Background Treatment with biologics is associated with increased risk of tuberculosis (TB).1,2 Before starting an anti-TNF, patients (pts) should undergo screening for latent TB, including Purified Protein Derivation (PPD) skin test. WHO guidelines recommend a PPD positivity cut-off value of ≥5mm.3 Higher cut-offs were considered in some countries with a high TB vaccination rate in the population.
Objectives To examine the effect of introducing more stringent screening rules on TB in clinical trials of the anti-TNF certolizumab pegol (CZP).
Methods The CZP safety database of TB cases from rheumatoid arthritis (RA) clinical trials was reviewed up to 30 Nov 2011. In the initial RA trials for CZP, pts were included if PPD was negative according to respective national guidelines. As many pts originated from high TB incidence countries and were TB-vaccinated, criteria for PPD positivity varied from <5 up to 20mm. In 2007, ongoing CZP protocols were amended dictating all pts be treated with INH if screening PPD score was ≥5mm. Additionally, a questionnaire administered every 6 months increased awareness of symptoms and risk factors for TB. The protocol amendment was implemented retrospectively; all patients in ongoing trials with a baseline PPD ≥5mm were treated with INH regardless of duration/exposure to CZP treatment. In the present work, clinical trials were assessed as two groups: trials initiated before the protocol amendment (early trials) (PHA001, CDP860-002, CDP870-004, NCT00544154, NCT00548834, NCT00160693, NCT00152386, NCT00175877, NCT00160602, NCT00160641) and recent trials initiated after protocol amendment (NCT00993668, NCT00674362, NCT00580840, NCT00717236, NCT00843778, NCT00753454). All TB cases were manually reviewed by independent experts, classified according to pre-defined standard procedures and validated by study authors. Incidence rates (IR) per 100 pt-years (PY) are reported.
Results The CZP safety database included 4049 pts (9277 PY). 44 TB cases were confirmed (IR: 0.47/100 PY), with the majority from Eastern Europe (21 cases, IR: 1.02/100 PY) and Central Europe (18 cases, IR: 0.58/100 PY). In Western Europe 3 cases (IR: 0.23/100 PY) were reported and in North America 1 case (IR: 0.05/100 PY). Early trials had higher rates of TB (42 cases, IR: 0.51/100 PY) compared to recent trials (cut-off PPD <5mm) (2 cases, IR: 0.18/100 PY). Recent CZP trials recruited fewer pts from Eastern and Central Europe compared to earlier trials, which may limit comparison. Of 44 pts who developed TB, only 2 were treated for latent TB by prophylactic INH prior to TB diagnosis. Out of the 44 cases, 11 TB cases were diagnosed after 2008 when the protocol amendment was enforced.
Conclusions Most TB cases occurred in regions with high background levels of latent TB. Following implementation of the WHO recommendations for PPD cut-off, the TB rate in CZP trials was similar to that seen with other anti-TNFs.4 Implementation of the 5mm rule had benefits even in pts already treated by anti-TNFs.
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Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma.
Disclosure of Interest J. Vencovsky Consultant for: UCB Pharma, Roche, Abbott, Pfizer, MSD, Speakers bureau: UCB Pharma, Pfizer, Roche and MSD, O. Lortholary Grant/research support from: MSD, Consultant for: MSD, Astellas, Gilead, Pfizer, Speakers bureau: Astellas, Gilead, Merck/Schering, Pfizer, J. Gomez-Reino Grant/research support from: MSD, Roche, UCB Pharma, Consultant for: BMS, GSK, MSD, Pfizer, Roche, UCB Pharma, Speakers bureau: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB Pharma, R. van Vollenhoven Grant/research support from: Abbott, Bristol Myers Squibb, GSK, MSD, Pfizer, Roche and UCB Pharma, Consultant for: Abbott, Bristol Myers Squibb, GSK, MSD, Pfizer, Roche and UCB Pharma, M. de Longueville Employee of: UCB Pharma, X. Mariette Grant/research support from: Pfizer, Roche, Consultant for: BMS, GSK, Pfizer, Roche, UCB Pharma