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A 65-year-old man with rheumatoid arthritis in sustained remission presented with a two-week history of right breast swelling. He had been receiving oral methotrexate (MTX) at a stable dose of 14 mg/week, oral folic acid 5 mg/week for over a year, with good adherence. Concomitant therapies, including prednisolone, sulfasalazine, tacrolimus, and adalimumab had been adjusted during the disease course (Supplementary Fig. 1). Medical history was otherwise unremarkable. Physical examination revealed a rubbery, concentric mound of tissue beneath the right nipple-areolar complex, although not apparent on visual inspection. Non-contrast-enhanced chest computed tomography demonstrated newly developed glandular tissue in the right subareolar area, compared with imaging obtained before treatment (Fig. 1A and 1B). Ultrasonography revealed diffusely distributed glandular tissue within the adipose tissue (Supplementary Fig. 2A). These findings were consistent with gynecomastia. Hepatic, renal, and thyroid functions were unremarkable. Serum levels of sex hormones, such as testosterone, estradiol, sex hormone-binding globulin, luteinizing hormone, and follicle-stimulating hormone were within normal limits. Normal levels of human chorionic gonadotropin, dehydroepiandrosterone, and prolactin ruled out testicular, adrenal, and pituitary tumors. Core needle biopsy excluded malignancy. Given the stable disease activity for 6 months, the MTX dose was reduced to 6 mg/week, while other medications were unchanged. The breast swelling improved over four months, which was confirmed by clinical examination and ultrasonography (Supplementary Fig. 2B). The clinical course suggested a probable association between methotrexate and gynecomastia.
Fig. 1
Non-contrast-enhanced chest computed tomography. A Before initiation of methotrexate therapy, showing no abnormal glandular tissue in the bilateral subareolar areas. B After 17 months of low-dose methotrexate therapy, demonstrating newly developed unilateral glandular enlargement in the right subareolar area (arrow), consistent with gynecomastia
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