- Email: [email protected]
Tamoxifen-induced remission of psoriasis
Tamoxifen-induced remission of psoriasis Alan S. Boyd, MD,a,b and Lloyd E. King, Jr, MD, PhDa Nashville, Tennessee Psoriasis vulgaris may be worsened or precipitated by numerous factors, including hormonal influences. Several lines of evidence suggest that female sex hormones such as estrogen and progesterone affect this condition. We describe a patient whose psoriasis responded favorably to administration of the antiestrogen compound tamoxifen. (J Am Acad Dermatol 1999;41:887-9.)
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recipitating factors for psoriasis include infection, trauma, stress and medications.1,2 Several lines of evidence suggest that psoriasis may be affected by the menstrual cycle: a peak onset of disease at menarche and in the early reproductive years,3,4 precipitation of psoriatic flares by oral contraceptives,3 and both improvement5 and deterioration6 of the condition with menses.2 We describe a patient whose psoriasis involved the perineal area, flared perimenstrually and whose condition improved after administration of the antiestrogen agent tamoxifen.
CASE REPORT A 39-year-old woman experienced burning and itching of the vulva and discharge in October 1997. Intravaginal nystatin cream (Mycostatin, Westwood-Squibb Pharmaceuticals, Buffalo, NY) worsened the condition and was discontinued. Patch testing (True Test, Glaxco Wellcome Inc, Research Triangle Park, NC) for a presumed contact dermatitis was negative. Several weeks later the vulvar area developed an exanthematous, confluent eruption with scaling and fissures. Topical clobetasol cream (Temovate, Glaxco Wellcome Inc) was minimally effective. Over the next 3 months pruritic, annular patches with erythema and scaling arose on the knees, elbows, and scalp. A vulvar biopsy disclosed psoriasiform dermatitis. Several courses of oral fluconazole diminished the vaginal pruritus and discharge but did not affect the cutaneous eruption. Ketoconazole shampoo (Nizoral, Janssen Pharmaceutica Inc, Titusville, NJ) and clobetasol cream only minimally affected the scalp condition. The vulvar dermatitis rou-
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Medicine (Dermatology)a and Pathologyb Vanderbilt University. Reprint requests: Alan S. Boyd, MD, 3900 The Vanderbilt Clinic, Nashville, TN 37232. E-mail: [email protected] Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/4/100417
tinely worsened 2 days before and 10 days after the onset of menses. The patient took no medications (including nonsteroidal antiinflammatory agents), did not drink alcohol, and had a family history of psoriasis. She denied any menstrual irregularities, hirsutism, deepening of the voice, or change in libido. Serum dehydroepiandrosterone sulfate (DHEA-S), free testosterone, and total testosterone were within normal limits. On presentation, the patient had diffuse erythema and scaling of the scalp; annular, well-demarcated patches of erythema and scaling on the elbows and knees; and an exanthematous vulvar eruption. Vaginal discharge was absent. Her nails were normal, and there was no involvement of the axillae, inframammary areas or inguinal folds. She was thought to have inverse psoriasis and was begun on oral methotrexate (Rheumatrex, Immunex Corp, Seattle, Wash). The drug was increased to 15 mg weekly for a month but was ineffective and was discontinued. Because the vulvar discomfort and vaginal discharge coincided repeatedly with the onset of her menstrual cycle, she was begun on tamoxifen (Novaldex, Zeneca Pharmaceuticals, Wilmington, Del) 10 mg by mounth twice daily 2 weeks after discontinuing the methotrexate. A punch biopsy of a plaque on her knee revealed the typical histologic features of psoriasis. Immunoperoxidase stains for estrogen and progesterone receptors were negative. At her next menstrual cycle she experienced a significant decrease in pruritus, flaring of the vulvar dermatitis and the length of the eruption. Over the ensuing 6 months the psoriasis on her scalp and extremities faded with diminished redness and scaling. Vaginal pruritus and discharge also resolved. The patient experienced occasional hot flashes but otherwise tolerated the medication well. She eventually discontinued the medication but has experienced no significant relapse of her disease.
DISCUSSION Evidence suggests that female sex hormones such as estrogen and progesterone play a significant role in the immune response and immune-associated disease; estrogens are thought to stimulate the immune system, whereas male hormones are believed to suppress it.7 887
888 Boyd and King
Psoriasis, now considered to be an immunologic disease, is affected by the hormonal milieu as well and women with widespread disease excrete increased amounts of urinary estrogen.8 In a study of 173 women with psoriasis, 16% reported that their disease deteriorated during menstruation and 4% experienced improvement. Amelioration of psoriasis during pregnancy and lactation is well known.5 Pustular disease (impetigo herpetiformis) during pregnancy also occurs.1 The exogenous administration of female sex hormones has produced varying effects on women with psoriasis. Although the administration of low dose estrogen has resulted in the remission of psoriatic arthritis,9 this hormone was not effective in preventing recurrent bouts of pustular psoriasis10 or improving chronic plaque psoriasis.11 Similarly, progesterone administration may induce pustular flares.12,13 Interestingly, pustular disease commonly occurs in the latter stages of pregnancy as endogenous levels of progesterone increase. Because our patient described a perimenstrual worsening of her disease, she was given oral tamoxifen. Tamoxifen is a nonsteroidal antiestrogen compound with partial estrogen receptor agonist activity.14 It does not suppress circulating levels of estrogen but competitively binds to the estrogen receptor and partially inhibits the entry of estrogen into target tissues. This drug is capable of inducing a diethylstilbesterol-like effect on exposed, unborn children. About a third of women who take tamoxifen will develop hot flashes and another third will have a change in menstrual habits, including amenorrhea. “Pulsing” the drug around the time of menstruation may alleviate some of these symptoms but has not been tried as yet. We were unable to find additional reports of tamoxifen use in women whose psoriasis flared perimenstrually. Stevens et al4 reported a 35-year-old woman with extensive psoriatic arthritis of 6 years duration whose joint disease flared at midcycle (day 14) and 7 days before the onset of menses. Treatment with methotrexate had been unsuccessful and she was begun on tamoxifen 20 mg twice daily and buserelin, a gonadotropin hormone-releasing hormone-blocking agent. The joint disease resolved within 2 months and she was taken off the tamoxifen and given buserelin in a monthly injection. Her cutaneous disease remained “well controlled” with these medications and, eventually, she tolerated administration of low dose estrogen replacement. The authors suggested that goserelin (Zoladex, Zeneca Pharmaceuticals), a medication similar to buserelin, may also be useful in women whose psoriasis flares perimenstrually. Tamoxifen has also been used to
J AM ACAD DERMATOL NOVEMBER 1999
treat a 47-year-old woman with polyarteritis nodosa whose condition flared with the administration of exogenous estrogens.14 Discontinuation of this medication and addition of tamoxifen 20 mg twice daily resulted in control of the vasculitic skin disease. How do estrogens and other sex hormones interact with the skin? Their role is dependent on host factors such as age and genetic makeup, as well as the immunologic event in question.2 Sex hormone receptors for these molecules are present in skin15 and epidermal cells metabolize estrogen and progesterone5 but it is unclear how they exert their cutaneous effects. We were not surprised that the immunoperoxidase stains for progesterone and estrogen receptors were negative because hormone binding varies in different body sites and immunoperoxidase methods of detection are often too insensitive.16 Estrogen receptors are present on T cells, are more commonly noted in the CD8 subset, and may represent a specific target of this hormone’s action.7 Estrogen also decreases T-helper cell activity (CD4).2 Effects of progesterone may be even more profound on CD4+ T cells. Estrogen receptors are present on vascular smooth muscle and endothelium and affect the immune response of macrophages and thymocytes.7 Some patients with psoriasis may be unusually sensitive to circulating estrogens or estrogen-like molecules. These patients, like ours, may benefit from estrogen-blocking agents such as tamoxifen. REFERENCES 1. O’Dricoll JB, Augst PJ. Exacerbation of psoriasis precipitated by an oestradiol-testosterone implant. Clin Exp Dermatol 1990;15: 68-9. 2. Mowad CM, Margolis DJ, Halpern AC, Suri B, Synnestvedt M, Guzzo CA. Hormonal influences on women with psoriasis. Cutis 1998;61:257-60. 3. Papamiltiades M, Belezos N. Vaginal cytology in psoriatic women. Dermatologica 1968;136:160-172. 4. Stevens HP, Ostlere LS, Black CM, Jacobs HS, Rustin MH. Cyclical psoriatic arthritis responding to anti-oestrogen therapy. Br J Dermatol 1993;129:458-60. 5. Boyd AS, Morris FL, Phillips CM, Menter MA. Psoriasis and pregnancy: hormone and immune system interaction. Int J Dermatol 1996;35:169-72. 6. McNeill ME. Multiple pregnancy-induced remission of psoriatic arthritis: case report. Am J Obstet Gynecol 1988;139:896-7. 7. Cutolo M, Sulli B, Seriolo B, Accardo S, Masi AT. Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 1995;13:217-26. 8. Shuster S. Systemic effects of skin disease. Lancet 1967;1:907-12. 9. McHugh NJ, Laurent MR. The effect of pregnancy on the onset of psoriatic arthritis. Br J Rheumatol 1989;28:50-2. 10. Braverman IM, Cohen I, O’Keefe E. Metabolic and ultrastructural studies in a patient with pustular psoriasis (von Zumbusch). Arch Dermatol 1972;105:189-96. 11. Spangler AS, Antoniades HN, Sotman SL, Inderbitizin TM.
J AM ACAD DERMATOL VOLUME 41, NUMBER 5, PART 2
Enhancement of the anti-inflammatory action of hydrocortisone by estrogen. J Clin Endocr 1969;29:650-5. 12. Shelley WB. Generalized pustular psoriasis induced by potassium iodide. J Am Med Assoc 1967;210:1009-14. 13. Murphy FR, Stolman LP. Generalized pustular psoriasis. Arch Dermatol 1979;115:1215-6. 14. Cvancara JL, Meffert JJ, Elston DM. Estrogen-sensitive cuta-
Boyd and King 889
neous polyarteritis nodosa: response to tamoxifen. J Am Acad Dermatol 1998;39:643-6. 15. Schmidt JB, Lindmaier A, Spona J. Hormone receptors in pubic skin of premenopausal and postmenopausal females. Gynecol Obstet Invest 1990;30:97-100. 16. Farhat MY, Lavigne MC, Ramwell PW. The vascular protective effectgs of estrogen. FASEB J 1996;10:615-24.
P
recipitating factors for psoriasis include infection, trauma, stress and medications.1,2 Several lines of evidence suggest that psoriasis may be affected by the menstrual cycle: a peak onset of disease at menarche and in the early reproductive years,3,4 precipitation of psoriatic flares by oral contraceptives,3 and both improvement5 and deterioration6 of the condition with menses.2 We describe a patient whose psoriasis involved the perineal area, flared perimenstrually and whose condition improved after administration of the antiestrogen agent tamoxifen.
CASE REPORT A 39-year-old woman experienced burning and itching of the vulva and discharge in October 1997. Intravaginal nystatin cream (Mycostatin, Westwood-Squibb Pharmaceuticals, Buffalo, NY) worsened the condition and was discontinued. Patch testing (True Test, Glaxco Wellcome Inc, Research Triangle Park, NC) for a presumed contact dermatitis was negative. Several weeks later the vulvar area developed an exanthematous, confluent eruption with scaling and fissures. Topical clobetasol cream (Temovate, Glaxco Wellcome Inc) was minimally effective. Over the next 3 months pruritic, annular patches with erythema and scaling arose on the knees, elbows, and scalp. A vulvar biopsy disclosed psoriasiform dermatitis. Several courses of oral fluconazole diminished the vaginal pruritus and discharge but did not affect the cutaneous eruption. Ketoconazole shampoo (Nizoral, Janssen Pharmaceutica Inc, Titusville, NJ) and clobetasol cream only minimally affected the scalp condition. The vulvar dermatitis rou-
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Medicine (Dermatology)a and Pathologyb Vanderbilt University. Reprint requests: Alan S. Boyd, MD, 3900 The Vanderbilt Clinic, Nashville, TN 37232. E-mail: [email protected] Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/4/100417
tinely worsened 2 days before and 10 days after the onset of menses. The patient took no medications (including nonsteroidal antiinflammatory agents), did not drink alcohol, and had a family history of psoriasis. She denied any menstrual irregularities, hirsutism, deepening of the voice, or change in libido. Serum dehydroepiandrosterone sulfate (DHEA-S), free testosterone, and total testosterone were within normal limits. On presentation, the patient had diffuse erythema and scaling of the scalp; annular, well-demarcated patches of erythema and scaling on the elbows and knees; and an exanthematous vulvar eruption. Vaginal discharge was absent. Her nails were normal, and there was no involvement of the axillae, inframammary areas or inguinal folds. She was thought to have inverse psoriasis and was begun on oral methotrexate (Rheumatrex, Immunex Corp, Seattle, Wash). The drug was increased to 15 mg weekly for a month but was ineffective and was discontinued. Because the vulvar discomfort and vaginal discharge coincided repeatedly with the onset of her menstrual cycle, she was begun on tamoxifen (Novaldex, Zeneca Pharmaceuticals, Wilmington, Del) 10 mg by mounth twice daily 2 weeks after discontinuing the methotrexate. A punch biopsy of a plaque on her knee revealed the typical histologic features of psoriasis. Immunoperoxidase stains for estrogen and progesterone receptors were negative. At her next menstrual cycle she experienced a significant decrease in pruritus, flaring of the vulvar dermatitis and the length of the eruption. Over the ensuing 6 months the psoriasis on her scalp and extremities faded with diminished redness and scaling. Vaginal pruritus and discharge also resolved. The patient experienced occasional hot flashes but otherwise tolerated the medication well. She eventually discontinued the medication but has experienced no significant relapse of her disease.
DISCUSSION Evidence suggests that female sex hormones such as estrogen and progesterone play a significant role in the immune response and immune-associated disease; estrogens are thought to stimulate the immune system, whereas male hormones are believed to suppress it.7 887
888 Boyd and King
Psoriasis, now considered to be an immunologic disease, is affected by the hormonal milieu as well and women with widespread disease excrete increased amounts of urinary estrogen.8 In a study of 173 women with psoriasis, 16% reported that their disease deteriorated during menstruation and 4% experienced improvement. Amelioration of psoriasis during pregnancy and lactation is well known.5 Pustular disease (impetigo herpetiformis) during pregnancy also occurs.1 The exogenous administration of female sex hormones has produced varying effects on women with psoriasis. Although the administration of low dose estrogen has resulted in the remission of psoriatic arthritis,9 this hormone was not effective in preventing recurrent bouts of pustular psoriasis10 or improving chronic plaque psoriasis.11 Similarly, progesterone administration may induce pustular flares.12,13 Interestingly, pustular disease commonly occurs in the latter stages of pregnancy as endogenous levels of progesterone increase. Because our patient described a perimenstrual worsening of her disease, she was given oral tamoxifen. Tamoxifen is a nonsteroidal antiestrogen compound with partial estrogen receptor agonist activity.14 It does not suppress circulating levels of estrogen but competitively binds to the estrogen receptor and partially inhibits the entry of estrogen into target tissues. This drug is capable of inducing a diethylstilbesterol-like effect on exposed, unborn children. About a third of women who take tamoxifen will develop hot flashes and another third will have a change in menstrual habits, including amenorrhea. “Pulsing” the drug around the time of menstruation may alleviate some of these symptoms but has not been tried as yet. We were unable to find additional reports of tamoxifen use in women whose psoriasis flared perimenstrually. Stevens et al4 reported a 35-year-old woman with extensive psoriatic arthritis of 6 years duration whose joint disease flared at midcycle (day 14) and 7 days before the onset of menses. Treatment with methotrexate had been unsuccessful and she was begun on tamoxifen 20 mg twice daily and buserelin, a gonadotropin hormone-releasing hormone-blocking agent. The joint disease resolved within 2 months and she was taken off the tamoxifen and given buserelin in a monthly injection. Her cutaneous disease remained “well controlled” with these medications and, eventually, she tolerated administration of low dose estrogen replacement. The authors suggested that goserelin (Zoladex, Zeneca Pharmaceuticals), a medication similar to buserelin, may also be useful in women whose psoriasis flares perimenstrually. Tamoxifen has also been used to
J AM ACAD DERMATOL NOVEMBER 1999
treat a 47-year-old woman with polyarteritis nodosa whose condition flared with the administration of exogenous estrogens.14 Discontinuation of this medication and addition of tamoxifen 20 mg twice daily resulted in control of the vasculitic skin disease. How do estrogens and other sex hormones interact with the skin? Their role is dependent on host factors such as age and genetic makeup, as well as the immunologic event in question.2 Sex hormone receptors for these molecules are present in skin15 and epidermal cells metabolize estrogen and progesterone5 but it is unclear how they exert their cutaneous effects. We were not surprised that the immunoperoxidase stains for progesterone and estrogen receptors were negative because hormone binding varies in different body sites and immunoperoxidase methods of detection are often too insensitive.16 Estrogen receptors are present on T cells, are more commonly noted in the CD8 subset, and may represent a specific target of this hormone’s action.7 Estrogen also decreases T-helper cell activity (CD4).2 Effects of progesterone may be even more profound on CD4+ T cells. Estrogen receptors are present on vascular smooth muscle and endothelium and affect the immune response of macrophages and thymocytes.7 Some patients with psoriasis may be unusually sensitive to circulating estrogens or estrogen-like molecules. These patients, like ours, may benefit from estrogen-blocking agents such as tamoxifen. REFERENCES 1. O’Dricoll JB, Augst PJ. Exacerbation of psoriasis precipitated by an oestradiol-testosterone implant. Clin Exp Dermatol 1990;15: 68-9. 2. Mowad CM, Margolis DJ, Halpern AC, Suri B, Synnestvedt M, Guzzo CA. Hormonal influences on women with psoriasis. Cutis 1998;61:257-60. 3. Papamiltiades M, Belezos N. Vaginal cytology in psoriatic women. Dermatologica 1968;136:160-172. 4. Stevens HP, Ostlere LS, Black CM, Jacobs HS, Rustin MH. Cyclical psoriatic arthritis responding to anti-oestrogen therapy. Br J Dermatol 1993;129:458-60. 5. Boyd AS, Morris FL, Phillips CM, Menter MA. Psoriasis and pregnancy: hormone and immune system interaction. Int J Dermatol 1996;35:169-72. 6. McNeill ME. Multiple pregnancy-induced remission of psoriatic arthritis: case report. Am J Obstet Gynecol 1988;139:896-7. 7. Cutolo M, Sulli B, Seriolo B, Accardo S, Masi AT. Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 1995;13:217-26. 8. Shuster S. Systemic effects of skin disease. Lancet 1967;1:907-12. 9. McHugh NJ, Laurent MR. The effect of pregnancy on the onset of psoriatic arthritis. Br J Rheumatol 1989;28:50-2. 10. Braverman IM, Cohen I, O’Keefe E. Metabolic and ultrastructural studies in a patient with pustular psoriasis (von Zumbusch). Arch Dermatol 1972;105:189-96. 11. Spangler AS, Antoniades HN, Sotman SL, Inderbitizin TM.
J AM ACAD DERMATOL VOLUME 41, NUMBER 5, PART 2
Enhancement of the anti-inflammatory action of hydrocortisone by estrogen. J Clin Endocr 1969;29:650-5. 12. Shelley WB. Generalized pustular psoriasis induced by potassium iodide. J Am Med Assoc 1967;210:1009-14. 13. Murphy FR, Stolman LP. Generalized pustular psoriasis. Arch Dermatol 1979;115:1215-6. 14. Cvancara JL, Meffert JJ, Elston DM. Estrogen-sensitive cuta-
Boyd and King 889
neous polyarteritis nodosa: response to tamoxifen. J Am Acad Dermatol 1998;39:643-6. 15. Schmidt JB, Lindmaier A, Spona J. Hormone receptors in pubic skin of premenopausal and postmenopausal females. Gynecol Obstet Invest 1990;30:97-100. 16. Farhat MY, Lavigne MC, Ramwell PW. The vascular protective effectgs of estrogen. FASEB J 1996;10:615-24.