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OP0307 Treatment of baff transgenic mice with ANTI-TNF: monoclonal ANTI-TNF are associated with a higher risk of lymphoma than etanercept
  1. G Nocturne1,
  2. L Bineta2,
  3. S Boudaoud2,
  4. J Pascaud2,
  5. R Seror1,
  6. C Nicco3,
  7. C Chereau3,
  8. F Mackay4,
  9. F Vincent4,
  10. T Lazure5,
  11. S Ferlicot5,
  12. L Stimmer6,
  13. S Roulland7,
  14. R Krzysiek8,
  15. S Hacein-Bey8,
  16. F Batteux3,
  17. X Mariette1
  1. 1Rheumatology
  2. 2INSERM U1184, le Kremlin Bicêtre
  3. 3U1016, Paris, France
  4. 4Melbourne University, Melbourne, Australia
  5. 5Pathology, le Kremlin Bicêtre
  6. 6CEA, Fontenay aux roses
  7. 7Marseille Luminy, Marseille
  8. 8Immunology, le Kremlin Bicêtre, France

Abstract

Background Risk of lymhoma in patients with rheumatoid arthritis (RA) and disease activity is the main risk factor. The impact of treatment, notably of anti-TNF, is unclear: decreasing the risk of lymphoma by controlling activity or alterring anti-tumor immunosurveillance. Anti-TNF are not associated with an increased risk of lymphoma in large epidemiologic studies. However, the risk might vary according to the type or to the dose of anti-TNF.

Objectives To assess if the risk of lymphoma might differ according to the type of anti-TNF, comparing monoclonal anti-TNF to the soluble receptor. For that, we used BAFF transgenic (Tg) mice as a model of autoimmunity-associated lymphomas. They develop lupus and Sjögren and 3% of them spontaneously developed lymphoma at 12–18 months

Methods Six months aged BAFF-Tg mice were treated with anti-TNF for 12 months: etanercept (ETA) (n=15, 8 mg/kgx3/week), monoclonal anti-mouse TNF: TN3 19.12 (n=15, 20 mg/kg/week), adalimumab (ADA) (n=12, 20 mg/kg/week) or controls (n=22). Sera were assessed monthly. Crude mortality was compared among the different groups. Histological examination of the spleen was performed. The Fisher's exact test was used to compare the incidence of lymphoma among the groups.

Results Adjunction of low dose of methotrexate during the 3 first days of treatment prevented immunization in the 3 groups for life. Using L929 cells, a cell line sensitive to TNF induced death, we confirmed that ADA was 8 to 12 times less efficient than ETA to inhibit soluble murine TNF. As expected, the mean level of ETA, TN3 and ADA were 7 μg/ml, 69 μ g/ml and 105 μg/ml, respectively. The level of auto-antibodies and serum Ig did not significantly differ among the groups. However, crude mortality was significantly higher in mice treated with monoclonal anti-TNF compared to controls (p=0.0001 for ADA and p=0.0003 for TN3) but not for mice treated with ETA (Figure). Incidence of lymphoma was higher in mice treated with monoclonal anti-TNF: 5/15 (33%) with TN3 (p=0.03/controls), 4/12 (33%) with ADA (p=0.054/controls), 0/15 with ETA and 1/22 (5%) in controls.

Conclusions Higher mortality and increased risk of lymphoma were observed in BAFF Tg mice treated with monoclonal anti-TNF compared to etanercept. This result may be linked either to the different mechanism of action between the soluble receptor and the monoclonals or to a difference of trough level observed in the different groups even if higher levels of ADA was mandatory given the difference of effect on mouse TNF. This study demonstrates the negative impact of a prolonged anti-TNF treatment on the risk of lymphoma in the context of BAFF increase.

Disclosure of Interest None declared

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