Aralık 2011

109-110

Soner ŞENEL¹,², Veli ÇOBANKARA³,⁴, Uğur KARASU³, Ufuk KUTLUANA³,⁵, Saadettin KILIÇKAP¹,⁶

Departments of ¹Internal Medicine, ²Rheumatology and ⁶Medical Oncology, Cumhuriyet University School of Medicine, Sivas
Departments of ³Internal Medicine, ⁴Rhemuatology and ⁵Gastroenterology, Pamukkale University School of Medicine, Denizli

Henüz kanıtlanmamış olmasına rağmen anti-tümör nekrozis faktör tedaviye bağlı kanser gelişimi halen tartışmalıdır. Elli üç yaşında bir kadın hasta halsizlik, kilo kaybı ve rektal kanama şikayeti ile kliniğimize başvurdu. Ankilozan spondilit tanısı alan hasta infliksimab ile tedavi edildi. Kolonoskopik incelemede çekumda ülsere ve kanayan polipoid görünümlü bir lezyon izlendi. Biyopsi materyalinin patolojik incelemesi adenokarsinom ile uyumlu idi. Biz bu vakada infliksimab gibi anti-tümör nekrozis faktör olan bir ilacın ciddi bir yan etkisi olasılığını tartıştık.

Ankilozan spondilit, anti-TNF, infliksimab, malignansi, adenokarsinom

Anti-tumor necrosis factor-? (TNF-?) treatment is effective in the treatment of various rheumatologic diseases, particularly rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis, and Crohn?s disease (1). Infliximab is a chimeric (mouse/human) IgG-1 anti-TNF-? monoclonal antibody that binds to soluble transmembrane TNF-? with high affinity and forms a complex with its receptor (2). The results of preliminary clinical studies have demonstrated that infliximab significantly improved clinical outcomes, quality of life and spinal inflammation in patients with AS (3). Anti-TNF-? treatment associated cancer risk has been poorly explored and the long-term risk is unknown.

We herein present an AS patient who developed colon adenocarcinoma 17 months after the initiation of infliximab treatment.

Tumor necrosis factor (TNF) has a documented tumor-reducing capacity, and treatment with anti-TNF drugs might thus theoretically promote formation of tumors (4).

There has been only one large national cohort of patients with AS that aimed to determine the overall cancer risk in AS. In this Swedish population-based cohort study, no overall increase in cancer risk was found. Colon cancer risk was not significantly increased, and moreover, rectal cancer was less common. Decreased risk of rectal cancer was thought to be due to the use of NSAIDs (5). Another study from Scotland quantified and compared risks for malignancy in patients with rheumatic conditions, and concluded that the risk of development of colorectal cancer was reduced in those patients (6). Bongartz et al. (7) recently reported a meta-analysis regarding the risk of malignancies in anti-TNF antibody-administered patients with RA. The authors concluded a dose-dependent increased risk for malignancies in those patients. Pharmacokinetic studies have already shown that infliximab doses beyond 3 mg/kg every 8 weeks lead to a high risk of overexposure with an excessive binding of TNF (8). However, in AS patients, the recommended infliximab dose is 3 to 10 mg/kg, and the recommended dose interval is every 6 weeks. There are a few reported cases demonstrating the development of gastrointestinal adenocarcinoma in patients with RA after infliximab therapy. St. Clair et al. (9) reported gastrointestinal adenocarcinoma in the 12th month of therapy in their randomized controlled trial with infliximab for early RA. The dose of infliximab was 6 mg/kg every 4 weeks. Lipsky et al.10 reported another patient who developed gastrointestinal adenocarcinoma after 26 weeks of infliximab therapy for RA at a dose of 10 mg/kg every 4 weeks. To our knowledge, there has been no report of a patient with AS who developed gastrointestinal cancer after infliximab. In this paper, we report an AS patient who developed gastrointestinal cancer after administration of this agent. Our patient had been treated with 5 mg/kg infliximab (400 mg) per 6 weeks for 17 months. There were no other risk factors for the development of malignancy. It has been suggested that long-term use of NSAIDs reduces the risk of development of colorectal cancer. The reduced need for NSAIDs after infliximab might also have increased the tumorigenesis.

In summary, we report herein an important possible serious adverse event of infliximab therapy in an AS patient. Although there is currently no definitive proof of a relation between infliximab therapy and colon cancer, thorough screening for subclinical malignancies may be needed in patients who are being considered for anti-TNF antibody treatment. The authors declare that they have no competing interests. Written consent was obtained from the patient.

Tumor necrosis factor (TNF) has a documented tumor-reducing capacity, and treatment with anti-TNF drugs might thus theoretically promote formation of tumors (4).

There has been only one large national cohort of patients with AS that aimed to determine the overall cancer risk in AS. In this Swedish population-based cohort study, no overall increase in cancer risk was found. Colon cancer risk was not significantly increased, and moreover, rectal cancer was less common. Decreased risk of rectal cancer was thought to be due to the use of NSAIDs (5). Another study from Scotland quantified and compared risks for malignancy in patients with rheumatic conditions, and concluded that the risk of development of colorectal cancer was reduced in those patients (6). Bongartz et al. (7) recently reported a meta-analysis regarding the risk of malignancies in anti-TNF antibody-administered patients with RA. The authors concluded a dose-dependent increased risk for malignancies in those patients. Pharmacokinetic studies have already shown that infliximab doses beyond 3 mg/kg every 8 weeks lead to a high risk of overexposure with an excessive binding of TNF (8). However, in AS patients, the recommended infliximab dose is 3 to 10 mg/kg, and the recommended dose interval is every 6 weeks. There are a few reported cases demonstrating the development of gastrointestinal adenocarcinoma in patients with RA after infliximab therapy. St. Clair et al. (9) reported gastrointestinal adenocarcinoma in the 12th month of therapy in their randomized controlled trial with infliximab for early RA. The dose of infliximab was 6 mg/kg every 4 weeks. Lipsky et al.10 reported another patient who developed gastrointestinal adenocarcinoma after 26 weeks of infliximab therapy for RA at a dose of 10 mg/kg every 4 weeks. To our knowledge, there has been no report of a patient with AS who developed gastrointestinal cancer after infliximab. In this paper, we report an AS patient who developed gastrointestinal cancer after administration of this agent. Our patient had been treated with 5 mg/kg infliximab (400 mg) per 6 weeks for 17 months. There were no other risk factors for the development of malignancy. It has been suggested that long-term use of NSAIDs reduces the risk of development of colorectal cancer. The reduced need for NSAIDs after infliximab might also have increased the tumorigenesis.

In summary, we report herein an important possible serious adverse event of infliximab therapy in an AS patient. Although there is currently no definitive proof of a relation between infliximab therapy and colon cancer, thorough screening for subclinical malignancies may be needed in patients who are being considered for anti-TNF antibody treatment. The authors declare that they have no competing interests. Written consent was obtained from the patient.

1. Criscione LG, St Clair EW. Tumor necrosis factor-alpha antagonists for the treatment of rheumatic diseases. Curr Opin Rheumatol 2002; 14: 204?11.

2. Knight D, Trinh M, Le J, et al. Construction and initial characterization of a mouse?human chimeric anti-TNF antibody. Mol Immunol 1993; 30: 1443?53.

3. Braun J, Baraliakos X, Golder W, et al. Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis, before and after successful therapy with infliximab: evaluation of a new scoring system. Arthritis Rheum 2003; 48: 1126?36.

4. Carswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumours. Proc Natl Acad Sci USA 1975; 72: 3666?70.

5. Feltelius N, Ekbom A, Blomqvist P. Cancer incidence among patients with ankylosing spondylitis in Sweden 1965-95: a population based cohort study. Ann Rheum Dis 2003; 62: 1185-8.

6. Thomas E, Brewster DH, Black RJ, Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer 2000; 88: 497-502.

7. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: 2275-85.

8. Nestorov I. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 2005; 34: 12-8.

9. St Clair EW, van der Heijde DM, Smolen JS, et al.; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004; 50: 3432-43.

10. Lipsky PE, van der Heijde DM, St Clair EW, et al.; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343: 1594-602.