Improvement in Dermatomyositis Rash Associated with the Use of Antiestrogen Medication

OBSERVATION Improvement in Dermatomyositis Rash Associated With the Use of Antiestrogen Medication

Danya Sereda, MD; Victoria P. Werth, MD

Background: Dermatomyositis (DM) is an autoim- erties. The second was taking anastrozole, an aromatase mune disorder that occurs more often in women than men inhibitor. When tamoxifen therapy was discontinued af- and causes highly symptomatic and inflammatory cuta- ter 4 years of use in the first patient, her DM rash wors- neous and proximal muscle disease. Corticosteroids have ened and remained difficult to control with conven- been the treatment of choice for myositis in DM, and an- tional immunosuppressant medication. timalarial agents for the skin disease of DM, with metho- trexate sodium, azathioprine, mycophenolate mofetil, cy- Conclusions: With the limited number of therapies closporine, and intravenous immunoglobulin used as available to manage DM skin eruptions, the discovery of steroid-sparing agents. Recently, reports supporting a role novel agents effective in treating this disease is vital. Us- for anti–tumor necrosis factor ␣ (TNF-␣) therapy in the ing antiestrogen medication in women with DM may treatment of DM have emerged. result in a significant improvement in their rash, possi- bly via the inhibition of TNF-␣ production by immune Observations: We describe 2 women who experi- or other cells. Further investigation into the use of an- enced an improvement in their DM-associated skin erup- tiestrogen therapy in DM is merited to evaluate long- tions while taking antiestrogen medication. The first pa- term risks and benefits. tient was taking tamoxifen, a selective estrogen receptor modulator that has been found to have anti–TNF-␣ prop- Arch Dermatol. 2006;142:70-72

ERMATOMYOSITIS (DM) IS The incidence of both adult and juve- an autoimmune disease nile DM is 2 to 3 times greater in female that primarily targets the than male patients, suggesting a patho- skin and limb girdle physiologic role for female sex hor- muscles.1 In some pa- mones.3,4 In general, estrogens exert im- tients, it manifests exclusively or predomi- munostimulatory effects, and androgens, D 5 nantly as cutaneous disease; in others, it immunosuppressive effects. Sex hor- affects the lungs, joints, gastrointestinal mones have been shown to be involved in system, and heart. The precise relation- connective tissue disorders such as rheu- ship between malignancy and DM has not matoid arthritis and lupus erythemato- been elucidated, but most experts agree sus and likely play a part in other auto- that patients with DM have an increased immune diseases including DM.6-8 risk of cancer.1,2 Age, sex, and risk-associated screening for occult malignancy is See also pages 65, recommended for all patients with DM. 109, and 113 Gottron papules are the most com- mon cutaneous manifestation of DM.1 Many lines of evidence have also impli- They are a palpable, symmetric skin erup- cated tumor necrosis factor ␣ (TNF-␣)in tion over the extensor surfaces of the meta- the pathogenesis of DM. First, UV light is carpophalangeal and interphalangeal joints known to be a potential trigger of the skin of the hands and are pathognomonic for eruption of DM, and in vitro studies have DM. Other skin findings include a helio- shown that UV-B light initiates release of trope rash of the periorbital and upper eye TNF-␣ from human keratinocytes and fi- Author Affiliations: Section of area and a V- or shawl-shaped macular ery- broblasts.9 Second, Werth et al10 have re- Dermatology, Universite´de thema over the chest and back. Hyperker- ported an association of DM with the -308A Montre´al (Dr Sereda); and atosis of the palmar and lateral surfaces of TNF-␣ promoter polymorphism, which Department of Dermatology, ␣ University of Pennsylvania the fingers is frequently present, referred mediates a markedly increased TNF- re- Health System, and to as mechanic’s hands. Less often, papu- sponse to UV-B. Finally, a pathogenic role Philadelphia Veterans Affairs lovesicular rashes, subcutaneous pannicu- for TNF-␣ has been implicated in condi- Hospital, Philadelphia litis, erosive lesions, or exfoliative eryth- tions clinically similar to DM such as ju- (Dr Werth). roderma are seen. venile DM and inflammatory myopa-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 thies.11-14 These findings form the rationale for new trials highly characteristic of amyopathic DM. The patient’s rash of anti–TNF-␣ therapy in patients with DM. improved on a maximum oral hydroxychloroquine dose of 200 mg twice daily but did not remit completely. REPORT OF CASES The patient was evaluated for underlying malignancy, and findings from periodic screenings for gyne- Case 1 was a 32-year-old white woman seen in 1993 with cologic or breast cancer (including mammogram) were a mass in her left breast. She was found to have stage 1 all negative. In 2003, she developed breast cancer, which breast carcinoma and was treated with a left partial mas- was treated with a lumpectomy and radiation therapy. tectomy, irradiation, and chemotherapy. Four months Adjuvant therapy with anastrozole, an aromatase inhibi- later, she developed an erythematous, violaceous skin tor, was also started to prevent recurrence of the breast eruption on her face, arms, and thighs. A skin biopsy find- cancer. One month after initiation of anastrazole treating was consistent with DM, and the patient began treatment, the patient’s DM rash subsided completely, and she ment with hydroxychloroquine sulfate, which tempo- was able to decrease her hydroxychloroquine dose for the rarily stabilized her eruption. first time since 1998. While the resolution of this pa- After 3 months, however, the rash deteriorated, and tient’s eruption coincided closely with the start of an- she began to experience dysphagia and weight loss. She astrozole therapy, it is also possible that treatment of the was admitted to the hospital for further evaluation. Find- underlying malignancy precipitated the improvement. It ings from another skin biopsy were again consistent with would be of interest to note whether her skin lesions DM. Her erythrocyte sedimentation rate was elevated (105 would recur if therapy with anastrozole was stopped. mm/h), and lactate dehydrogenase and aspartate trans- aminase levels increased (to 401 and 178 U/L, respec- COMMENT tively). Her creatine kinase levels at the time of admis- sion are not known. Anti-ribonucleoprotein (anti-RNP) Tamoxifen, a SERM, is currently the most extensively used antibody findings were negative, and anti-Jo-1 and Mi-2 hormonal treatment for all stages of hormone-responsive antibodies were not measured. Her chest radiogram was breast cancer.15 It has also been approved for the preven- normal other than postoperative changes in the left chest tion of breast cancer in high-risk women.16 Generally, wall. An esophagogram was normal. SERMs exert antiestrogen effects on certain tissues (eg, The patient began treatment with oral prednisone at 30 breast) and paradoxical estrogen agonist effects on other mg/d, which was increased to a maximum of 60 mg/d and tissues (eg, bone). The molecular mechanisms underly- eventually tapered. The patient’s rash and dysphagia im- ing these tissue-specific actions have not been fully eluci- proved during therapy with prednisone, and the patient was dated. Unique physiologic effects, however, seem to in- discharged. volve distinctive SERM estrogen receptor conformations The patient also took twice-daily 10-mg doses of oral and binding of different adaptor proteins to either posi- tamoxifen, a selective estrogen receptor modulator (SERM), tively or negatively regulate target gene transcription.17 as an adjuvant therapy from 1993 until 1997 to prevent re- In postmenopausal women with or without a history of currence of her breast cancer. During this time, her rash breast cancer, tamoxifen augments spine and hip bone min- resolved, and she did not require therapy for her DM. eral density (BMD) more than 1% per year.18 In premeno- There were no signs of malignancy on regular physical pausalwomen,however,tamoxifenisassociatedwithamean examinations, blood work, or imaging. In 1997, however, annual loss in spine BMD of 1.44%. Patients taking tamox- shortly after her tamoxifen treatment was discontinued, she ifen are at increased risk for venous thromboembolism, and experienced an exacerbation of her DM skin eruption. She approximately1%ofpostmenopausalwomentakingtamox- has since continued to manifest a heliotrope malar rash, ery- ifen for 5 years will have a thromboembolic event.19 Tamox- thema over her anterior superior chest and upper back, in- ifen also increases the occurrence of localized endometrial volvement of the extensor surface of the arms, and Gottron cancer, benign uterine disease, and cataracts. papules over the extensor surfaces of her hands, despite Aromatase inhibitors, such as anastrozole, constitute therapy with various immunosuppressants including pred- another class of hormonal treatment approved for adju- nisone,choloroquine,quinacrinehydrochloride,andmetho- vant therapy in postmenopausal women with breast can- trexate. The absence of evidence of a recurrent or new ma- cer.20 Anastrozole is a potent, selective, nonsteroidal in- lignancy argues against a paraneoplastic process underly- hibitor of aromatase and blocks the conversion of androgens ing her skin exacerbation. Antiestrogen therapy was not to estrogen. Aromatase is expressed in ovarian, adipose, reimplemented in this patient, but it would be interesting skin, muscle, bone, and brain cells.21 Recent phase 3 trials to determine if subsequent exposure to antiestrogen medi- suggest that aromatase inhibitors may be superior to ta- cation would again mitigate her DM rash. moxifen in the adjuvant setting, and they may replace ta- Case 2 was a 49-year-old white woman seen in 1998 for moxifen as the adjuvant therapy of choice for postmeno- a pronounced erythematous rash following sun exposure. pausal women with breast cancer.22 Compared with patients Her rash was prominent over the malar distribution, the taking tamoxifen, those taking anastrozole have a de- upper extensor arms, and the dorsum of her hands includ- creased risk of vascular and uterine adverse events but a ing the knuckles (Gottron papules). She also had some peri- slightly increased risk of fractures.23 ungual erythema and capillary changes in the nail bed. Labo- Antiestrogen drugs such as tamoxifen and other SERMs ratory findings, including evaluation of creatine have been found to inhibit the production of cytokines phosphokinase and aldolase, were essentially normal. A skin and factors such as interleukin 10, TNF-␣, and trans- biopsy was not performed as the clinical presentation was forming growth factor ␤1.24,25 Carruba et al24 showed that

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 estradiol increases TNF-␣ synthesis and apoptosis in mac- Funding/Support: This article was funded in part by grants rophagelike cells, while the combination of estradiol and from the Lupus Research Institute, National Institutes of tamoxifen completely abolishes induction of TNF-␣.In Health (1K24AR002207-01), and a Veterans Affairs Merit addition, toremifene, another SERM, has been shown to Review Grant (Dr Werth). reduce TNF-␣ secretion by monocytes.25 Estrogen, there- fore, may have a proinflammatory effect, which is mediated through TNF-␣ production by immune or other REFERENCES cells and inhibited by certain antiestrogen medications. 1. Yazici Y, Kagen LJ. Clinical presentation of the idiopathic inflammatory myopathies. Based on experimental evidence supporting a patho- Rheum Dis Clin North Am. 2002;28:823-832. genic role for TNF-␣ in DM, researchers have attempted 2. 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