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. Author manuscript; available in PMC: 2013 Sep 22.
Published in final edited form as: Immunotherapy. 2013 Mar;5(3):265–299. doi: 10.2217/imt.13.10

Table 1. Serious infections, data from observational studies.

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
Baeten et ala
2003[1]
SpA 107		 NA Hospitalized
infections		 Not defined 191.5
pt yrs		 Infliximab None Incidence
4.2/100 pt yrs		 NA
DREAM
Kievit et al
2011 [2]
RA 1560		 Duration: 5.5-6.2
yrs
HAQ: 1.3-1.4
DAS 5.0-5.2		 US FDA
Definition of
SAEsb 		Not defined 5 yrs Etanercept
Infliximab
Adalimumab		 None Incidence
2.6/100 pt yrs		 Not studied
Flendrie 2003c
[3]		 RA 230 Duration: 11.6
yrs
DAS: 6.1		 NA 12 months from
start of therapy		 NA Etanercept
Infliximab
Adalimumab		 None 12 cases of
serious
infections
leading to drug
discontinuation		 NA
Kiely 2003 [4] Open label study
of 20 RA patients
receiving
infliximab and
leflunomide		 NA Not defined While on drug 32 weeks NA NA 6 episodes of
infections: 4
requiring
antibiotics; 1
death		 NA
Burmester
2009j
[5]
Long term
safety study of
36 trials of
adalimumab
(RCTs, OLTs,
LTEs)		 6 Rheumatic
diseases (RA,
PsA, AS, CD,
Psoriasis, JIA)
19041 patients		 NA NA 1st dose of drug
to 70 days after
last dose		 10 yrs Adalimumab None Events/ 100
patient yrs
RA 4.65
PsA 2.81
AS 1.11
JIA 2.76
PsO 1.32
CD 5.18		 NA
RABBIT Listing
2005 [6]		 RA
858/601		 Duration: 9,8 yrs
vs. 6 yrs
DAS: 6.1vs 6.0
vs. 5.4		 E2A
Harmonization
guidelinesb 		12 months from
start of therapy,
irrespective to
further changes
in therapy after
the index dose		 12 months Etanercept
Infliximab		 Non Biologic
DMARDs		 Incidence /100
pt yrs: 6.4, 6.2
vs. 2.3 (p
0.0016)
RR (CI)
2.16 (0.9-5.4),
2.13 (0.8-5.5)
respectively		 No
BSRBRd
Dixon 2006 [7]		 RA
7664/1354		 Duration: 12 vs.
6 yrs
HAQ: 2.1 vs. 1.5
DAS: 6.6+/−1.0
vs. 5.1+/−1.4		 Confirmed
Infections
leading to
hospitalization/
death		 “Receiving
treatment”:
defined as 1st
missed dose		 Median:
1.26 yrs/
0.94 yrs		 Etanercept
Infliximab
Adalimumab		 Non Biologic
DMARDs		 IRR 1.03 (95%
CI, 0.68-1.57)		 No
BSRBR Dixon
2007 [8]		 RA
8659/2170		 Duration: 12 vs.
7 yrs
HAQ: 2.1 vs 1.5
DAS: 6.6 vs. 5.0		 As detailed
above		 1st 90 days of
treatment		 NA Etanercept
Infliximab
Adalimumab		 Non biologic
DMARDs		 IRR (CI) 4.6
(1.8-11.9)		 IRR (CI)
Eta 4.1 (1.5-
10.8)
Inf 5.6 (2.1-
15.1)
Ada 3.9 (1.3-
11.2)
TennCare
Databasee
Grijalva 2010 [9]		 RA 14586 pts/
>20000 drug
episodes		 NA Pneumonia or
any infection
requiring
hospitalization		 Start of new
medication+180
days		 180 days Etanercept
Infliximab
Adalimumab		 Non biologic
DMARDs, steroids		 HR for
hospitalized
infection (CI);
MTX referent
1.31 (0.78-2.19)		 NA
SABER project
Grijalva 2011
[10]		 RA 10484, IBD
2323, Psoriasis
and SpA 3215		 NA Hospitalized
infections		 Start of
medication to
discontinuation
or discontinued
enrollment or
serious
infections or 12
months of follow
up		 Duration
of study
1998-2007		 Etanercept
Infliximab
Adalimumab		 Non biologic
DMARDs		 HR (CI)
RA: 1.05 (0.91-
1.21)
IBD: 1.10 (0.83-
1.46)
Psoriasis and
SpA: 1.05 (0.76-
1.45)		 Infliximab
HR (CI)
vs. Etanercept
1.26 (1.07-1.47)
vs. adalimumab
1.23 (1.02-1.48)
Genovese
2009f [11]		 185 pts received
biologies after
withdrawing from
rituximab RA
clinical trial
programme (153
received anti TNF
agent)		 Duration: 11.9
yrs
DAS: 7.0		 Met the
regulatory
criteria for
SAEs or
required IV abx		 Median:
11 months
after
receiving
the
medication		 Etanercept
Infliximab
Adalimumab		 None Rate of serious
infection/ 100
patient yrs (CI)
Before TNF
inhibitor
6.63 (3.57-
12.32)
After TNF
inhibitor 4.93
(2.46-9.85)		 Not studied
BSRBR
Galloway 2011g
[12]		 RA
11881/3673		 1. Median: 11
yrs vs. 6 yrs
2. Mean: 2.0 vs.
1.5
3. Mean: 6.6 vs.
5.1		 “Serious”
septic Arthritis :
requiring IV
antibiotic,
hospitalization or death		 While on anti-
TNF therapy or
within 90 days of
1st missed dose		 Duration
of study:
2001-2009		 Etanercept
Infliximab
Adalimumab		 Non Biologic
DMARDs		 HR (CI) 2.3 (1.2-
4.4)		 Eta 2.5 (1.3-4.9)
Inf 2.4 (1.0-5.8)
Ada 1.9 (0.9-
4.0)
U.S.
Administrative
database
Curtis 2007
[13]		 RA
2393/2933		 NA Specific case
definitions
developed by
investigators,
who reviewed
medical
records		 “Ever-exposed”:
≥1 dose of TNF
agent/ ≥3 doses
of MTX
1st 6 months of
treatment		 Median:
17 months		 Etanercept
Infliximab
Adalimumab		 MTX HR (CI),1.9 (1.3-
2.8)


HR (CI),1.9 (1.3-2.8)		 Not studied
U.S.
Administrative
database Curtis
2007h [14]		 RA
2272/2933		 NA Same as above New users of
anti-TNF agent,
current use		 NA Etanercept,
Infliximab		 MTX IRR (CI)
< 6 mo therapy
Infliximab
2.4 (1.23-4.68)
Etanercept
1.61 (0.75-3.47)
> 6 mo therapy		 At < 6 mo,
infliximab had
higher risk of
serious
infections as
compared to
etanercept
Infliximab
1.14 (0.55-2.24)
Etanercept
1.37 (0.74-2.53)
Galloway 2011
(BSRBR)
[15]		 RA 11798/3598 Duration: 11 yrs
vs. 6 yrs
HAQ: 2.0 vs. 1.5
DAS: 6.6 vs. 5.1		 Infections
requiring IV
Abx or leading
to
hospitalization
or death		 While on anti-
TNF therapy or
within 90 days
1st missed dose		 Median:
3.9 yrs vs.
2.6 yrs		 Etanercept,
Infliximab,
Adalimumab		 Non biologic
DMARDs		 HR (CI)
Overall: 1.2 (1.1-
1-5
1st 6 months: 1.8
(1.3-2.6)
By age:
< 55 yrs: 1.2
(0.8-1.6)
55-64 yrs: 1.4
(1.1-1.9)
65-74 yrs: 0.9
(0.7-1.2)
> 75 yrs: 1.5
(0.9-2.6)		 No
U.S. Veterans
[16]		 RA
1465/11772/13367		 NA Hospitalized
infections		 While on
medication+ 5
half lives or 1
dosing interval +
1 half life
whichever was
longer		 Study
Duration:
Oct 1998-
Sep 2005		 Etanercept,
Infliximab,
Adalimumab		 Gp 1: HCQ, SSZ,
Gold, Penicillamine
Gp 2: MTX,
Leflunomide,
Azathioprine,
Cyclophosphamide,
Cyclosporine,
Anakinra		 HR (CI)
Anti-TNF
biologic vs. Gp
1: 1.24 (1.02-
1.5)

Gp 2 vs. Gp 1:
1.08 (0.95-1.24)		 HR (CI)
Infliximab vs.
Etanercept 1.51
(1.14-2.00)
Adalimumab vs.
Etanercept 0.95
(0.68-1.33)
Askling 2007
[17]		 RA 4167/10295 NA Hospitalized
infections		 While on
therapy		 Study
duration:
Jan 1999-
Dec 2003		 Etanercept,
Infliximab,
Adalimumab		 Non-biologic
DMARDs		 RR (CI)
1st Anti-TNF
1st yr: 1.43
(1.18-1.73)
2nd yr: 1.15
(0.87-1.50)
After 2 yrs: 0.82
(0.62-1.50)
2nd Anti-TNF:
2.10 (1.36-3.27)
Kroesen 2003
[18]		 RA 60 NA Infections
requiring IV
Antibiotics or
hospitalization		 While on
therapy		 Anti-TNF
therapy:
1999-
2002,
Control: 2
yrs prior to
anti-TNF
initiation		 Etanercept,
Infliximab Etanercept, Infliximab, Adalimumab		 Non-biologic
DMARDs Non-biologic DMARDs		 Incidence/
treatment yr
Anti-TNF
therapy arm:
0.181/ yr
Control arm:
0.008/yr
(p value NA)		 Anti-TNF arm:
11/60.65
treatment yrs
Control arm: 1/
123 treatment yrs
Salliot 2007
[19]		 Rheumatic
diseases(> 95%
RA, SpA)
623 pts		 Duration: 12.1
yrs		 Life threatening
infections,
requiring
hospitalization
or sequelae		 While on
therapy		 Mean 1.3
yrs vs. 1.1
yrs		 Etanercept,
Infliximab,
Adalimumab		 Non-biologic
DMARDs		 Incidence/100
patient yrs
Anti-TNF
biologic arm:
10.5 +/−86.9
Control (prior to
anti-TNF
initiation): 3.4+/−
38.7/100 patient
yrs
P=0.03, NNH 14
Neven 2005
[20]		 168 RA patients
treated w/
infliximab		 Duration: 10 yrs Infections
requiring
hospitalization
or IV antibiotics		 NA Study
duration:
Apr 2000-
Oct 2002		 Infliximab
(Low dose:
3 mg/kg:
n=132)
(High dose:
3-7.5 mg/kg:
n=36)		 None 0.07 events/
patient/ yr in
both groups		 NA
U.S.
Administrative
Database
Curtis 2011
[21]		 RA 4916/2931 NA Hospitalized
infections		 Current usage+
90 days		 Median:
7.7
months		 Biologic
Free (no
biologic use
in last yr)		 Biologic switchers Incidence rate/
100 person-yrs
Biologic Free:
4.6
Switchers: 7.0		 Etanercept 0.64
(0.49-0.84) and
adalimumab
HR (CI) 0.52
(0.39-0.71)had
lower risk of
infection vs.
infliximab
Bernatsky 2010
[22] 7
observational
studies		 RA 1,24357
subjects		 NA Serious
infections,
primarily
hospitalized
infections.
Excluded
clinical trials		 While on drug
(duration of trial)		 0.4-6.3 yrs Etanercept
Infliximab
Adalimumab		 Placebo or non
biologic DMARD		 RR (CI) 1.37
(1.18-1.6)		 Not studied
Case control
studies
Bernatsky 2007
[23]		 23733 RA patients
on DMARDS: 261
(1.1%) were on
anti-TNF agents		 NA Hospitalized
infections		 Prescription
within 45 days
prior to index
date		 6.3 yrs Cases
(hospitalized
infections)		 Controls (no
hospitalized
infections)		 RR (CI) in TNF
users: 1.93
(0.70-5.34)		 NA
a

2 cases of TB reactivation

b

US FDA definition of SAE: events disabling daily activities persistently or significantly, needing hospitalization or being life threatening, E2A Harmonization guidelines: events that are life threatening, require hospitalization, congenital anomalies or result in disability or death

c

2 cases of TB reactivation

d

Increased risk of serious skin and soft tissue infections IRR 4.28 (1.06-17.17)

e

HR for pneumonia (CI), MTX referent 1.61 (0.85-3.03)

f

88.6% patients had peripheral B cell depletion at the time of biologic initiation

g

No difference in risk of prosthetic joint septic arthritis in 2 groups

h

Adalimumab excluded due to small numbers

i

Risk of serious infections decreased significantly as trial duration increased

j

Rates of infection for early RA 2.76/100 pt yrs, established RA 4.91/ 100 pt yrs