Table 4.

Observational data on risk of infection and malignancy with TNF-α antagonists.

Study	Year	Registry	Period	Anti-TNF-α Agents Included in Analysis	Type of Infection	DMARD Control	Anti-TNF-α	Adalimumab	Etanercept	Infliximab
Infection
Listing¹¹	2005	RABBIT	2001–2003	Etanercept, infliximab	Serious infections
					Rate per 100 PY (95% CI)	2.28 (1.3–3.9)	—	—	6.42 (4.5–9.1)	6.15 (4.0–9.5)
					Adjusted RR (95% CI)	Referent	—	—	2.16 (0.9–5.4)	2.13 (0.8–5.5)
Dixon¹²	2007	BSRBR	Up to July 2006	Adalimumab, etanercept, infliximab	Serious infections
					Rate per 100 PY (95% CI)	3.92 (3.23–4.71)	6.32 (5.94–6.72)	5.42 (4.55–6.40)	6.17 (5.60–6.78)	6.89 (6.24–7.60)
					Adjusted IRR (95% CI)	Referent	1.35 (0.99–1.85)	1.25 (0.88–1.77)	1.34 (0.97–1.86)	1.41 (1.02–1.97)
Tubach²²	2009	RATIO	2004–2007	Adalimumab, etanercept, infliximab	Tuberculosis
					Rate per 100 PY (95% CI)	—	0.116 (0.0106–0.2229)^a	0.215 (0.0–0.5217)^a	0.0093 (0.0–0.0094)	0.1875 (0.0001–0.03748)^a
					SIR (95% CI)	—	12.2 (9.7–15.5)	29.3 (20.3–42.4)^a	1.8 (0.7–4.3)^a	18.6 (13.4–25.8)^a
Gomez-Reino²³	2009	BIOBADASER	March 2002–Jan 2006	Adalimumab, etanercept, infliximab	Tuberculosis
Gomez-Reino²³	2009	BIOBADASER	March 2002–Jan 2006	Adalimumab, etanercept, infliximab	Rate per 100 PY (95% CI)	—	—	0.176 (0.024–1.254)	0.114 (0.028–0.459)	0.383 (0.159–0.921)
Strangfeld²⁶	2009	RABBIT	2001–2006	Adalimumab, etanercept, infliximab	Herpes zoster
					Rate per 100 PY (95% CI)	0.56 (0.36–0.83)	1.01 (0.78–1.30)	1.11 (0.79–1.51)	0.89 (0.56–1.33)	1.11 (0.79–1.51)^c
					Adjusted HR (95% CI)	—	1.63 (0.97–2.74)	1.8 (1.1–3.2) ^c	1.4 (0.7–2.6)	1.8 (1.1–3.2)
					p	—	0.07	0.03	0.33	0.03
Dixon²¹	2010	BSRBR	Up to April 2008	Adalimumab, etanercept, infliximab	Tuberculosis
					Rate per 100 PY (95% CI)	0.00 (0.00)	0.095 (0.063–0.138)	0.144 (0.072–0.258)	0.039 (0.013–0.092)	0.136 (0.068–0.244)
					Adjusted IRR (95% CI)	—	—	4.2 (1.4–12.4)	Referent	3.1 (1.0–9.5)
Malignancy
Geborek³⁹	2005	SSATG/ARTIS	1999–2002	Etanercept, infliximab	All cancers
					SIR (95% CI)	1.4 (1.1–1.8)	1.1 (0.6–1.8)	—	—	—
					Lymphoma (95% CI)	1.3 (0.2–4.5)	11.5 (3.7–26.9)	—	—	—
Wolfe³⁸	2007	US NDB	1998–2005	Adalimumab, etanercept, infliximab	All cancers
					OR (95% CI)	—	1.0 (0.8–1.2)	0.7 (0.3–1.6)	1.0 (0.8–1.3)	1.0 (0.8–1.3)
					p	—	0.858	0.393	0.962	0.820
					Lymphoma
					OR (95% CI)	—	1.0 (0.5–2.0)	1.3 (0.2–10.0)	1.3 (0.6–2.8)	0.9 (0.4–2.1)
					p	—	0.967	0.826	0.460	0.898
					Melanoma
					OR (95% CI)	—	2.3 (0.9–5.4)	0.8 (0.1–6.6)	2.4 (1.0–5.8)	2.6 (1.0–6.7)
					p	—	0.070	0.822	0.054	0.056
					NMSC
					OR (95% CI)	—	1.5 (1.2–1.8)	0.9 (0.5–1.8)	1.2 (1.0–1.5)	1.7 (1.3–2.2)
					p	—	< 0.001	0.828	0.081	< 0.001
Askling⁴⁰	2009	ARTIS	1999–2006	Adalimumab, etanercept, infliximab	All cancers
Askling⁴⁰	2009	ARTIS	1999–2006	Adalimumab, etanercept, infliximab	RR (Anti-TNF-α vs biologics-naive)	_	1.0 (0.9–1.2)	1.3 (0.9–2.0)	0.8 (0.6–1.0)	1.1 (0.9–1.3)
Askling⁴¹	2009	ARTIS	1998–2006	Adalimumab, etanercept, infliximab	Lymphoma
					Rate per 100 PY (95% CI)	—	0.096 (0.063–0.141)	—	—	—
					RR (Anti-TNF-α vs general population)	—	2.72 (1.82–4.08)	—	—	—
					RR (Anti-TNF-α vs anti-TNF-naive)	—	1.35 (0.82–2.11)	—	—	—
Mariette⁴²	2010	RATIO	2004–2006	Adalimumab, etanercept, infliximab	Lymphoma
					Rate per 100 PY (95% CI)	—	0.04 (0.007–0.08)	0.065 (0.0–0.16)	0.02 (0.0–0.05)	0.069 (0.0–0.15)
					SIR (95% CI)	—	2.4 (1.7–3.2)	4.1 (2.3–7.1)	0.9 (0.4–1.8)	3.6 (2.3–5.6)
					p	—	< 0.0001	< 0.001	0.72	< 0.001

↵a Includes data acrosss multiple indications.
b Reported rate observed after September 2003, when all 3 agents became fully available in Spain;
↵c Represents pooled results for adalimumab and infliximab.
TNF-α: tumor necrosis factor-α; RABBIT: German biologics register; PY: patient-years; RR: relative risk; BSRBR: British Society for Rheumatology Biologics Register; IRR: incidence rate ratio; RATIO: French Research Axed on Tolerance of Biotherapies; SIR: standardized incidence ratio; BIOBADASER: Spanish biologics register; SSATG/ARTIS: South Swedish Anti-TNF Group Register/Swedish biologics register; US NDB: US National Data Bank for Rheumatic Diseases; HR: hazard ratio; NMSC: nonmelanotic skin cancer.