Prof Dr.Zeki KILIÇASLAN

Istanbul UniversityFaculty of Medicine, Chest Depertament.

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) Antagonists

Turkey’s Experience

Treatment of Latent TB in Anti-TNF-Alpha TherapyPreparing 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 .

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.

For treatment of Latent TB, the cut-off diameter of PPD is recommended to be≥ 10 mm

Treatment of Latent TB in Anti-TNF-Alpha TherapyPreparing a guideline-1

Second meeting of SRER, May 2005. Izmir

Rheumatologists and Chest Specialists.

Second meeting of SRER 7 May 2005 / İzmir

ParticipantsN. 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 

Treatment of Latent TB in Anti-TNF-Alpha TherapyPreparing a guideline-1

• 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

Treatment of Latent TB in Anti-TNF-Alpha TherapyPreparing 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.

Treatment of Latent TB in Anti-TNF-Alpha TherapyPreparing a guideline-2005

2nd SRER censensus report 7 May 2005 / İzmir

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-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’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

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

Rheumatologic diseases (n; 1204 );

Rheumatoid Artrit: 469 (39% )

SA: 446 (37 %)

Diğer: 289 (24% )

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

Anti-TNF-Alpha Drugs ( n; 1156 )

Infliximab 475 (41.1 %)

Etanercept 537 (46.4%)

Adalimumab 144 (12.5 %)

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

BCG state (n:886 ):

Vaccination ratio : 83. 7 % (%72.2- % 89.1)

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

Abnormal chest x-ray on initial screening

Ankara % 11.6

Cerrahpaşa % 12.1

İstanbul % 45.8 (? )

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

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)

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

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)

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

Cases given INH chemoprophylaxis

Mean : % 69.9

Range: % 64- % 82.7 *

* Istanbul Faculty of Medicine

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

INH Toxicity

Drug interrupted ; % 5.9 (28/484)

Drug stopped : % 0.4 (2/484)

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

TB diagnosed cases

8/1319 : % 0.6

Pulmonary TB: 6

Extra pulmonary TB: 2

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

• 8 TB Cases• 4 cases ( % 0.3, 4/1319) appeared despite following the guideline (3 cases had not prophylaxis indication + 1 case used INH )

Treatment with Tumor Necrosis Factor-Alpha (TNF-α) AntagonistsTurkey’s Experience for TB

Çağatay T et al. Turkish Thoracic S. Congres-2008Zuhur F et al. Turkish Thracic S. Congres-2007Hanta I et al. Clinical Rheumatology 2008Elbek O et al Turkish Thoracic S. Congres-2007Yalçın A et al Turkish Thoracic S. Congres-2007

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-years in 55.000 RA patients.(3)

The treatment with TNF-alpha antagonists and Tuberculosis.

(3) M.H. Schiff,Ann. Rheum. Dis. 65 (2006) 889–894.

(1)F. Wolfe, Arthritis Rheum. 50 (2004) 372–379.

(2)J. Askling, Arthritis Rheum. 52 (2005) 1986–1992.

Results;

There is a 10 times increase in TB risk even when the guideline is applied.

The use of IGRA’s testsinstead of TST should be discussed.

The treatment with TNF-alfa antagonists and Tuberculosis.

Risk of cancer in Turkish patients after treatment with TNF antagonists

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

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.

The treatment with TNF-alfa antagonists and Cancers.

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 aboveSensitivity: % 72 % 63 Specificity: % 56 % 70

There is a weak concordance (Kappa: 0.27)

TST and Quantiferon-TB Test for diagnosis of latent TB infection ?

Tülin ÇAĞATAY at .Turkish Thracic S. Congres-2008

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

TST and Quantiferon-TB Test for diagnosis of latent TB infection ?

Tülin ÇAĞATAY et al.Turkish Thracic S. Congres-2008

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

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

Does Anti TNF-Alfa treatment change TST response ?

Is it necessary to repeat TST among first TST- negative cases after one year treatment ?

Tülin ÇAĞATAY et al.Turkish Thracic S. Congres-2008

Does Anti TNF-Alfa treatment change TST response ?

N. Inanc · H. Direskeneli . Rheumatol Int (2006) 27:67–71

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

Anti TNF-Alfa treatment and other serious infections

N. Inanc · H. Direskeneli . Rheumatol Int (2006) 27:67–71

Anti TNF-Alfa treatment and other serious infections

Anti TNF-Alfa treatmentTurkey’s experience

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 purposesbecause of rapid increase in Anti TNF-

Alfa treatment.

Result

THANK YOU

the estimated rate of TB among RA patients treatedwith INF in the US was 24.4 cases per 100,000, compared to abackground TB in RA patients of 6.2 cases per 100,000 peryear in US [89]. F. Wolfe, K. Michaud, J. Anderson, K. Urbansky, Tuberculosisinfection in patients with rheumatoid arthritis and the effectof infliximab therapy, Arthritis Rheum. 50 (2004) 372–379.

In global clinical trial data released by Abbott pharmaceuticalsin N10,000 RA patients, all of whom were screenedfor latent TB, the event rate of TB per 100 patient-yearswas 0.24 in longstanding RA (N3 years) and 0.11 per 100patient-years in early RA [91].

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

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

A Spanish study evaluated the effectiveness ofrecommendations set forth to prevent reactivation of latentTB in patients treated with TNFα antagonists [95]. Rates ofactive TB after implementation of the recommendationsdecreased by 78% (incidence risk ratio 0.22, 95% CI: 0.03–0.88, p=0.008), highlighting the effectiveness of their implementedstrategies.The importance of TB prevention recommendations washighlighted in a recent report from the BIOBADASER registry,which evaluated new cases of active TB in 5198 patientstreated with TNF antagonists after the dissemination ofrecommendations to prevent reactivation of latent TBinfection [94]. Fifteen active TB cases were noted (rate172 per 100,000 patient-years, 95% CI 103–285). Theprobability of developing active TB was 7 times higherwhen recommendations were not followed.

Also, the FDA recentlyapproved QuantiFERON-TB Gold test, which measuresinterferon-γ production after 16–24 h incubation ofwhole blood with synthetic peptides [96].

SONUÇ