Infliximab is a chimeric mouse-human monoclonal IgG antibody directed against soluble and cellular tumor necrosis factor-alpha (TNF-alpha) and is approved for use in the United States for treatment of refractory Crohn’s Disease (CD) and fistulizing CD. Infliximab is an immunomodulatory agent with immunosuppressive properties. We report on an individual with a distant history of malignant melanoma that developed widespread melanoma metastases after receiving several infusions of infliximab.CASE REPORT: A 68-year-old hypertensive man presented with new onset dyspnea and diffuse pulmonary nodules. Thirty-two years previously, a melanoma had been radically excised from his right ankle. He also had a 15-year history of CD and a five-year history of IgA nephropathy. For the CD, he had received azathioprine for one year and had chronically received prednisone. During the past year, he had received five 500 mg infusions of infliximab; the most recent infusion had been two months prior. For the IgA nephropathy, he had received mycophenolate mofetil.The patient was hospitalized because of shortness of breath, dry cough and fatigue for three days. He had lost 15 pounds over the prior month. He denied symptoms of chills, fevers, night sweats, hemoptysis, and chest pain. A chest radiograph and CT scan of the thorax revealed diffuse moderate-sized pulmonary nodules.He had had a negative PPD one year ago. Medications included prednisone and mycophenolate mofetil. He was afebrile and hemodynamically stable with a saturation of 94% on 6 L/min of oxygen. He had no adenopathy, the lung fields were clear, and there was no hepatosplenomegaly or clubbing/cyanosis of his digits.Transbronchial biopsies were performed, but no diagnosis was made. Worsening hypoxemia necessitated mechanical ventilation. Wedge resection was performed and the pathology was consistent with metastatic melanoma. The patient was extubated and he expired shortly thereafter.DISCUSSION: To date, in all chronically immunosuppressed populations, an increased risk for the development of malignancies has not been found. However, in epidemiologic studies of immunosuppressed renal and cardiothoracic transplant populations, an increased incidence of cutaneous neoplasms has been documented compared with age-matched controls.TNF-alpha is a complex cytokine with immunomodulatory properties. In vitro studies have demonstrated that TNF-alpha augmented the activated-macrophage destruction of murine melanoma and carcinoma cells. In randomized, human studies, TNF-alpha has been added to melphalan and low dose interferon-gamma therapy, and a selective coagulation and necrosis of tumor microvasculature has resulted. Such evidence supports the idea that TNF-alpha has anti-tumor capability. However, other studies also have demonstrated that TNF-alpha has tumor promoter activity. When TNF-alpha was given to rats with fibrosarcomas, it promoted metastases.It is unclear what relationship exists between antibodies to TNF-alpha, such as infliximab, and the development of neoplasms. While evidence suggests that immunosuppression and life-threatening infections are associated with its use, infliximab therapy has not been associated with the development of malignancies. Longer-term population-wide surveillance will be required to identify such a link.Because of the possible tumor promoting effects of infliximab, we believe it important to report on our patient. We find it curious that he presented with metastatic melanoma 32 years after apparently curative resection of his tumor. While exposure to other immunosuppressives such as prednisone, azathioprine and mycophenolate mofetil cannot be discounted as contributing to the development of metastatic melanoma, the proximate cause seems likely to be treatment with infliximab.
Infliximab has many properties, one of which is immunosuppression. There may be a relationship between infliximab infusions and the development or promotion of metastatic cancer. Patients who are to receive infliximab and who have a history of cancer require close observation for the development of metastatic disease.
M.N. Solomon, None.