Are there reports of squamous cell carcinoma after tumour necrosis factor alpha (TNF-alpha) inhibit

Fråga: Are there reports of squamous cell carcinoma after tumour necrosis factor alpha (TNF-alpha) inhibitor treatment? The question concerns a 51-year-old woman with rheumatoid arthritis (RA). Three and a half years ago treatment with methotrexate was initiated; the dose was later reduced due to mouth sores. The same year infliximab (Remicade) was added, a treatment that was seponated nine months later due to insufficient effect. Thereafter she was treated with etanercept (Enbrel) for 16 months. Both etanercept and methotrexate was thereafter withdrawn, due to reduced effect. Gold sodium thiomalate (Myocrisin) was initiated, and withdrawn after two months due to eosinophilia and mouth ulcers. Adalimumab (Humira) in combination with methotrexate was then initiated. Three months later a growing tongue squamos cell carcinoma was found and adalimumab and methotrexate was seponated.

Sammanfattning: A few cases of squamous cell carcinoma after TNF-alpha inhibitor treatment are described in the literature. However, the incidence of squamous cell carcinomas in patients treated with tumour necrosis alfa inhibitors does not seem to be increased compared with the general population.

Svar: Tumor necrosis factor is an inflammation mediator and affects cell immunity, and the tumour necrosis factor alpha (TNF-alpha) inhibitors may therefore affect the defence against infections and malignancies (1). The TNF-alpha inhibitors have been connected with the development of malignancies, mostly lymphomas. However, patients with rheumatoid arthritis (RA) and Crohn´s disease already have an increased risk of developing lymphomas (2).

The greatest risk factor for developing oral squamous cell carcinoma (SCC) is tobacco use, but other major risk factors include chronic inflammation (especially ulcerative lichen planus) and human papilomavirus (HPV). Immunosuppression is also connected with an increased risk of squamous cell carcinoma, since all immunosuppressed patients are more susceptible to oncogenic viruses such as HPV (3).

A few cases of squamous cell carcinoma (SCC) in connection to tumour necrosis factor alpha treatment have been published. In a case series, seven patients with squamous cell carcinomas after etanercept treatment are described. All patients received subcutaneous etanercept (25 mg) twice weekly due to RA, and they had all received methotrexate prior to or in combination with etanercept. All patients had actinic damage. The tumours were on chronically sun-exposed skin, and had arisen over a period of two to four weeks before presentation and had grown rapidly. Four of the patients had a history of basal cell carcinomas (4). A case of cutaneous squamous cell carcinoma of the penis after subcutaneous etanercept (25 mg) treatment in a patient with psoriasis has been published. He had previously been treated with methotrexate, cyclosporine, hydroxyurea, and an attempt of psoralen plus UVA therapy had also been done. Two months after initiation of etanercept an erythematous and indurated papule was found which was growing rapidly and squamous cell carcinoma was diagnosed after histological analysis (5). One case with multiple squamous cell carcinoma four months after initiation of infliximab for RA has been found. The patient had a prior history of multiple nonmelanoma skin cancers and had an extensive history of sun-exposure (6). In the Swedish RA-register there are three cases of squamous cell carcinoma registered after TNF-alpha inhibitor treatment, two located in the skin appearing after infliximb treatment and one located on the female genitalia after etanercept treatment (7). No cases have been found after adalimumab treatment.

A retrospective analysis of an etanercept clinical trials´ database and a postmarketing surveillance database to determine the incidence of cutaneous squamous cell carcinoma in patients treated with etanercept for RA has been done. At clinical trial monitoring visits cutaneous squamous cell carcinoma was diagnosed clinically and confirmed via histologic examination of biopsies. Incidence rates in two studies in Minnesota (low sun exposure) and Arizona (high sun exposure) were age- and sexadjusted to the clinical trials´ population. In the clinical trials´database only four cases of squamous cell carcinoma was found from a total of 1442 patients, which is lower than the expected incidence of squamous cell carcinoma based on the Minnesota- and Arizona studies (5.9-13.1 cases). In the postmarketing database 25 cases out of 125 000 patients were found, which also was less than expected (8). In a prospective database with information on adverse events for 1440 patients with RA treated with etanercept, the overall rate of malignancies was not greater than expected. Only two cases of squamous cell carcinoma were reported in this database. Based on the Minnesota- and Arizona studies, the expected rate in this population would be 5.1-11.5 cases (9).

Additionally, a Danish study found a significantly increased risk of developing squamous cell carcinoma in patients with RA compared to the general population (10).

There are several factors making it difficult to evaluate if there is a causal relationship between the treatment with TNF-alpha inhibitors and the development of squamous cell carcinoma in the present case. First of all, the patient had been treated with several different drugs that may have contributed to the event. Secondly, the patient had problems with mouth sores and ulcers before initiating treatment with TNF-alpha inhibitors, and the contribution of these is unknown. Thirdly, we have no information about the patients´ smoking habits, which is the greatest risk factor. Lastly, patients with RA are already at an increased risk of developing malignancies, including squamous cell carcinoma.