Table 52Infections in patients with rheumatoid arthritis and treated with biologic DMARDs

StudyStudy Design
Study PopulationDrugResultsQuality Rating
*Alonoso-Ruiz et al. 2008126Meta-analysis
13 trials
7,087 patients
St least 6 months
Pts with RAADA ETA, INFRelative 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., 2005281Retrospective cohort study
467,770 person-years
Pts with RA in daily clinical care in SwedenETA, INFFourfold increase of risk for TB for ETA and INF compared with conventional DMARDsGood
Bergstrom et al., 2004325Retrospective cohort study
3 years
Pts with inflammatory arthritis in daily clinical care, U.S.ETA, INFPts treated with INF or ETA are more likely to develop symptomatic coccidiomycosis than pts on synthetic DMARDsFair
*Bernatsky et al., 2007218Nested case-control
Up to 23 years
RA pts registered in claims databases in QuebecAnti-TNFs (not specified), oral DMARDs, corticosteroidsNo 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., 2010270Meta-analysis
7 studies of administrative claims or electronic health records
Studies estimating overall risk of serious infection in RA pts initiating biologic DMARDsBiologic DMARD use vs. no useBiologic DMARD use increased risk of serious infection (pooled adjusted RR, 1.37, 95% CI, 1.18 to 1.60)Fair
Bongartz et al., 2006271Meta-analysis
3 to 12 months
Pts with active RA despite MTX treatmentADA, INFStatistically 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., 2006219Retrospective cohort
Up to 5 years
RA pts with ≥1 claim for anti-RA drugs in U.S. databaseSeveral oral DMARDs, ANK, ETA, INF, corticosteroidsAdjusted 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)
*Cohen et al., 2006158
24 weeks
Pts with RA with inadequate response to previous or current treatment with anti-TNF agentsRTX+MTX, MTXThe rate of serious infection was 5.2 and 3.7 per 100 pt-yrs in the RTX+MTX and MTX groups, respectivelyFair
Combe et al., 2006145RCT
Up to 2 years
Active RA despite SSZ treatmentETA, SSZ, ETA+SSZSignificantly 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, 278Retrospective cohort study
Up to 67 months
Pts with RA enrolled in a large U.S. health care organizationMTX, TNF-alpha antagonistsRisk 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., 2007326Retrospective cohort
1 year followup
RA pts that were TNF-alpha antagonist naïveTNF-alpha antagonistsPerioperative 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., 2006268Prospective cohort study
11,220 pt-years
Pts with active RA despite MTX treatmentADA, ETA, INFNo differences among anti-TNF drugs for risk of serious infections. Similar risk for serious infections between anti-TNF drugs and oral DMARDsFair
*Dixon et al., 2010279
Prospective cohort study
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 DMARDsAdjusted 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
Prospective cohort study
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 DMARDsAdjusted 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 INFFair
Gomez-Reino et al., 2003282Retrospective cohort study
1.1 years
Pts with RA in daily clinical care in SpainETA, INFHigher risk of TB for ETA and INF than oral DMARDsFair
*Greenberg et al., 2010226
Prospective cohort
15,047 person-years
Pts with RA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registryMTX, oral DMARDs, anti-TNF agents, PREDAdjusted 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., 2010240Retrospective cohort
Up to 180 days
Tennesee Medicaid-enrolled RA pts initiating DMARD useMTX, LEF, SSZ, HCQ, biologic DMARDs (ADA, ETA, INF), steroidsCompared 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., 2010327Case-control
Pts with RA that underwent joint surgeryETN, INF, DMARDsHigher 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., 2001283Database analysis
70 cases of TB
NA, AERS data
Pts treated with INFINFTB may develop soon after initiation of INF treatmentFair
*Keystone et al., 2008168
RAPID-1 Trial
52 weeks
Pts with RA that received MTX for ≥6 months prior to baselineMTX, CTZ+MTXOccurrence of serious infections was higher in pts treated with CTZ than those on MTX aloneFair
Lee et al., 2002286Database analysis
10 cases of histoplasmosis
NA, AERS data
Pts treated with ETA and INFETA, INFHistoplasmosis infections may be a serious complication of treatment with anti-TNF agents; pts on INF had a higher rate of infections than pts on ETAFair
*Leombruno et al., 2009255Meta-analysis
18 trials 8,808 patients
Average 0.8 years
RA pts on anti-TNF therapyADA, ETA, INFAnti-TNF treatment did not increase seirious infection (OR, 1.21; 95% CI, 0.89 to 1.63)Fair
Listing et al., 2005274Prospective cohort study
Up to 12 months
Pts with RA in daily clinical care in GermanyAKA, ETA, INFHigher risk of infections for AKA, ETA, INF compared with DMARDsFair
*Migliore et al., 2009328Retrospective cohort
138 with RA
Followup not specified
Pts 65 years old or more with RA, PsA, or Ankylosing SpondylitisETA, ADA, INFInfection rate: ETN 18.51%, ADA 20.51%, INF 15.55%Fair
Mohan et al., 2004284Database analysis
25 cases of TB
NA, AERS data
Pts treated with ETAETAMedian interval between first dose and diagnosis of TB was 11.5 monthsFair
*Salliot et al., 2009272Meta-analysis
12 RCTs
RA patients receiving ABA, ANK, or RTXABA, ANK, RTXNo increase in risk of serious infection for ABA or RTX; high doses of ANK increased risk of serious infectionFair
Salliot et al., 2006275Case series
Pts with different rheumatic diseases; primary care-based cohortADA, ETA, INFRates of serious infections in daily practice were higher than ones reported in efficacy trialsFair
*Schiff et al., 200866RCT
1 year
Pts with RA despite treatment with MTX, anti-TNF therapy naiveABA +MTX, INF +MTX, MTXSerious infections were reported more with INF (8.5%) than ABA (1.9%)Fair
*Schneeweiss et al., 2007222Retrospective cohort
Up to 8 years
Medicare beneficiaries ages 65 and older with RATNF-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., 2003287Database analysis
15 cases of listeria infection
NA, AERS data
Pts treated with ETA and INFETA, INFPts on INF had a higher rate of infections than pts on ETAFair
*Smitten et al., 2008223Retrospective cohort
26.6 months
Pts with RA from U.S. PharMetrics dataADA, ANK, ETA, INFBiologic DMARDs slightly increased risk of hospitalized infection (RR, 1.21; 95% CI, 1.02 to 1.43).Good
*Smitten et al., 2007224Retrospective 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, INFRisk of herpes zoster infection with biologic DMARD:
(PM: OR,1.54; 95% CI, 1.04 to 2.29)
*Smolen et al., 2009167
RAPID 2 study
24 weeks
Pts with RA with prior MTX use for ≥6 monthsMTX, CTZ+MTXSerious infection occurred more frequently in CTZ pts vs. pts treated with MTX monotherapyFair
St. Clair et al., 200482
ASPIRE study
54 weeks
Early, aggressive RA; MTX-naiveMTX, INF+ MTXSignificantly 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., 2009225Prospective cohort
up to 36 months
RA pts initiating biologic therapy or switching to another DMARDADA, ETA, INFAdjusted 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)
Wallis et al., 2004280Database analysis
649 cases of granulomatous infections
NA, AERS data
Pts treated with ETA and INFETA, INFPts on INF had a higher rate of granulomatous infections than pts on ETAFair
*Wiens et al., 2010183Meta-analysis
21 studies
6,503 patients
8 weeks to 3 years
Pts with RA with or without concomitant MTXADA, ETA, INFEffect 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
22 weeks
Pts with active RA despite MTX treatmentINF+MTX, MTXRisk of serious infections was similar between placebo and 3 mg/kg infliximab. 10 mg/kg infliximab led to increased risk of serious infectionsGood
Wolfe et al., 2004285Prospective cohort study with historic control
3 years
Pts with RA in daily clinical care in U.S.INF, oral DMARDsTB was more common in pts treated with INF than with oral DMARDsFair
Wolfe et al., 2006237Prospective cohort study
3.5 years
Pts with RAADA, ETA, INFNo increased risk for hospitalization for pneumonia for ADA, ETA, and INF compared with a historic controlFair

New study added since last review.

ABA = abatacept; ADA = adalimumab; AE = adverse event; AERS = adverse event reporting system; ANK = anakinra; CI = confidence interval; CTZ = certolizumab; DMARD = disease-modifying antirheumatic drug; ETA = etanercept; HR = hazard ratio; INF = infliximab; kg = kilogram; LEF = leflunomide; mg = milligram; MTX = methotrexate; NA = not applicable; OR = odds ratio; RA = rheumatoid arthritis; RCT = randomized controlled trial; RR = rate ratio; RTX = rituximab; SSZ = sulfasalazine; TB = tuberculosis; TCZ = tocilizumab; TNF = tumor necrosis factor

From: Results

Cover of Drug Therapy for Rheumatoid Arthritis in Adults: An Update
Drug Therapy for Rheumatoid Arthritis in Adults: An Update [Internet].
Comparative Effectiveness Reviews, No. 55.
Donahue KE, Jonas DE, Hansen RA, et al.

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