Prof Dr.Zeki KILIÇASLAN Istanbul University Faculty of Medicine, Chest Depertament .

1. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience Prof Dr.Zeki KILIÇASLAN Istanbul University Faculty of Medicine, Chest Depertament.

2. Treatment of Latent TB in Anti-TNF-Alpha Therapy Preparing a guideline-1 Attempts to reduce TB risk started in 2002,just after TNF-Alpha antagonists entered into use The meeting of The Society for Resarch and Education in Rheumatology( SRER). Istanbul. March 2002 .

3. Treatment of Latent TB in Anti-TNF-Alpha Therapy Preparing a guideline-1 For treatment of Latent TB, the cut-off diameter of PPD is recommended to be ≥ 10 mm Direskeneli H, Kılıçaslan Z, İnanç M, et al: Evaluation of patients fortuberculosis prior to treatment with anti-tumor necrosis factor- biological agents. Marmara Medical Journal 2002;15:273-6.

4. Treatment of Latent TB in Anti-TNF-Alpha Therapy Preparing a guideline-1 Second meeting of SRER, May 2005. Izmir Rheumatologists and Chest Specialists. Second meeting of SRER 7 May 2005 / İzmirParticipantsN. Akkoç, O. Aydıntuğ, A. Cefle, N. Çakır, V. Çobankara, L. Çöplü, A. Dinç, H. Direskeneli, E. Doğanavşargil, E. Erken, İ. Ertenli, İ. Fresko, B. Göker, A. Gül, V. Hamuryudan, Ş. Haznedaroğlu, A. Işık, M. İnanç, Y. Karaaslan, G. Keser, S. Kirazlı, C. Korkmaz, F. Oksel, F. Önen, G. Öngen, M. Özhan, Ş. Özkara, S. Pay, T. Pırıldar, T. Şentürk, E. Terzioğlu, E. Tunç, R. Tunç, E.S. Uçan, Ş. Yavuz, H. Yazıcı, E. Yücel Those who prepared consensus report: G. Keser, H. Direskeneli, N. Akkoç, M. İnanç, Ş. Özkara, G. Öngen, A. Gül, E.S. Uçan, İ. Ertenli, H. Yazıcı, E. Doğanavşargil

5. Treatment of Latent TB in Anti-TNF-Alpha Therapy Preparing a guideline-2005 • Around 3000 patients have used anti-TNF treatment • 13 of 2000 patients were diagnosed TB. • 6 cases were not evaluated for latent TB • 1 case did not use adviced INH treatment • 6 cases were not recommended to use INH • because of their PPD <10mm • There is no TB case among users of prophilactic treatment according to 2002 guideline. 2nd SRER censensus report 7 May 2005 / İzmir

6. Treatment of Latent TB in Anti-TNF-Alpha Therapy Preparing a guideline-2005 • Cases recommended INH treatment; • Chest x-ray is normal and TST is positive( ≥5 mm ) • Cases have suspected fibrocalcified lesions. • Close contacts with TB patients last one year. • Health workers having high TB risk. 2nd SRER censensus report 7 May 2005 / İzmir

7. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB 5 Medical centers (Medical Faculty of İstanbul, Medical Faculty of Cerrahpaşa , Medical faculty of Çukurova ,Medical Faculty of G.Antep , Medical Faculty ofAnkara ) The evaluations of 1319 cases. Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

8. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB Total case; 1319 Female: 53.2 % Male: 46.8 % Mean age : 39.2- 41.2 Mean follow-up period: 5.9 months- 15.8 months Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

9. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB Rheumatologic diseases (n; 1204 ); RheumatoidArtrit: 469 (39% ) SA: 446 (37 %) Diğer: 289 (24% ) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

10. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB Anti-TNF-Alpha Drugs ( n; 1156 ) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

11. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB BCG state (n:886 ): Vaccination ratio : 83. 7 % (%72.2- % 89.1) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

12. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB Abnormal chest x-ray on initial screening Ankara % 11.6 Cerrahpaşa % 12.1 İstanbul % 45.8 (? ) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

13. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB TST Results (n:1101 ) ≥5 mm ; 618 ( % 56.1 ) < 5 mm ; 483 (% 43.9) Mean TST diameter : 7.53 mm (n:484) Mean TST diameter :10.3 mm (n:115) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

14. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB TST Results (n:1101 ) The booster effect TST negative(< 5 mm)number: 410 (2 center) Booster test number : 271 (% 66.1) Booster effect (+) : 24 (% 8.1) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

15. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB Cases given INH chemoprophylaxis Mean : % 69.9 Range: % 64- % 82.7 * * Istanbul Faculty of Medicine Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

16. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB INH Toxicity Drug interrupted ; % 5.9 (28/484) Drug stopped : % 0.4 (2/484) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

17. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB TB diagnosed cases 8/1319 : % 0.6 Pulmonary TB: 6 Extra pulmonary TB: 2 Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

18. Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists Turkey’s Experience for TB • 8 TB Cases • 4 cases ( % 0.3, 4/1319) appeared despite following the guideline (3 cases had not prophylaxis indication + 1 case used INH ) Çağatay T et al. Turkish Thoracic S. Congres-2008 Zuhur F et al. Turkish Thracic S. Congres-2007 Hanta I et al. Clinical Rheumatology 2008 Elbek O et al Turkish Thoracic S. Congres-2007 Yalçın A et al Turkish Thoracic S. Congres-2007

19. The treatment with TNF-alpha antagonists and Tuberculosis. Increase in TB risk with TNF-alpha antagonists USA: 4 times (1) Sweden: 2 times (2) In a global study, TB risk was found 0.11-0.24 % in 10.000 RA patients (3) In USA it was % 0.02 per 100 patient-yearsin 55.000 RA patients.(3) (1)F. Wolfe, Arthritis Rheum. 50 (2004) 372–379. (2)J. Askling, Arthritis Rheum. 52 (2005) 1986–1992. (3) M.H. Schiff,Ann. Rheum. Dis. 65 (2006) 889–894.

20. The treatment with TNF-alfa antagonists and Tuberculosis. Results; There is a 10 times increase in TB risk even when the guideline is applied. The use of IGRA’s tests instead of TST should be discussed.

21. The treatment with TNF-alfa antagonists and Cancers. 26 Rheumatology centers. 2199 patient(1247 female, 952 Male) Mean age : 41.8 years 943 AS , 931 RA, 132 PsA, 127 JCA, 66 Other Etanercept 923 (1028.54 patient-year) İnfliximab 853 (1014.68 patient-year) Adalimumab 259 (223.69 patient-year) More than one 164 Risk of cancer in Turkish patients after treatment with TNF antagonists

23. The treatment with TNF-alfa antagonists and Cancers. This nationwide survey did not show an increased risk of cancer associated with TNF antagonist use when data with three drugs were considered together On the other hand, there was an increase of cancer risk with etanercept use when these agents were considered separately and this trend was also present among RA patients taken as a separate group.

24. TST and Quantiferon-TB Test for diagnosis of latent TB infection ? Preliminary presentation of 70 cases. If we use the Quantiferon –TB Gold Test as a gold standart; The value of TST for diagnosis of Latent TB ; 5 mm and above 10 mm and above Sensitivity: % 72 % 63 Specificity: % 56 % 70 There is a weak concordance (Kappa: 0.27) Tülin ÇAĞATAY at .Turkish Thracic S. Congres-2008

25. TST and Quantiferon-TB Test for diagnosis of latent TB infection ? Preliminary presentation of 70 cases. BCG effect; 11 out of 70 patients “indeterrminate result” (all BCG vaccinated) In 48 BCG vaccinated patients : The sensitivity of TST test (≥ 5 mm) for latent TB was 50 % Tülin ÇAĞATAY et al. Turkish Thracic S. Congres-2008

26. Does Anti TNF-Alfa treatment change TST response ? TST enduration diameters were compared before and after treatment in 182 cases treated with TNF-α Antagonists. 1st TST 2nd TST 6.60 ± 0.51’ mm 15±0.55 (p<0.001) mm Tülin ÇAĞATAY et al.Turkish Thracic S. Congres-2008

27. Does Anti TNF-Alfa treatment change TST response ? In 26 out of 87 first TST- negative cases (29.8 %) second TST turned to positive ( ≥ 5 mm) In logistic regression analysis, no independent variable affecting TST diameter increase was found but the use of TNF-Alpha antagonists Tülin ÇAĞATAY et al.Turkish Thracic S. Congres-2008

28. Does Anti TNF-Alfa treatment change TST response ? Is it necessary to repeat TST among first TST- negative cases after one year treatment ? Tülin ÇAĞATAYet al.Turkish Thracic S. Congres-2008

29. Anti TNF-Alfa treatment and other serious infections 130 RA patients treated with DMARDs and 48 RA patients treated with TNF-Alpha antagonists were compared. N. Inanc · H. Direskeneli . Rheumatol Int (2006) 27:67–71

30. Anti TNF-Alfa treatment and other serious infections N. Inanc · H. Direskeneli . Rheumatol Int (2006) 27:67–71

31. Anti TNF-Alfa treatment and other serious infections N. Inanc · H. Direskeneli . Rheumatol Int (2006) 27:67–71

32. Anti TNF-Alfa treatment Turkey’s experience Result Evaluation of these cases became a heavy burden for the chest clinics of major hospitals. More specific organizations can be needed for registration and follow-up purposes because of rapid increase in Anti TNF-Alfa treatment.

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34. the estimated rate of TB among RA patients treated with INF in the US was 24.4 cases per 100,000, compared to a background TB in RA patients of 6.2 cases per 100,000 per year in US [89]. F. Wolfe, K. Michaud, J. Anderson, K. Urbansky, Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy, Arthritis Rheum. 50 (2004) 372–379. In global clinical trial data released by Abbott pharmaceuticals in N10,000 RA patients, all of whom were screened for latent TB, the event rate of TB per 100 patient-years was 0.24 in longstanding RA (N3 years) and 0.11 per 100 patient-years in early RA [91].

35. In an analysis of the US postmarketing safety of ADA from Abbott-supported trials from 2002 to 2004 of pre-screened patients with an estimated 55,384 patients years of exposure, 11 patients were reported to have TB, yielding a rate of 0.02 per 100 patient-years [91]. Three of the eleven (27%) had extrapulmonaryTB

36. The relative risk of TB in RA patients on anti-TNF therapy compared to a control RA group not treated with TNFα antagonists was 4.0 (95% CI: 1.3–12). The calculated relative risk of TB in the control RA population compared to the general Swedish population was 2.0 (95% CI 1.2–3.4)

37. A Spanish study evaluated the effectiveness of recommendations set forth to prevent reactivation of latent TB in patients treated with TNFα antagonists [95]. Rates of active TB after implementation of the recommendations decreased by 78% (incidence risk ratio 0.22, 95% CI: 0.03– 0.88, p=0.008), highlighting the effectiveness of their implemented strategies. The importance of TB prevention recommendations was highlighted in a recent report from the BIOBADASER registry, which evaluated new cases of active TB in 5198 patients treated with TNF antagonists after the dissemination of recommendations to prevent reactivation of latent TB infection [94]. Fifteen active TB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103–285). The probability of developing active TB was 7 times higher when recommendations were not followed.

38. Also, the FDA recently approved QuantiFERON-TB Gold test, which measures interferon-γ production after 16–24 h incubation of whole blood with synthetic peptides [96].

40. SONUÇ