Tamoxifen-induced vasculitis

Introduction

Tamoxifen binds to the estrogen receptors (ER) and exerts either estrogenic or antiestrogenic effects, depending on the specific organ. Tamoxifen is used for the treatment of women with ER-positive metastatic breast cancer or following primary excision of an ER+ tumor as an adjuvant treatment to prevent recurrence and extend overall survival and also for the prevention of breast cancer in high-risk patients such as those with a strong family history or prior nonmalignant breast pathology. The common adverse reactions to tamoxifen include vasomotor symptoms (hot flashes), atrophy of the lining of the vagina, menstrual irregularities, vaginal bleeding and discharge, and pruritus vulvae and occur with increasing severity in post-menopausal women. Increased risk of endometrial cancer is because of partial agonist activity and thrombosis-related phenomena like deep vein thrombosis, pulmonary emboli and stroke. However, there are very few reports about its ability to induce vasculitis. ¹

In case of drug-induced hypersensitivity vasculitis, antibodies are directed against the drug-modified proteins or foreign molecules, which results in immune complex formation. The clinical manifestations can be mild and self-limiting, or severe and even fatal; skin lesions are the most common amongst them. It is always important to consider drug hypersensitivity as a cause of vasculitis, since discontinuation of the offending agent usually leads to resolution.^2,3

Case history

A 45-year-old female patient underwent modified radical mastectomy in 2013 for left infiltrating lobular carcinoma of breast which was ER/PR positive and Her 2 Neu negative. Following the surgery, she was started on tab tamoxifen 20 mg OD in 2014. Six months after taking tamoxifen, she developed asymptomatic reddish lesions over both the legs (Figure 1). On examination, there were erythematous non-blanchable papules on both legs. A provisional diagnosis of palpable purpura was given after which immunofluorescence assay (Figure 2) and skin biopsy of the lesions confirmed the diagnosis of cutaneous vasculitis. The patient was started on dapsone 100 mg OD for two weeks. The symptoms subsided, but after two weeks, the lesions recurred. The patient was continued on tab tamoxifen 20 mg OD, and she continued to have vasculitis for past three years, which was relieved with dapsone. She had relief of symptoms when on dapsone therapy, but the lesions recurred when the drug was stopped.

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Figure 1.

Lesions on the leg.

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Figure 2.

Immunofluorescence image.

Discussion

Estrogen acts as a potent antagonist in malignant breast cells, blood vessels and at some peripheral sites, partial agonist in uterine endometrium, bone, liver and pituitary. Till recently, tamoxifen was considered as the standard hormonal treatment of breast cancer in both pre- and post-menopausal women, but now aromatase inhibitors have risen to prominence mainly for post-menopausal women. In early cases, tamoxifen is given as post-mastectomy adjuvant therapy, while in advanced cases, it is a constituent of palliative treatment. Response rates are high in ER-positive breast carcinomas, but some ER-negative tumours also respond, suggesting additional non-hormonal mechanism of action. Recurrence rate in ipsilateral as well as contralateral breasts is reduced by tamoxifen, but benefits of prophylactic therapy beyond five years are not proven. Possible mechanisms that might be involved in drug-induced vasculitis are: (i) The drug or metabolite suspected of causing the vasculitis acts as a hapten and binds to a protein, forming a complex to stimulate antibody formation ³ or (ii) Drugs may bind to enzymes such as myeloperoxidase and cause the enzyme to act as the antigen ⁴ or (iii) Drugs can bind to complement components and impair the role of the classical pathway of the complement cascade to dispose of immune complexes in a timely manner, thus predisposing to tissue deposition. ⁵

There have been evidence of cutaneous vasculitis as paraneoplastic presentation of solid organ malignancies including breast carcinoma. ⁶ However, in this patient, paraneoplastic etiology of cutaneous vasculitis can be ruled out, as the occurrence of cutaneous vasculitis was observed after nearly one year of the removal of breast tumor only after the patient was started on tamoxifen, and there were no signs of vasculitis during the course of the malignancy. Hence, the appearance of vasculitis symptoms can be attributed to adverse drug reaction of tamoxifen.

Other drugs causing cutaneous vasculitis include allopurinol, thiazides, gold, sulfonamides, phenytoin and penicillin. ⁷ Some other cutaneous side effects of tamoxifen include skin rashes, itchiness of vulva, tingling sensation, hair loss and rarely angioedema.

The causality of the adverse drug reaction was analysed using Naranjo's algorithm, ⁸ which gave us a score of 7, denoting “probable” causality.

At present, tamoxifen is the only hormonal chemotherapeutic agent that can be prescribed as a post-operative management of breast carcinoma in pre-menopausal women. In a view of the absence of alternative medications to tamoxifen in pre-menopausal women, this makes it imperative to have a strict vigil on this agent, and it highlights the need for a newer and better alternative to treat these patients.