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 |
2 cases of TB reactivation
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
2 cases of TB reactivation
Increased risk of serious skin and soft tissue infections IRR 4.28 (1.06-17.17)
HR for pneumonia (CI), MTX referent 1.61 (0.85-3.03)
88.6% patients had peripheral B cell depletion at the time of biologic initiation
No difference in risk of prosthetic joint septic arthritis in 2 groups
Adalimumab excluded due to small numbers
Risk of serious infections decreased significantly as trial duration increased
Rates of infection for early RA 2.76/100 pt yrs, established RA 4.91/ 100 pt yrs