Table 3. Tuberculosis (TB) and Opportunistic infections, data from observational and pharmacovigilance studies and meta-analyses.

	No. of patients (TNF/ Comparator)	Baseline disease characteristics	Definition of infections	At Risk Period	Duration of follow up	Biologic Arm	Comparator Arm	Reported Incidence	Difference b/n anti-TNF agents
Observational studies
TB
BSRBR Dixon 2010[31]	RA 10712/ 3232	Duration: 11 yrs vs. 6 yrs HAQ:2.0 (0.6) vs. 1.5 (0.8) DAS: 6.6 (1.0) vs. 5.1(1.3)	Physician reported, 60% were "verified"	Ever on Drug	3.2 yrs vs. 2.3 yrs	Etanercept Infliximab Adalimumab	Non biologic DMARDs	40 TB casesa in anti- TNF cohort, none in DMARD cohort -Rate 118/ 100000 pt yrs	IRR (CI) with ETA as referent INF: 2.2 (0.9-5.8) ADA: 4.2 (1.8-9.9)
Askling 2005[32]	RA Anti-TNF 2500/ Inpatient RA cohort 31,185/ Early RA cohort 2430	HAQ: 1.5 / −/ 0.8 DAS: 5.8/-/3.6	Hospitalized infections, ICD codes	Ever on drug	Duration of study 1999- 2004	Etanercept Infliximab	Non biologic DMARDs	15 TB casesb in anti- TNF cohort RR (CI) Vs. Inpatient Register: 4.0 (1.3-12) Vs. Early arthritis: 4.1 (0.8-21)	RR (CI) ETA vs. INF 0.5 (0.1-2.4)
BIOBADASER Gomez-Reino 2007 [33]	Rheumatic diseases 5198	NA	+ Culture for M TB	Ever on drug	03/2002- 01/2006	Latent TB Infection (LTBI) guidelines not followed Etanercept, Adalimumab, Infliximab	LTBI guidelines followed Etanercept, Adalimumab, Infliximab	IRR (CI) 7.01 (1.6-64.7)	No difference in 3 anti- TNF agents
OIs
Salmon-Ceron et al[34]	Various autoimmune diseases 57711 patient yrs of TNF use	Duration: 9.5 yrs	Physician confirmed	Current or prior TNF use Median time of OI from start of therapy: 16.2 yrs	Duration of study 2004- 2007	Etanercept, Adalimumab, Infliximab	General French population in Incidence study, Etanercept, Adalimumab, Infliximab in Case control study	45 cases of OI 15 bacterial, 18 severe viral, 10 fungal, 2 parasitic 26% ICU admission rate, 9% mortality Rate of OI/100000 pt yrs: 151.6	Adalimumab vs. ETA 0R (CI) 10 (2.3-44.4) infliximab vs. ETA 17.6 (4.3-72.9)
CORRONA Greenberg et al 2010 [35]	RA 4659/1274	Duration: 11.41(9.6) yrs vs. 10.1 (9.8) yrs HAQ: 0.4 (0.4) vs. 0.3 (0.4)	Physician reported	Current use of medication	1.4 yrs	Etanercept, Infliximab, adalimumab	Non MTX, non biologic DMARDs	IRR Overall infection (CI) 1.52 (1.30-1.78) IRR opportunisticc infection (CI) 1.67 (0.95-2.94)	NA
Herpes zoster/ Varicella Zoster Virus
RABBIT Strangefeld 2009 [36]	RA 3266/ 1774	Duration: 9 yrs vs. 6 yrs DAS: 5.8 (1.3) vs. 5.0 (1.3)	Reported by rheumatologist or Patient reports confirmed by medical records	Current use of medication	5 yrs	Etanercept, Infliximab, Adalimumab	Non biologic DMARDs	HR (CI) Anti TNF as a class: 1.63 (0.97-2.74) Etanercept: 1.36 (0.73-2.55) Ada/ Inf: 1.82 (1.05- 3.15)	Higher incidence of multidermatomal and ophthalmic zoster:2.5% in TNF gp, w/ most cases reported in antibody gp vs. 0.9% in control gpd
BIOBADASER Garcia Dovel et al 2010 [37]	Various autoimmune diseases 4655 patients on TNF agents	NA	Hospitalized infection w/ VZV (Chicken pox/ shingles) as reported to BIOBADASER	Current use of medication	8 yrs	Etanercept, Infliximab, Adalimumab	General Spanish population	SIR (CI) for hospitalization due to shingles 9 (3-20) SIR (CI) for hospitalization due to chickenpox 19(5-47)	NA
McDonald et al 2009 [38]	RA 20357	NA	ICD 9 codes for HZ in a clinical encounter	Current use of medication	71607 patient yrs	Severe RA (Etanercept, Infliximab, Adalimumab)	Mild RA (HCQ, SSZ, Gold, penicillamine) Mod RA (MTX, Leflunomide, azathioprine, cyclophosphamide, cyclosporine, anakinra	Incidence rate: Anti-TNF biologic gp: 10.6/1000 patient yrs Mild RA 8/1000 patient yrs (p< 0.01) Mod RA 11.18/1000 patient yrs (NS vs. severe RAA)	Hazard vs.. Infliximab HR (CI) Etanercept 0.62 (0.4- 0.95) Adalimumab 0.53 (0.31- 0.91)
Pharmacovigilance Reports
Wallis 2004 [39]	NA	NA	As reported to FDA AERS Database	NA	NA	Etanercept, Infliximab	None	Granulomatous infections/ 100,000 pts: Etanercept: 74 Infliximab: 239	Infliximab with 3 fold risk of granulomatous infections (vs. etanercept), highest increase in risk with infliximab in the 1st 3 months of treatmente
Keane 2001[40]	NA	NA	Reported to FDA Medwatch	NA	NA	Infliximab	None	Rate of TB/100,000 pts: 24.4f	NA
Tsiodras et al 2008[41]	NA	NA	Case reports in MEDLINE/ PubMed	NA	NA	Etanercept, Infliximab, Adalimumab	None	Cases of invasive fungal infections Infliximab 226 Etanercept 44 Adalimumab 11g
Meta- analyses
Singh 2011 [29] 160 RCTs and 46 extension studies	Any indication other than HIV: 60630 subjects	NA	NA	While on drug (duration of study)	RCTs: Median 6 months Ltes: 13 months	5 Anti-TNF agents, Abatacept, Anakinra, Rituximab, Tocilizumab	Placebo or Non Biologic DMARD	OR (CI) of TB reactivation in biologic arm vs. placebo 4.68 (1.18- 18.60)h	NA
Burmester 2009 [5] 36 trials (RCTs, OLTs, LTEs)	6 Rheumatic diseases 19041 patients	NA	NA	1st dose of drug to 70 days after last dose	10 yrs	Adalimumab	None	Event rate/100 pt yrs TB 0-0.30 OI 0-0.09 Histo 0-0.03	NA

^a62% cases were extrapulmonary

^b33% had extrapulmonary TB

^cMost frequent OI: Varicella (82 cases) zoster, other common OIs: Pneumocystis jeroveci, TB

^dOther factors associated with increased risk of HZ: Age HR 1.28, CI 1.05-1.55, Glucocorticoids, > 10 mg/ day 2.52 (1.12-5.65)

^eMost common infection: M TB, 2nd MC: Histoplasmosis*Rate of infections calculating using manufacturer reports of approx. no. of patients treated with anti-TNF agent

^fRate of infections calculating using manufacturer reports of approx. no. of patients treated with anti-TNF agent 70% of cases of TB developed after 3 or fewer infusions of infliximab. Approx. 60% cases had extrapulmonary disease

^gMost common IFI s were histoplasmosis (30%), candidiasis (23%), aspergillosis (23%)

^hIncluded bacterial infections and OIs in most studies