The incidence of tuberculosis in patients treated with certolizumab pegol across indications: impact of baseline skin test results, more stringent screening criteria and geographic region

Abstract

Objectives: We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening.

Methods: TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration ≥5 up to ≥20 mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD≥5 mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD≥5 mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts.

Results: 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J-RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD≥5 mm patients who received 9 months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD≥5 mm patients.

Conclusions: Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy.

Keywords: Anti-TNF; Autoimmune Diseases; Tuberculosis.

Figure 1

Evaluation for signs and symptoms of the tuberculosis (TB) questionnaire (sample).

Figure 2

Study design of CZP trials included in the safety analysis for the incidence of tuberculosis (TB). CZP, certolizumab pegol; OLE, open label extensions; RA, rheumatoid arthritis;

Figure 3

Summary of TB cases across indications and trial periods. †A total of 42 TB cases were reported in rheumatoid arthritis (RA) trials initiated or completed prior to protocol amendment; 20 cases in original RA trials (completed prior to protocol amendment) and 22 in intermediate RA trials (initiated before but completed after the introduction of more stringent PPD screening criteria in 2007). *Of the 22 TB cases in patients with RA from intermediate RA trials (RAPID1 and RAPID2), 9 cases were reported after protocol amendment. AxSpA, axial spondyloarthritis; PsA, psoriatic arthritis; IR, incidence rates; PY, patient-years; TB, tuberculosis.

Figure 4

Cumulative incidence of tuberculosis (TB) in certolizumab pegol (CZP)-treated patients with rheumatoid arthritis (RA) in the pooled RA safety database (N=4049) in relation to study year. Cumulative incidence of TB in RA trials between 1998 and the safety data-cut in November 2011. The cumulative number of recruited patients in each study year are also presented. *Vaccine study, CERTAIN, DOSEFLEX, REALISTIC.

Figure 5

PPD status of CZP-treated patients with RA in the pooled RA safety database (N=4049) at baseline and TB incidence by INH treatment. †One patient who developed TB started INH treatment 393 days after the first CZP dose was administered. INH was administered from 517 to 251 days before TB was diagnosed. CZP, certolizumab pegol; PPD, purified protein derivative; INH, isoniazid; RA, rheumatoid arthritis; TB, tuberculosis.