*Alonoso-Ruiz et al. 2008126 | Meta-analysis 13 trials 7,087 patients St least 6 months | Pts with RA | ADA ETA, INF | Relative risk of infections compared with control group: ADA (RR, 1.1; 95% CI, 0.9 to 1,2); ETA (RR, 1.0; 95% CI, 0.9 to 1.0); INF (RR, 1.2; 95% CI, 1.1 to 1.3) | Good |
Askling et al., 2005281 | Retrospective cohort study 62,321 467,770 person-years | Pts with RA in daily clinical care in Sweden | ETA, INF | Fourfold increase of risk for TB for ETA and INF compared with conventional DMARDs | Good |
Bergstrom et al., 2004325 | Retrospective cohort study 985 3 years | Pts with inflammatory arthritis in daily clinical care, U.S. | ETA, INF | Pts treated with INF or ETA are more likely to develop symptomatic coccidiomycosis than pts on synthetic DMARDs | Fair |
*Bernatsky et al., 2007218 | Nested case-control 23,733 Up to 23 years | RA pts registered in claims databases in Quebec | Anti-TNFs (not specified), oral DMARDs, corticosteroids | No statistical association between anti-TNF use and risk for all infections requiring hospitalization (RR, 1.9; 95% CI, 0.7 to 5.3) | Fair |
*Bernatsky et al., 2010270 | Meta-analysis 7 studies of administrative claims or electronic health records | Studies estimating overall risk of serious infection in RA pts initiating biologic DMARDs | Biologic DMARD use vs. no use | Biologic DMARD use increased risk of serious infection (pooled adjusted RR, 1.37, 95% CI, 1.18 to 1.60) | Fair |
Bongartz et al., 2006271 | Meta-analysis 5,014 3 to 12 months | Pts with active RA despite MTX treatment | ADA, INF | Statistically significantly higher risk of serious infections for ADA and INF compared with placebo (3.6% vs. 1.7%; OR, 2.0; 95% CI, 1.3 to 3.1) | Fair |
*Brassard et al., 2006219 | Retrospective cohort 112,300 Up to 5 years | RA pts with ≥1 claim for anti-RA drugs in U.S. database | Several oral DMARDs, ANK, ETA, INF, corticosteroids | Adjusted rate ratio of developing TB: Biologic DMARDs:1.5 (95% CI, 1.1 to 1.9); INF:1.6 (95% CI, 1.0 to 2.6) ETA:1.2 (95% CI, 0.9 to 1.8) ANK:1.3 (95% CI, 0.8 to 2.1) | Fair |
*Cohen et al., 2006158 REFLEX Trial | RCT 520 24 weeks | Pts with RA with inadequate response to previous or current treatment with anti-TNF agents | RTX+MTX, MTX | The rate of serious infection was 5.2 and 3.7 per 100 pt-yrs in the RTX+MTX and MTX groups, respectively | Fair |
Combe et al., 2006145 | RCT 260 Up to 2 years | Active RA despite SSZ treatment | ETA, SSZ, ETA+SSZ | Significantly more infections in ETA and ETA+SSZ than in SSZ group (47% vs. 31% vs. 13%; P<0.05) at 6 months; similar pattern at 2 years (P<0.001) | Fair |
*Curtis et al., 2007277, 278 | Retrospective cohort study 5,326 Up to 67 months | Pts with RA enrolled in a large U.S. health care organization | MTX, TNF-alpha antagonists | Risk of hospitalization with a bacterial infection for those receiving TNF-alpha antagonists was 1.94 (95% CI, 1.32 to 2.83) compared with pts that received MTX only; risk highest in first 6 months – ETA: 1.61, 95% CI, (0.75 to 3.47) INF 2.40, 95% CI, (1.23 to 4.68) | Good |
*den Broeder et al., 2007326 | Retrospective cohort 1,219 1 year followup | RA pts that were TNF-alpha antagonist naïve | TNF-alpha antagonists | Perioperative continuation of anti-TNFs not associated with increased risk of surgical site infection. Wound dehiscence in patients that continued anti-TNFs compared with patients that temporarily discontinued anti-TNF treatment (OR, 11.2; 95% CI, 1.4 to 90). | Fair |
Dixon et al., 2006268 | Prospective cohort study 8,973 11,220 pt-years | Pts with active RA despite MTX treatment | ADA, ETA, INF | No differences among anti-TNF drugs for risk of serious infections. Similar risk for serious infections between anti-TNF drugs and oral DMARDs | Fair |
*Dixon et al., 2010279 BSRBR | Prospective cohort study 13,739 7,345 person-years (DMARD cohort) 34,025 person-years (anti-TNF cohort) | Pts with RA from the British Society for Rheumatology Biologics Register (BSRBR) | ADA, ETA, INF vs. oral DMARDs | Adjusted incidence rate ratio of TB cases compared with ETA: INF 3.1 (95% CI, 1.0 to 9.5) and ADA 4.2 (1.4–12.4) | Fair |
*Galloway et al., 2011269 BSRBR | Prospective cohort study 15,396 3.9 years (anti-TNF cohort) 2.6 years (DMARD cohort) | Pts with RA from the British Society for Rheumatology Biologics Register (BSRBR) | ADA, ETA, INF vs. oral DMARDs | Adjusted hazard ratio for serious infection in anti-TNF cohort: 1.2 (95% CI, 1.1 to 1.5). No significant difference in serious infection incidence between ADA, ETA, and INF | Fair |
Gomez-Reino et al., 2003282 | Retrospective cohort study 1,540 1.1 years | Pts with RA in daily clinical care in Spain | ETA, INF | Higher risk of TB for ETA and INF than oral DMARDs | Fair |
*Greenberg et al., 2010226 CORRONA | Prospective cohort 7,971 15,047 person-years | Pts with RA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registry | MTX, oral DMARDs, anti-TNF agents, PRED | Adjusted incidence rate ratio (IRR) for infections withanti-TNF agents compared with oral DMARDs (IRR, 1.52; 95% CI, 1.30 to 1.78, P<0.001); opportunistic infections (IRR, 1.67; 95% CI, 0.95 to 2.94 P=0.077) | Fair |
*Grijalva et al., 2010240 | Retrospective cohort 28,906 Up to 180 days | Tennesee Medicaid-enrolled RA pts initiating DMARD use | MTX, LEF, SSZ, HCQ, biologic DMARDs (ADA, ETA, INF), steroids | Compared with MTX biologic DMARDs increased risk of hospitalization due to pneumonia (HR, 1.31; 95% CI, 0.78 to 2.19) or serious infections (HR, 1.65; 95% CI, 0.85 to 3.03) | Good |
*Kawakami et al., 2010327 | Case-control 128 | Pts with RA that underwent joint surgery | ETN, INF, DMARDs | Higher risk of surgical site infections in anti-TNF group vs. oral DMARD group (OR, 21.80; 95% CI, 1.231 to 386.1, P=0.036) | Fair |
Keane et al., 2001283 | Database analysis 70 cases of TB NA, AERS data | Pts treated with INF | INF | TB may develop soon after initiation of INF treatment | Fair |
*Keystone et al., 2008168 RAPID-1 Trial | RCT 982 52 weeks | Pts with RA that received MTX for ≥6 months prior to baseline | MTX, CTZ+MTX | Occurrence of serious infections was higher in pts treated with CTZ than those on MTX alone | Fair |
Lee et al., 2002286 | Database analysis 10 cases of histoplasmosis NA, AERS data | Pts treated with ETA and INF | ETA, INF | Histoplasmosis infections may be a serious complication of treatment with anti-TNF agents; pts on INF had a higher rate of infections than pts on ETA | Fair |
*Leombruno et al., 2009255 | Meta-analysis 18 trials 8,808 patients Average 0.8 years | RA pts on anti-TNF therapy | ADA, ETA, INF | Anti-TNF treatment did not increase seirious infection (OR, 1.21; 95% CI, 0.89 to 1.63) | Fair |
Listing et al., 2005274 | Prospective cohort study 1,529 Up to 12 months | Pts with RA in daily clinical care in Germany | AKA, ETA, INF | Higher risk of infections for AKA, ETA, INF compared with DMARDs | Fair |
*Migliore et al., 2009328 | Retrospective cohort 138 with RA Followup not specified | Pts 65 years old or more with RA, PsA, or Ankylosing Spondylitis | ETA, ADA, INF | Infection rate: ETN 18.51%, ADA 20.51%, INF 15.55% | Fair |
Mohan et al., 2004284 | Database analysis 25 cases of TB NA, AERS data | Pts treated with ETA | ETA | Median interval between first dose and diagnosis of TB was 11.5 months | Fair |
*Salliot et al., 2009272 | Meta-analysis 12 RCTs | RA patients receiving ABA, ANK, or RTX | ABA, ANK, RTX | No increase in risk of serious infection for ABA or RTX; high doses of ANK increased risk of serious infection | Fair |
Salliot et al., 2006275 | Case series 709 NR | Pts with different rheumatic diseases; primary care-based cohort | ADA, ETA, INF | Rates of serious infections in daily practice were higher than ones reported in efficacy trials | Fair |
*Schiff et al., 200866 | RCT 431 1 year | Pts with RA despite treatment with MTX, anti-TNF therapy naive | ABA +MTX, INF +MTX, MTX | Serious infections were reported more with INF (8.5%) than ABA (1.9%) | Fair |
*Schneeweiss et al., 2007222 | Retrospective cohort 15,597 Up to 8 years | Medicare beneficiaries ages 65 and older with RA | TNF-alpha antagonists (ADA, ETA, INF) | Compared with MTX use, TNF-alpha did not increase risk of serious bacterial infections (RR, 1.04; 95% CI, 0.63 to 1.72) | Fair |
Slifman et al., 2003287 | Database analysis 15 cases of listeria infection NA, AERS data | Pts treated with ETA and INF | ETA, INF | Pts on INF had a higher rate of infections than pts on ETA | Fair |
*Smitten et al., 2008223 | Retrospective cohort 24,530 26.6 months | Pts with RA from U.S. PharMetrics data | ADA, ANK, ETA, INF | Biologic DMARDs slightly increased risk of hospitalized infection (RR, 1.21; 95% CI, 1.02 to 1.43). | Good |
*Smitten et al., 2007224 | Retrospective cohort 12,272 (PM) 38,621 (GPRD) 12.3 to 38.8 months | Pts with RA from the PharMetrics (PM) database and UK General Practice Research database (GPRD) | ANK, ETA, INF | Risk of herpes zoster infection with biologic DMARD: (PM: OR,1.54; 95% CI, 1.04 to 2.29) | Fair |
*Smolen et al., 2009167 RAPID 2 study | RCT 619 24 weeks | Pts with RA with prior MTX use for ≥6 months | MTX, CTZ+MTX | Serious infection occurred more frequently in CTZ pts vs. pts treated with MTX monotherapy | Fair |
St. Clair et al., 200482 ASPIRE study | RCT 1,049 54 weeks | Early, aggressive RA; MTX-naive | MTX, INF+ MTX | Significantly more patients in the INF+MTX than in the MTX group had more than one serious infection (5.3 vs. 2.1%; P<0.05) | Fair |
*Strangfeld et al., 2009225 | Prospective cohort 5,040 up to 36 months | RA pts initiating biologic therapy or switching to another DMARD | ADA, ETA, INF | Adjusted HR for Herpes Zoster. All anti-TNFs: (HR, 1.63; 95% CI, 0.97 to 2.74) ADA or INF (HR, 1.82; 95% CI, 1.05 to 3.15) ETA (HR, 1.36; 95% CI, 0.73 to 2.55) | Good |
Wallis et al., 2004280 | Database analysis 649 cases of granulomatous infections NA, AERS data | Pts treated with ETA and INF | ETA, INF | Pts on INF had a higher rate of granulomatous infections than pts on ETA | Fair |
*Wiens et al., 2010183 | Meta-analysis 21 studies 6,503 patients 8 weeks to 3 years | Pts with RA with or without concomitant MTX | ADA, ETA, INF | Effect estimate of serious infections compared with placebo: ADA (2.22, 95% CI, 0.83 to 5.99, P=0.11), ETA (0.89, 95%CI, 0.54 to 1.48, P=0.66), INF (0.96, 95%CI, 0.39 to 2.38, P=0.93) | Fair |
Westhovens et al., 2006155 START study | RCT 1,084 22 weeks | Pts with active RA despite MTX treatment | INF+MTX, MTX | Risk of serious infections was similar between placebo and 3 mg/kg infliximab. 10 mg/kg infliximab led to increased risk of serious infections | Good |
Wolfe et al., 2004285 | Prospective cohort study with historic control 17,242 3 years | Pts with RA in daily clinical care in U.S. | INF, oral DMARDs | TB was more common in pts treated with INF than with oral DMARDs | Fair |
Wolfe et al., 2006237 | Prospective cohort study 16,788 3.5 years | Pts with RA | ADA, ETA, INF | No increased risk for hospitalization for pneumonia for ADA, ETA, and INF compared with a historic control | Fair |