Is there an increased risk of malignancies in patients treated with infliximab?/nThe question conce

Fråga: Is there an increased risk of malignancies in patients treated with infliximab? The question concerns a 50-year-old woman treated with infliximab (Remicade) for rheumatoid arthritis. One year after initiation of therapy, a lobular infiltrated cancer in her right breast was found. Other drugs: methotrexate, paracetamol, lansoprazole (Lanzo), tramadol (Tradolan), celecoxib (Celebra), folic acid (Folacin), calciumcarbonate/vitamin D (Calcichew-D3) and vitamins.

Sammanfattning: TNF-alfa antagonist treatment has been connected with the development of lymphomas. However, patients with reumathoid arthritis or Crohn´s disease are already at an increased risk of lymphoma development. We have found no published evidence that infliximab could cause breast cancer.

Svar: Infliximab is a human-murine antibody that binds to TNF-alfa (TNF-alfa antagonist), thereby reducing the activity of TNF-alfa. It is used for the treatment of rheumatoid arthritis (RA) and Crohn´s disease (1).

The risk of malignancies during TNF-alfa antagonist treatment has been debated. In clinical trials, 18 out of 1372 patients developed new or recurrent malignancies, both lymphomas and solid tumours. However, this was similar to the expected frequency in patients with RA or Crohn´s disease, who receive immunosuppressants regularly (2).

Malignancies, mostly lymphomas, have also been reported in post marketing studies. In one study reviewing the FDA post marketing adverse event reporting system, 26 cases of lymphomas in patients treated with either etanercept (18) or infliximab (8) were found. The majority of the cases (81 percent) were non-Hodgkin´s lymphomas. The lymphomas occurred shortly after initiation of treatment, within a median time of eight weeks. In two cases, spontaneous regress of the lymphoma was seen after TNF-alfa antagonist treatment was stopped (3). Case reports of lymphomas and leukemia have also been found in the literature (4,5,6).

In the Swedish adverse drug reaction register, there are eight reports of neoplasms (four lymphomas), which has been judged as possibly related to infliximab treatment (out of a total of 343 reports). There is also one report of breast cancer. However, this was judged as unlikely, because of the short time (five months) from initiation of therapy to solid tumour development (7).

There is evidence for an increased risk of lymphomas in patients with RA, and probably also in Crohn´s disease. A twofold increase of the risk of lymphoma in patients with RA compared to the general population has been reported. The risk also increases with the severity of the disease and with continuous use of immunosuppressants. Patients treated with TNF-alfa antagonists are likely to have a more severe disease, and to have received immunosuppressive treatment previously, meaning that they are already at an increased risk of lymphoma development (8,9,10).

Recently, a signal from WHO, discussing whether infliximab could aggravate silent breast cancer, has been published. The WHO database holds 30 reports of breast cancer in connection to infliximab treatment. Ten of these were registered as aggravated breast neoplasms. The indication was only mentioned for four of the women (three Crohn´s disease and one psoriasis). Most of the women had taken concomitant drugs, such as hormone replacement therapy and other immunomodulators (11).

The present case was judged as unlikely by the regional adverse drug reactions monitoring centre, because of the rapid development of the tumour after initiation of infliximab therapy.