Three cases of malignant neoplasm, pneumonitis, and pancytopenia during treatment with low-dose methotrexate

Abstract

A 77-year-old man with chronic obstructive pulmonary disease was treated with low-dose methotrexate (7.5-15 mg per week). After 15 months a diagnosis of urothelial carcinoma of the bladder was made; after a further 6 months pneumonitis and pancytopenia developed. The patient died due to massive pulmonary hemorrhage. A malignant teratoma was diagnosed in a 65-year-old asthmatic man 16 months after initiation of methotrexate therapy (15 mg per week). The patient died 4 months later due to fulminant progression of the neoplasm. A third malignant neoplasm (dermal squamous cell carcinoma) was seen in a 64-year-old woman with rheumatoid arthritis after 13 months treatment with 7.5 mg methotrexate per week. These three cases, while obviously not proving a causal relationship between long-term treatment with low-dose methotrexate and development of malignant neoplasm, do call for stringent treatment criteria, close surveillance, and prospective studies.

Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate

“…As in this study, previously reported cancers have been heterogeneous: thymoma,6 acute and chronic leukaemia,7 23bladder urothelial cancer, mediastinal teratoma, and squamous cell carcinoma of the thoracic skin 8. However, non-Hodgkin lymphoma is the main type of cancer reported 9–15 20 23 (table 4).…”

Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients

“…Adverse central nervous system reactions including headache, dizziness and memory impairment were also reported [79]. Overall, approximately a quarter of the patients with MTX pneumonitis [10, 14, 15, 22, 29, 30, 37, 39, 40, 42, 43, 45, 48, 50, 52, 55–57, 60, 61, 63, 67, 68] (and one of the nine present cases) demonstrated extrapulmonary effects of the drug. Thus, it is helpful to look for extrapulmonary symptoms and signs when entertaining a diagnosis of MTX pneumonitis.…”

“…Concomitant side‐effects due to MTX were present in 32 cases [10, 14, 15, 22, 29, 30, 37, 39, 40, 42, 43, 45, 48, 50, 55–57, 60, 61, 63, 67, 68]: liver enzyme elevation or liver dysfunction (12 cases), oral ulcer (six cases), skin rash (six cases), stomatitis (three cases), haematological complications such as pancytopenia or leukopenia or acute megaloblastic anaemia (five cases), hypercalcaemia (one case); and convulsion (one case). The cumulative dose of these patients ranged 42–9,800 mg.…”

“…Forty‐seven (38.2%) patients were treated with MTX only. Concomitant drugs administered with MTX included antineoplastic agents [19, 24, 25, 30, 35, 44, 45, 48, 53, 54], nonsteroidal anti‐inflammatory drugs (NSAIDs) [14, 17, 20, 21, 23, 27, 28, 31, 33, 36, 41, 57, 59, 60, 63, 66, 68, 69] and others [10, 15, 17, 22, 27, 32, 34, 37, 38, 42, 46, 49, 59–61, 65, 67, 69]. Thirty‐nine patients received systemic corticosteroids (prednisone 5–50 mg·day ‐1 , or methylprednisolone 4 mg· day ‐1 ; doses were not described in five) during MTX therapy [10, 14, 15, 17, 19, 20, 22–24, 27, 32, 34, 35, 37, 42, 45, 49, 59, 61, 65, 66, 69].…”

Gallbladder squamous cell carcinoma in the setting of low‐dose methotrexate use

“…Our patient had been on long‐term oral methotrexate at the time of diagnosis. Dermal squamous cell carcinoma has been reported in the setting of low‐dose methotrexate, 2 but we could not identify any such reports for squamous cell carcinoma of the gallbladder. Low‐dose methotrexate in rheumatic disease is not carcinogenic, and has only modest cytotoxic activity 3 .…”