organ transplant recipients. J AM ACAD DERMATOL 1989;21:167-79. 4. Bershad S, Rubinstein A, Paterniti JR, et al. Changes in plasma lipidsand lipoproteinsduring isotretinointherapy for acne. N Engl J Med 1985;313"981-5. 5. Ballantyne CM, Podet EJ, Patsch WP et ~1. Effects of cyclosporine therapy on plasma llpoprotein levels. JAMA 1989;262:53-6. 6. Kahan BD. Drug therapy---cyclo~porine.N Engl J Med 1989;321 : 1725-38. 7. Shalita AR, Cunningham W J, Leyden J J, et al. Isotretinoin treatnaent of ache and related disorders: an update. J AM ACADDERMATOL1983;9:629-38.
Erythema multiforme after verapamil treatment To the Editor: [n their article "Angioedema from Calcium Channel Blockers," Sadick et al. (J AM ACADDERMATOL1989;21:132-3) reported patients with periorbital angioedema after the use of calcium channel blockers and reviewed cutaneous side effects of these agents, which ineluded verapamil. Verapamil-induced skin reactions were alopecia, maculopapular eruptions, ecchymosis, purpuric vasculiticlesions, urticaria, and hyperkeratosis. Erythema multiforme, however, was not mentioned. We report the case of a hypertensive patient in whom 511
512
Journal of the American Academy of Dermatology
Correspondence
erythema mnltiforme developed during verapamil treatment in a dose of 240 mg once daily. After 7 days of the treatment, the patient noticed an itching macular eruption on the extremities. There was no history of a recent infection or any drug intake other than verapamil. Physical examination revealed erythematous macules with characteristic iris lesions located in a symmetric fashion on the extensor aspects of arms and legs. The mucosal surfaces were intact and systemic findings were normal. The results of routine laboratory investigations were within normal limits. Histopathologie examination of the specimen obtained from a skin lesion disclosed findings consistent with erythema multiforme. Verapamil was stopped and oral prednisolone, 40 mg daily, was started. The lesions subsided within a few days and disappeared in a week. Nazif Kf~rkq~o]lu, MD, and Ferda Alaybeyi, PhD, Turkish Health and Therapy Foundation Ahmet ~lrs, Hospital Emek, 06510, Ankara, Turkey
Reply To the Editor." The report of erythema multiforme after verapamil treatment is not surprising. Type IV delayed hypersensitivity eruptions have been reported with veraparnil, nifedipine, and diltiazem. In addition, the strong antigenicity of this class of drugs may manifest as type I urtiearia/angioedema as well as type III immune complex vasculitic disease. It is hoped that the case reported by Kfirkqiio~lu and Alaybeyi as well as our review will continue to make physicians aware of the wide spectrum of hypersensitivity reaction patterns that can occur in up to 14% of patients treated with this class of medications. ]Veil S. Sadick, MD 40 E. 72nd St. New York, N Y 10021
Dominant dystrophic epidermolysis bullosa with intraepidermal type VII collagen To the Editor: An article by Fine et al. (J AM ACAD DEP,MATOL 1990;22:188-95) described a new subset of dystrophic epidermolysis buUosa (EB) characterized by the presence at birth of extensive blisters, which regress during the first year of life. In addition, these patients demonstrate granular intracytoplasmic deposits of LH7:2 in the basilar keratinocytes. Two patients exhibited an autosomal dominant mode of transmission. We recently had the opportunity to examine a newborn with similar findings, also with a dominant inheritance pattern. Our patient is a white female term infant born Jan. 22, 1990 to an 18-year-old mother, gravida 2, para 2. The pregnancy and vaginal delivery were uncomplicated. The patient was born with blisters on the extremities, hands, feet, trunk, face, and oral mucosa. After 3 weeks of age, she also began to have nail involvement. The lesions
healed without scarring; when the patient was 9 weeks old bullae were smaller and fewer, sparing the oral mucosa and primarily involving the extremities. At 6 months of age, the patient developed only an occasional blister. The patient is gaining weight and developing normally. The mother stated that during her first 6 months of life, she also had blisters. These spontaneously resolved at 6 months of age, and she has no sequelae. Her first child is unaffected. Three saucerized excisions were performed on freshly induced blisters. One specimen was processed for light microscopy, which failed to reveal a blister; however, marked edema of the papillary dermis was noted. A portion of the second specimen was processed for transmission electron microscopy, which showed a bulla with the basement membrane attached to the epidermal side of the split. Immunofluorescence mapping performed by us and by Dr. Fine demonstrated bullous pemphigoid antigen, laminin, and type IV collagen on the roof of an obvious subepidermal cleavage plane. Additional monoclonal antibody studies performed by Dr. Fine revealed GB3 antigen in the normal linear array along the dermoepidermal junction. However, LH7:2 antigen was present in a granular array both along the dermoepidermal junction and in a perinuclear distribution within epidermal cytoplasm. This is the sixth reported ease of dystrophic epidermolysis buliosa demonstrating intraepidermal type VII collagen. The clinical features of this case and the four reported by Fine and colleagues suggest that this subset of dystrophic EB has a fairly good prognosis with marked improvement or resolution occurring during the first year of life. Our patient demonstrated a subset of dystrophic EB with an autosomal dominant inheritance characterized by widespread blisters present at birth that either completely cease or markedly diminish during the first year of life. These cases stress the importance of immunomapping and basement membrane-specific monoclonal antibody studies. The performance of these studies will allow early diagnosis of a form of dystrophic EB that may spontaneously resolve within the first year of life. Martha L. McCollough, MD, a Ronald E. Grimwood, MD, ~ and William J. Grabski, M D a Brooke Army Medical Center a and Wilford Hall Medical Center, b San Antonio, Texas
Small malignant melanomas To the Editor: I read with interest the article by Kamino et al. (J AM ACAD DERMATOL1990;22:1032-8). Among the eases reported in this article was a small melanoma developing in a patient with a history of a previous large melanoma. The second melanoma was aneuploid, where-