Table 2.

Summary Data on TB Reactivation with the Use of Anti-TNF Therapies in IBD and Other Rheumatological Conditions

Publication	Brief description of methodology	Country	Key findings
Meta-analyses
Bonovas et al. (2016)20	Meta-analysis of 49 RCTs, focused on risk of infections with biologics	NA	Odds of TB numerically higher with biologics vs placebo (OR, 2.04; 95% CI, 0.71–5.89).
			9 Cases (0.36%) of TB infection with biologics vs 1 (0.07%) with placebo.
Ford et al. (2013)21	Meta-analysis of 22 RCTs, focused on risk of opportunistic infections with anti-TNF in IBD	NA	Risk of TB numerically higher with anti-TNF vs placebo (RR, 2.52; 95% CI, 0.62–10.21).
			8 Cases (0.2%) of TB infection with anti-TNF vs zero with placebo.
			All except 1 case occurred in trials that screened patients for exposure prior to entry.
Review
Cantini et al. (2014)40	RCTs, PMS, national registries; focused on risk of TB with anti-TNF	NA	Increased risk of TB with any of the 3 anti-TNF drugs.
			A 3–4 times higher risk with infliximab & adalimumab vs etanercept.
Observational studies from Asian countries (in reverse chronological order)
Tan et al. (2017)41	Review of RA patients treated with anti-TNF agents (77%) and other drugs; 2003–2014; n=301	Malaysia	3.7% of the patients developed TB.
Hong et al. (2017)42	Insurance database analysis; 2011-2013; n=38,830 IBD patients	South Korea	Incidence of TB: 5-ASA (1.44 per 1,000 PY), corticosteroids (2.09), immunomodulators (2.85), anti-TNF (5.54).
			Incidence of TB significantly higher in those using anti-TNF vs not using anti-TNF (SIR, 6.53; 95% CI, 5.99–7.09).
Puri et al. (2017)43	Retrospective data analysis; n=79 UC patients treated with infliximab	India	Despite TB screening, 7 (8.8%) patients developed TB.
			3 Patients (42%) developed disseminated disease, 4 (57%) developed pulmonary disease.
Jung et al. (2015)39	Database analysis; 2005–2009; 8,421 patients; 10,021 PY exposure (patients prescribed anti-TNFs)	South Korea	Compared to etanercept (reference), IRR for TB: infliximab (IRR, 6.8; 95% CI, 3.74–12.37), adalimumab (IRR, 3.45; 95% CI, 1.82–6.55).
			Compared to ankylosing spondylitis (reference), IRR for TB: IBD (IRR, 5.97; 95% CI, 3.34–10.66), RA (IRR, 1.02; 95% CI, 0.57–1.83), and psoriatic arthritis (IRR, 1.00; 95% CI, 0.14–7.30).
Byun et al. (2015)44	Retrospective cohort study; 2001–2013; n=525 IBD patients	South Korea	Incidence of TB: overall (1.84 per 1,000 PY), anti-TNF-α (4.89 per 1,000 PY), non-anti-TNF-α (0.45 per 1,000 PY).
			Crude incidence of TB significantly higher in patients receiving TNF-α blockers compared to TNF-α-blocker-naïve patients (3.1% vs 0.3%, p=0.011).
			LTBI diagnosed in 17 (10.6%) patients; none experienced reactivation of TB.
Byun et al. (2015)45	Retrospective cohort study; 2001–2013; n=873 IBD patients	South Korea	The adjusted SIR of TB was 41.7 (95% CI, 25.3–58.0), compared with that of the matched general population.
			19/25 Patients (76%) developed TB within 2–62 months of initiation of TNF-α inhibitor treatment despite screening negative for LTBI; 3 patients with LTBI (12%, 3/25) developed TB 3 months after completion of chemoprophylaxis.
Çekiç et al. (2015)46	Retrospective study; 2007–2014; n=76 IBD patients treated with infliximab and adalimumab	Turkey	45 Patients (59.2%) had LTBI and received isoniazid (INH) prophylaxis.
			During the follow-up period, active TB was identified in 3 (4.7%) patients who were not receiving INH prophylaxis–of these, 2 patients had negative IGRA and TST results and 1 patient had positive IGRA and TST results and had received adequate treatment for TB.
Chen et al. (2008)47	Cohort of RA patients treated with adalimumab; n=43	Taiwan	All patients underwent serial TSTs and QuantiFERON-TB Gold assays.
			Of the 43 RA patients who received adalimumab therapy, 4 (9.3%) developed active TB after starting adalimumab therapy.
Takeuchi et al. (2008)48	Post-marketing surveillance trial; 2003–2004; n=5,000 RA patients treated with infliximab	Japan	The rate of TB was 0.3%.
			Half the cases were extrapulmonary TB.
Seong et al. (2007)49	Single-center cohort; 2001–2005; n=193 RA patients treated with infliximab and etanercept	South Korea	In the infliximab-treated RA group, 2 cases of TB developed during 78.17 PY of follow-up (2,558 per 100,000 PY), and there was no case of TB during 73.67 PY of follow-up in the etanercept-treated RA group.
			The risk of TB was higher in RA patients treated with infliximab (RR, 30.1; 95% CI, 7.4–122.3) compared with the general Korean population.
Kumar et al. (2006)50	Review of patients with rheumatic diseases treated with infliximab; n=176	India	Reactivation TB developed in 10.6% of spondyloarthropathy (SpA) patients treated with standard regimen of infliximab.
			Patients treated with lower doses of infliximab did not develop TB.
Navarra et al. (2006)51	Review of patients with rheumatic diseases treated with infliximab; n=64	Philippines	Of the 64 patients reviewed, 5 (7.8%) developed active TB, at an interval of 1.5 to 15 months after initiation of treatment with infliximab.
			Four of the 5 patients had undergone TB screening.
Observational studies from non-Asian countries (in reverse chronological order)
Thi et al. (2018)52	Database analysis; 2007–2015; n=596 IBD patients treated with anti-TNF	UK	1.0% Patients developed TB. Of these, 5 patients had a negative LTBI screening, and 1 had indeterminate test.
			2 Patients developed miliary TB, 2 abdominal TB, 1 pleuro-pulmonary TB and 1 both pulmonary and pericardial TB.
Ramos et al. (2018)53	Retrospective review of IBD patients with LTBI (on TST/IGRA) who subsequently received biologics; n=35	USA	One patient on adalimumab after 6 months of INH developed TB reactivation.
			TB reactivation rate: 0.98 cases per 100 PY.
Carpio et al. (2016)54	Multicenter study; TB in anti-TNF-treated IBD patients	Spain	50 TB cases in IBD patients treated with anti-TNF.
			34% of TB cases were disseminated and 26% extrapulmonary.
			30 Patients (60%) developed TB despite compliance with recommended preventive measures.
Abitbol et al. (2016)55	Multicenter study; TB in anti-TNF-treated IBD patients	France	44 TB cases in IBD patients treated with anti-TNF.
			Each patient had TB-negative screening before starting anti-TNF: TST (n=25), IGRA test (n=12), or both (n=7).
			40 Patients (91%) with at least 1 extrapulmonary involvement.
Jauregui-Amezaga et al. (2013)56	Database analysis; IBD patients treated with anti-TNF between 2000–2011; n=423	Spain	7 Patients (1.65%) developed TB. Of these, 6 had a negative LTBI screening.
			3 Patients developed pulmonary TB and 4 developed extrapulmonary disease.
Mañosa et al. (2013)57	Cohort of anti-TNF treated IBD patients; n=330	Spain	1.2% Patients developed active TB.

TB, tuberculosis; TNF, tumor necrosis factor; IBD, inflammatory bowel disease; RCT, randomized controlled trial; NA, not applicable; OR, odds ratio; CI, confidence interval; RR, relative risk; PMS, post-marketing study; RA, rheumatoid arthritis; 5-ASA, 5-aminosalicylic acid; PY, person-year; SIR, standardized incidence ratio; UC, ulcerative colitis; IRR, incidence rate ratio; LTBI, latent tuberculosis infection; IGRA, interferon-gamma release assay; TST, tuberculin skin test.