Intervention Review

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Etanercept for the treatment of rheumatoid arthritis

  1. Anne Lethaby1,†,
  2. Maria Angeles Lopez-Olivo2,‡,
  3. Lara J Maxwell3,
  4. Amanda Burls4,
  5. Peter Tugwell5,6,7,*,
  6. George A Wells8

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 13 JUN 2012

DOI: 10.1002/14651858.CD004525.pub2


How to Cite

Lethaby A, Lopez-Olivo MA, Maxwell LJ, Burls A, Tugwell P, Wells GA. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD004525. DOI: 10.1002/14651858.CD004525.pub2.

Author Information

  1. 1

    University of Auckland, Department of Obstetrics and Gynaecology, Auckland, New Zealand

  2. 2

    The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, Houston, Texas, USA

  3. 3

    University of Ottawa, Centre for Global Health, Institute of Population Health, Ottawa, Ontario, Canada

  4. 4

    City University London, School of Health Sciences, London, UK

  5. 5

    Faculty of Medicine, University of Ottawa, Department of Medicine, Ottawa, Ontario, Canada

  6. 6

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

  7. 7

    University of Ottawa, Institute of Population Health & Department of Epidemiology and Community Medicine, Ottawa, Ontario, Canada

  8. 8

    University of Ottawa, Department of Epidemiology and Community Medicine, Ottawa, Ontario, Canada

  1. Joint first author

  2. Joint first author

*Peter Tugwell, Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada. tugwell.bb@uottawa.ca. kerry.obrien@uottawa.ca.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

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Characteristics of included studies [ordered by study ID]
Bathon 2000 (ERA)

MethodsMethod of randomisation not reported
Allocation concealment not reported
Blinding not reported, but treatments provided in identical containers
Multicentre parallel group study
Power calculation not reported
No of participants randomised = 632
No of participants analysed = 632
Intention-to-treat analysis
Source of funding: Immunex (pharmaceutical company)


ParticipantsInclusion:
At least 18 years; RA max 3 years; no other illnesses; no treatment with MTX; at high risk for radiographic progression
No exclusion criteria reported
Location: centres in the USA


Interventions
  1. Etanercept 10 mg SC twice weekly
  2. Etanercept 25 mg SC twice weekly
  3. MTX (initially 7.5 mg increasing to 20 mg at week 8)


(PBO controlled)
Duration: 12 months


OutcomesACR20, ACR50, ACR70
Radiographic: TSS, Erosion Score, Joint Space Narrowing Score; withdrawals; adverse events


NotesEarly RA; MTX naive; most erosions and RF+


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding (performance bias and detection bias)
Clinical outcomes
Low riskNot explicitly described but PBO controlled; assessors of radiographic scores unaware of assignment

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskAnalyses were intention to treat: inclusion of all participants who received at least 1 dose of the study drug

Selective reporting (reporting bias)Low riskNo evidence of a prior published protocol but wide range of outcomes assessed

Other biasUnclear riskDrug company funding with no guarantees described to ensure that the results were not influenced

Combe 2006

MethodsMethod of randomisation was computer generated

Allocation concealment not described

Double blinding

Multicentre, parallel group study

Power calculation not reported

No of participants randomised = 260

No of participants analysed = 254

Authors stated that they used a modified intention to treat analysis: "all randomly assigned patients who received any test article and provided efficacy data at baseline"

Measures to deal with missing data included LOCF

Source of funding: Wyeth (some authors either paid consultants or employees of Wyeth)


ParticipantsInclusion:

At least 18 years; diagnosis of adult onset RA; disease duration ≤ 20 years; swelling in ≥ 6 joints, ≥ 6 tender joints, morning stiffness ≥ 45 minutes, ESR ≥ 28 mm/h or CRP ≥ 20 mg/L

Previous stable doses of SSZ at least 4 weeks prior to the study, without signs of toxicity

Exclusion:

Previous treatment with etanercept or other TNF antagonist; treatment with DMARDs other than SSZ in 3 months before baseline; treatment with other biological agents or immunosuppressants within 6 months prior to the study entrance; or steroid injection in 4 weeks before study start; relevant co-morbidities; pregnancy or lactation

Stable doses of NSAIDs, analgesics or prednisone were allowed


Interventions
  1. Etanercept 25 mg SC twice weekly + oral PBO once daily
  2. SSZ tablets (2, 2.5 or 3 g daily) + SC PBO twice weekly
  3. Etanercept 25 mg SC twice weekly + SSZ tablets (2, 2.5 or 3 g daily)


Duration: 2 years


OutcomesACR20, ACR50, ACR70

DAS44-ESR

SJC, TJC, morning stiffness, physician and participant global assessment, pain-VAS, general health-VAS, ESR, CRP

Functional status (HAQ)

EuroQoL

Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskMethod of randomisation was computer generated

Allocation concealment (selection bias)Unclear riskAllocation concealment not described

Blinding (performance bias and detection bias)
Clinical outcomes
Low riskStated double blind and treatments were identical

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskAnalyses were based on a modified intention to treat: inclusion of all participants who received at least 1 dose of the study drug

Selective reporting (reporting bias)Unclear riskNo evidence of a prior published protocol but wide range of outcomes assessed

Other biasUnclear riskSource of funding: Wyeth (some authors either paid consultants or employees of Wyeth)

Emery 2008 (COMET)

MethodsMethod of randomisation was computer generated

Allocation concealment not described

Double blinding reported but masking removed for primary analysis of data at 1 year for publication. Data also unblinded for medical management of participants if needed

Multicentre, parallel group study (22 countries, 70 centres)

Power calculation reported (90% power to show a significant difference in remission; 94% power to show significant difference in radiographic progression)

No of participants randomised = 542

No of participants analysed = 542 (for safety outcomes). n = 528 for clinical efficacy. n = 476 for radiographic progression at end of first year

Authors stated that they used a modified intention-to-treat analysis: remission - all participants who received at least 1 dose of the drug and reported both baseline and at least 1 on-treatment DAS28 result; radiographic progression - all participants with valid baseline and follow-up radiographs. Measures to deal with missing data included LOCF and imputation by linear extrapolation

Source of funding: Wyeth (many authors either paid consultants or employees of Wyeth)


ParticipantsInclusion:

At least 18 years; diagnosis of adult onset RA; disease duration between 3 months and 2 years; DAS28 ≥ 3.2; either Westergren ESR ≥ 28 mm/h or CRP ≥ 20 mg/L

Exclusion:

Previous treatment with MTX, etanercept or other TNF antagonist; treatment with other DMARDs or steroid injection in 4 weeks before baseline; important concurrent medical diseases; other relevant co-morbidities

Location: 22 countries, 70 centres in Europe, Latin America, Asia and Australia


Interventions
  1. Etanercept 25 mg SC twice weekly + MTX oral 7.5 mg/week (titration up to a maximum of 20 mg/week over 8 weeks if necessary)
  2. MTX oral 7.5 mg/week (with titration if necessary) + PBO SC injection


Duration: 2 years


OutcomesRemission (DAS28 < 2.6)

Change in modified TSS (from baseline to end of year 1)

Functional status (HAQ Disability Index)

Employment status

Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated

Allocation concealment (selection bias)Low riskCentral control by computer

Blinding (performance bias and detection bias)
Clinical outcomes
Unclear riskStated as double blind, but masking removed for primary analysis of data for the publication

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskReasons documented for dropouts. Methods employed to deal with missing data: LOCF or imputation by linear extrapolation

Selective reporting (reporting bias)Low riskNo protocol for study identified but wide range of outcomes assessed

Other biasUnclear riskGood baseline comparability. Drug company funding with no guarantees to ensure results not influenced

Hu 2009

MethodsMethod of randomisation not described

Method of allocation concealment not described

Blinding not described but treatments appeared identical

Multicentre, parallel group study (6 centres)

Power calculation not reported

No of participants randomised = 238

No of participants analysed = 238

Drop-outs: 17 in treatment group (reasons given) and 12 in control group (reasons given)

Intention-to-treat analysis (LOCF for drop-outs)

Source of funding: not reported


ParticipantsInclusion criteria:

18-65 years of age; active RA (as defined by ACR 1987 criteria: swelling in ≥ 6 joints, ≥ 6 tender joints, morning stiffness ≥ 45 minutes, ESR ≥ 28 mm/h, CRP ≥ 20 μg/mL)

Exclusion criteria:

Any serious illness (heart, liver, renal, blood or other vital organs); pregnant or breastfeeding; previous treatment with Yisaipu or other biological agents; no efficacy to treatment with MTX; joint injection of corticosteroids within past 4 weeks; any acute or chronic infection or past history of active TB; any tumour or family history of tumour

Stable doses of NSAIDs or prednisone were allowed but all DMARDS were discontinued at least 4 weeks prior to the study

Location: 6 hospitals in China


Interventions
  1. Yisaipu 25 mg SC twice weekly + oral PBO
  2. MTX 3 x 2.5 mg (increasing to 5 mg) per week + PBO injection


Duration: 6 months


OutcomesACR20, ACR50, ACR70

Withdrawals

Adverse events


NotesYisaipu is a rhTNFR:Fc available in China. The authors claim it has the same structure as etanercept


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed only as "randomly assigned"

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
Clinical outcomes
Low riskStated double blind and treatments were identical

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskAnalysis by intention to treat (LOCF for drop-outs)

Selective reporting (reporting bias)Low riskNo protocol sighted but all important outcomes measured

Other biasUnclear riskFunding not reported

Kameda 2010

MethodsRandomisation was computer generated and stratified by baseline age, disease duration, disease activity and institution

Method of allocation concealment not described

No blinding

Multicentre, parallel group study (34 centres in Japan)

Power calculation not reported

No of participants randomised = 151

No of participants analysed = 147 (safety), 142 (efficacy)

Dropouts: 4 in treatment group (reasons given) and 12 in control group (reasons given)

Modified intention-to-treat analysis: all participants who took the study drugs and had a valid baseline and at least 1 on-therapy value for each end point (LOCF for drop-outs)

Source of funding: not reported, however, many authors were paid consultants of Wyeth


ParticipantsInclusion criteria:

≥ 18 years of age; RA (as defined by ACR 1987 criteria); active disease; swelling in ≥ 6 joints, ≥ 6 tender joints, ESR ≥ 28 mm/h, adequate safety profiles; RA functional class I-III. Treatment with MTX at least 6 mg/week in 3 months before baseline (stable dose)

Exclusion criteria:

Treatment with > 10 mg/day prednisolone; treatment with DMARDs other than MTX; previously treated with any biological agent


Interventions
  1. Etanercept SC twice weekly + oral MTX (6-8 mg/week)
  2. Etanercept SC twice weekly


Duration: 2 year


OutcomesEULAR criteria

DAS28 and remission rate

ACR20, ACR50, ACR70)

van der Heijde-modified Sharp Score

Withdrawals

Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was performed on the University Hospital Medical Information Network's web site"

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described

Blinding (performance bias and detection bias)
Clinical outcomes
High riskNot blinded

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskModified intention-to-treat analysis: all participants who took the study drugs and had a valid baseline and at least 1 on-therapy value for each end point (LOCF for drop-outs)

Selective reporting (reporting bias)Low riskNo protocol sighted but all important outcomes measured

Other biasUnclear riskSource of funding: not reported, however, many authors were paid consultants of Wyeth

Klareskog 2004 (TEMPO)

MethodsRandomisation method not described
Allocation concealment
Triple blinding
Multicentre (N = 19), parallel group study
Power calculation for sample size
No of participants randomised = 686
No of participants analysed = 682 (4 did not receive treatment)
Modified intention-to-treat analysis (those who received the study drug). Other missing data estimated by LOCF or linear extrapolation
Source of funding: Wyeth Research (pharmaceutical company)


ParticipantsInclusion:
≥ 18 years of age; disease duration 6 months to 20 years; active RA; less than satisfactory response to at least 1 DMARD (except MTX); treatment with MTX in last 6 months; toxic effects from previous MTX treatment
Exclusion:
Previous treatment with etanercept or other TNF antagonist; previous treatment with immunosuppressive drugs in past 6 months; use or any investigative drug or biological agent in past 3 months; use of any other DMARD or steroid injection in past 4 weeks; presence of co-morbidity
Location: 17 centres in Europe, Australia and Israel


Interventions
  1. Etanercept 25 mg SC twice weekly + MTX
  2. Etanercept 25 mg SC twice weekly
  3. MTX (7.5 mg escalating to 20 mg) oral/week


PBO controlled
Duration: 3 years


OutcomesACR20, ACR50, ACR70
Radiographic: TSS; Erosion Score; Joint Space Narrowing Score
HAQ; DAS
Satisfaction
Adverse events
Withdrawals


NotesTrial has continued open label


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not described

Allocation concealment (selection bias)Low riskCentralised telephone randomisation

Blinding (performance bias and detection bias)
Clinical outcomes
Low riskTriple blinding (participants, investigators and assessors)

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskClear descriptions of methods for dealing with missing data (LOCF, linear extrapolation and assumption that participants withdrawing from the study had no response to treatment)

Selective reporting (reporting bias)Low riskNo access to prior protocol to check for selective reporting but wide range of outcomes measured

Other biasUnclear riskDrug company funding with no guarantees described to prevent influence on results

Marcora 2006

MethodsComputer-generated list of random numbers
Allocation concealment not reported
Only investigators measuring outcomes were blinded
Single centre, parallel group study
Power calculation not reported
No of participants randomised = 26
No of participants analysed = 24 (2 in MTX group dropped out: 1 lost to follow-up and 1 started physical training)
Not intention-to-treat analysis
Source of funding: Wyeth provided the etanercept treatment


ParticipantsInclusion:
≥ 18 years of age; diagnosis of RA; < 6 months history of RA; active disease
Exclusion:
Previous treatment with DMARD or corticosteroid treatment; recent history of important infection; concurrent disease; cognitive impairment; any other cachectic disease; taking drugs or supplements affecting muscle mass; participating in physical training
Location: Clinic in Welsh Hospital


Interventions
  1. Etanercept 25 mg SC twice weekly
  2. MTX 7.5 mg/week escalating to 20 mg/week if necessary


Duration: 6 months


OutcomesPhysical function (handgrip strength; arm-curl test; walking velocity; sit to stand test)
HAQ
Adverse events
DAS28


NotesPrimary objective to assess effects of treatment on cachexia


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated list of random numbers

Allocation concealment (selection bias)Unclear riskMethod not described

Blinding (performance bias and detection bias)
Clinical outcomes
High risk"Patients and clinician. . . . . aware of treatment allocation" but assessors were blinded

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskMinimal drop-outs

Selective reporting (reporting bias)Unclear riskNo prior published protocol identified

Other biasUnclear riskDrug company funding with no guarantees described to prevent influence on the results

Moreland 1999

MethodsBlocked randomisation with stratification by study site
Allocation concealed
Double blinding
Multicentre (n = 13), parallel group study
Power calculation not reported
No of participants randomised = 246
No of participants analysed = 234 (12 not eligible after randomisation)
Intention-to-treat analysis by counting withdrawals as non-responders and using last available observation for drop-outs
Source of funding: Immunex (pharmaceutical company)


ParticipantsInclusion:
≥ 18 years of age; active RA; inadequate response to a DMARD
90% of participants had used MTX previously
Location: 13 centres in North America


Interventions
  1. Etanercept 10 mg SC twice weekly
  2. Etanercept 25 mg SC twice weekly
  3. PBO SC twice weekly


Concomitant treatment with oral steroids, analgesics and NSAIDs allowed
Washout period for previous DMARDs
Duration: 6 months


OutcomesACR20, ACR50, ACR70
Radiographic: TJC; SJC
HAQ
Adverse events
Withdrawals


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlocked randomisation with stratification according to study site

Allocation concealment (selection bias)Low riskRandomisation code housed with the sponsor

Blinding (performance bias and detection bias)
Clinical outcomes
Low riskDouble blind, participants and key personnel

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskReasons for withdrawal clearly specified with methods stated to deal with missing data

Selective reporting (reporting bias)Low riskNo prior published protocol identified but wide range of outcomes measured

Other biasUnclear riskDrug company funding with no guarantees described to prevent influence on results

Weinblatt 1999

MethodsMethod of randomisation not reported
Allocation concealment not reported
Double blinding
Multicentre, parallel group study
Power calculation for sample size
No of participants randomised = 89
No of participants analysed = 89 (2 withdrew in etanercept group because of adverse events; 4 withdrew in MTX group because of lack of efficacy, 1 because of myocardial infarction, 1 lost to follow-up)
Intention-to-treat analysis (participants who withdrew were considered not to have a response and for individual measures, last observation was used in the analysis)
Source of funding: Immunex (pharmaceutical company)


ParticipantsInclusion:
≥ 18 years of age; diagnosis of RA; active disease
Exclusion not reported
Location: centres in North America


Interventions
  1. Etanercept 25 mg SC twice weekly + MTX
  2. MTX + etanercept PBO


All participants had been taking MTX prior to study for at least 6 months
All participants received folic acid and were allowed to use NSAIDs or steroids during study
Duration: 6 months


OutcomesACR20, ACR50, ACR70
Radiographic: TJC; SJC
HAQ
Adverse events
Withdrawals


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo method of randomisation described

Allocation concealment (selection bias)Unclear riskNo description of method used to conceal allocation

Blinding (performance bias and detection bias)
Clinical outcomes
Low riskStated as "double blinded"

Incomplete outcome data (attrition bias)
Clinical outcomes
Low riskClear descriptions of reasons for withdrawal of dropouts

Selective reporting (reporting bias)Low riskNo prior published protocol identified but wide range of outcomes measured

Other biasUnclear riskDrug company funding with no guarantees described to prevent influence on results

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

ACP 2001Summary of Bathon 2000 with no new information provided

Angel 2010Outcome is arterial stiffness. Participants are a mixed group of RA and other diseases. Not randomised

Anis 2009Data is from the COMET trial. Outcome not listed as an eligible outcome

Benucci 2011Three arms were included: adalimumab + leflunomide or MTX

Etanercept + leflunomide or MTX

Infliximab + leflunomide or MTX

Blank 2009Intervention is etanercept + rituximab. Not an RCT

Bliddal 2006Trial of intra-articular injection of etanercept

Boesen 2008Trial of intra-articular injection of etanercept

Chen 2006Study duration only 12 weeks. Does not meet the inclusion criteria of this review

Cuomo 2006Four arms were included: MTX + sulphasalazine

MTX + adalimumab

MTX + etanercept

MTX + infliximab

De Filippis 2006CCT compares etanercept vs. infliximab

De Stefano 2010CCT compares etanercept + MTX versus etanercept + leflunomide

Garnero 2002Patient subset from published studies looking at collagen markers and joint destruction. The relationship of collagen markers to joint destruction was not an outcome of interest

Genovese 2002Study was an extension of the Bathon study at 24 months. All participants who completed the Bathon study were eligible and were given etanercept 25 mg and were followed forward for 5 years

Genovese 2004Compares etanercept monotherapy vs. etanercept (half dose) + anakinra versus etanercept + anakinra

Gerlag 201012-week RCT with an open-label etanercept arm. Does not meet the inclusion criteria of this review

Holman 2008Participants are a mixed group of RA + psoriatic arthritis. Intervention is mixed: etanercept or adalimumab

Iwamoto 2009Observational study

Johnsen 2006Comparison of doses of etanercept. 1 arm had a dose of 50 mg of etanercept twice weekly - this dose does not meet the inclusion criteria for this review

Kavanaugh 2008Retrospective analysis of TEMPO trial. Analysis of changes in responders and non-responders

Keystone 2004Study was less than 6 months in duration and included a dose of etanercept (50 mg) which does not meet the inclusion criteria of this review

Keystone 2009Results of TEMPO and other earlier trials

Koumakis 2009intervention is a combination of therapies

Lan 2004Study duration only 12 weeks - this does not meet the inclusion criteria of this review

Lisbona 2008Study duration only 6 weeks. Does not meet the inclusion criteria of this review

Lukas 2009Subgroup from TEMPO. Agreement between readings of joint scores

Lukas 2010Subgroup from TEMPO. Relationship between inflammation and repair

Lukina 2001Compared TNF alpha (?drug) to interferon gamma to placebo. Drugs given intramuscularly daily for 5 days with outcome determination at days 7 and 28. Even if etanercept used, study duration too short to meet inclusion criteria

Luzi 2009Not randomised. Interventions are etanercept + MTX vs. etanercept + MTX + steroids

Machado 2009Outcome not listed as an eligible outcome

Moreland 19973-month study only so does not meet inclusion criteria

Moreland 2001Examined all participants who had received at least 1 dose of etanercept in controlled or open-label trials for efficacy and safety at a date removed from trial. Doesn't meet inclusion criteria

Paleolog 1998Looked at synovial cells from participants treated with anti-TNF alpha

Roux 2011Trial of intra-articular injection of etanercept

Saleem 2009Interventions are: combination therapy of a TNF agent (any) + MTX vs. DMARDs

Sennels 2008Study duration only 16 weeks. Does not meet the inclusion criteria of this review

van Riel 2006Study duration only 16 weeks. Does not meet the inclusion criteria of this review

Weinblatt 2007Compares etanercept + abatacept vs. etanercept + placebo

Weinblatt 2008Dose of etanercept did not meet the inclusion criteria of the review and study duration too short (12 weeks)

Weisman 2007Study duration only 16 weeks. Does not meet the inclusion criteria of this review

 
Characteristics of ongoing studies [ordered by study ID]
EMPIRE 2006

Trial name or titleEMPIRE (Etanercept and Methotrexate in Patients to Induce Remission in Early arthritis)

MethodsMulticentre, double-blind, placebo-controlled RCT

ParticipantsInclusion: aged 18-80 years; articular synovitis within 3 months of diagnosis; either rheumatoid factor antibody positive or anti-cyclic citrullinated peptide positive; not pregnant; negative TB screening test

Exclusion: previous treatment with DMARDs, etanercept or TNF drugs; HIV; significant concurrent medical diseases; cancer or history of cancer; chronic infection of upper respiratory tract; ongoing or active infection; liver function abnormality; renal disease; leukopenia; thrombocytopenia, etc. (large list of exclusions)

InterventionsEtanercept + MTX vs. placebo + MTX

OutcomesPrimary: proportion in clinical remission at 12 months (defined as absence of symptoms and signs of inflammatory arthritis: i.e. SJC = 0; TJC = 0)

Secondary: number of participants in clinical remission at 18 months (see above for definition of remission); disease activity measures (VAS; EMS, TJC, SJC, CRP, ESR); functional, work and quality of life assessments (HAQ; WIS, WDA, EuroQol; SF-36); proportion of participants achieving 26 weeks of remission; DAS28; radiographic change

Starting dateOctober 2006

Contact informationA.Keenan@Leeds.ac.uk

NotesFunded by Wyeth

France 2008

Trial name or titleAn Open-Label, Randomised Study to Evaluate the Radiographic Efficacy and Safety of Enbrel (Etanercept) Added to Methotrexate in Comparison with Usual Treatment in Subjects with Moderate Rheumatoid Arthritis Disease Activity

MethodsRandomised open-label parallel group study

ParticipantsInclusion: meet the ACR 1987 revised criteria for RA; documented evidence confirmed by a blinded 3rd party assessor of at least 1 erosion observed by x-ray; received MTX as stable dose for 28 days prior to the screening visit

Exclusion: previous treatment with etanercept, infliximab, adalimumab, other TNF-alpha inhibitors, anakinra or other biological agents; previous combination DMARD therapy; receipt of any DMARD, other than MTX, within 28 days of screening

InterventionsEtanercept + MTX vs. usual treatment (not defined)

OutcomesPrimary: radiographic disease progression (not defined) at week 52

Secondary: clinical outcomes, QoL and safety (not defined)

Starting dateJune 2008

Contact informationclintrialparticipation@wyeth.com

NotesEstimated completion June 2010. Funded by Wyeth

Japanese 2006

Trial name or titleA Randomised, Double-Blind, Multi-Centre, Comparative Study Evaluating the Efficacy and Safety of Etanercept and Methotrexate in Japanese Subjects with Active Rheumatoid Arthritis

MethodsMulticentre, double-blind (subjects, carers, investigators, outcome assessors), parallel group RCT

ParticipantsInclusion: Japanese citizen living in Japan; 20 to 75 years; diagnosed ≤5 years from time of first visit

Exclusion: Etanercept or TNF inhibitors such as infliximab, or adalimumab in the past; other rheumatic diseases or conditions that could predispose the person to infection, pregnant or lactating women

InterventionsEtanercept 10 or 25 mg SC twice weekly for 52 weeks vs. MTX (up to 8 mg/week) oral for 52 weeks

OutcomesPrimary: radiographic scores (change in modified TSS from baseline) at 52 weeks

Secondary: adverse events incidence at 52 weeks

Starting dateJune 2006

Contact informationclinicaltrialparticipation@wyeth.com

NotesEstimated completion: October 2010. Funded by Wyeth

Jobanputra 2005

Trial name or titleRemission Induction in Very Early Rheumatoid Arthritis: a Comparison of Etanercept plus Methotrexate plus Steroid with Standard Therapy

MethodsRandomised single-blind pilot study

ParticipantsInclusion: aged > 18 years; synovial swelling of at least 1 joint confirmed by clinical assessment; seropositivity for RF and anti-CCP antibody; adequate birth control measures if fertile; if female, not pregnant; informed consent

Exclusion: duration of symptoms attributable to inflammatory joint disease of > 12 weeks; previous history of inflammatory arthritis; previous use of DMARDs or anti-TNF agents; current inflammatory condition; history of other evidence of latent or active infection; virus or bacterial vaccination within 3 months before treatment; history of joint prosthesis infection of administration of antibiotics for a suspicion of this; serious and uncontrolled existing disease; bleeding disorder or use of anticoagulants; malignancy or history of malignancy

InterventionsEtanercept + MTX + parenteral steroid vs. conventional therapy (parental steroid plus MTX if necessary)

OutcomesPrimary: percentage of participants in drug-free clinical remission at week 48 (having withdrawn therapy at week 24) (defined as DAS28 < 2.6 plus no clinical evidence of joint swelling)

Secondary: percentage of participants in clinical remission (see above) at week 24 (when drugs are withdrawn if remission achieved); percentage of participants in clinical remission at weeks 24 and 48 according to ARA criteria; percentage of participants with radiological remission at week 24 (no MRI or radiological remission at week 24); clinical disease activity measures (ACR rates; DAS28; HAQ, EuroQol) at 24 and 48 weeks; rate of progression of radiological change according to van Heijde modification of the TSS from baseline to week 48 and 96; biological predictors of response to therapy

Starting dateDecember 2005

Contact informationDr P. Jobanputra, Selly Oak Hospital, Birmingham

NotesEstimated completion: December 2008. Funded by University Hospital of Birmingham NHS Trust and NHS R & D support funding

Takeuchi 2005

Trial name or titleEfficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan

MethodsRandomised, open-label, parallel group study

ParticipantsInclusion: aged ≥ 18 years; meet the ACR 1987 criteria for RA; at least 6 tender joints and 6 swollen joints; either CRP > 2 mg/dL or ESR no less than 28 mm at 1 hour; ACR functional class I-III; receiving MTX 6 mg/week for a minimum of 3 months at stable dose for at least 4 weeks at the time of enrolment

Exclusion: those requiring concurrent use of prednisone > 10 mg/day or its equivalent; the start of dose increments of prednisone equivalents within 3 months of enrolment; anti-RA therapy except for MTX or prednisone equivalents; previous treatment with etanercept or any other biological treatment

InterventionsEtanercept (25 mg SC twice a week) + MTX (oral, 6-8 mg/week) vs. etanercept (25 mg SC twice a week) alone

OutcomesPrimary: ACR50 and DAS28 "good response" at 24 weeks; TSS at 52 weeks

Secondary: ACR20 and ACR70 at 24 weeks

Starting dateJune 2005

Contact informationDr T. Takeuchi, Saitama Medical Center, Kawagoe, Saitama, Japan

NotesEstimate completion: October 2010

 
Comparison 1. Summary of findings table: etanercept (ET) 25 mg + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD (partial responders to DMARDs)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR5041198Risk Ratio (M-H, Random, 95% CI)1.96 [1.33, 2.89]

    1.1 24 weeks
189Risk Ratio (M-H, Random, 95% CI)11.69 [1.66, 82.47]

    1.2 52 weeks
1499Risk Ratio (M-H, Random, 95% CI)1.44 [1.24, 1.68]

    1.3 104 weeks
1151Risk Ratio (M-H, Random, 95% CI)5.84 [2.50, 13.64]

    1.4 156 weeks
1459Risk Ratio (M-H, Random, 95% CI)1.55 [1.30, 1.85]

 2 ACR7041198Risk Ratio (M-H, Random, 95% CI)2.22 [1.50, 3.29]

    2.1 24 weeks
189Risk Ratio (M-H, Random, 95% CI)9.82 [0.59, 163.15]

    2.2 52 weeks
1499Risk Ratio (M-H, Random, 95% CI)1.71 [1.35, 2.16]

    2.3 104 weeks
1151Risk Ratio (M-H, Random, 95% CI)6.93 [1.72, 27.94]

    2.4 156 weeks
1459Risk Ratio (M-H, Random, 95% CI)2.30 [1.73, 3.04]

 3 Remission (DAS < 2.6)2987Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.60, 2.31]

   3.1 24 weeks
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 52 weeks
1528Risk Ratio (M-H, Fixed, 95% CI)1.79 [1.43, 2.26]

   3.3 104 weeks
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.4 156 weeks
1459Risk Ratio (M-H, Fixed, 95% CI)2.13 [1.56, 2.92]

 4 HAQ (mean improvement from baseline)41227Mean Difference (IV, Fixed, 95% CI)-0.36 [-0.43, -0.28]

    4.1 24 weeks
189Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.62, 0.02]

    4.2 52 weeks
1528Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.42, -0.18]

    4.3 104 weeks
1151Mean Difference (IV, Fixed, 95% CI)-0.49 [-0.67, -0.31]

    4.4 156 weeks
1459Mean Difference (IV, Fixed, 95% CI)-0.36 [-0.48, -0.24]

 5 Total Sharp Score2903Mean Difference (IV, Random, 95% CI)-3.83 [-7.67, 0.01]

   5.1 24 weeks
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    5.2 52 weeks
1476Mean Difference (IV, Random, 95% CI)-2.13 [-3.20, -1.06]

   5.3 104 weeks
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    5.4 156 weeks
1427Mean Difference (IV, Random, 95% CI)-6.09 [-9.22, -2.96]

 6 Total withdrawals41241Risk Ratio (M-H, Random, 95% CI)0.53 [0.36, 0.77]

    6.1 24 weeks
189Risk Ratio (M-H, Random, 95% CI)0.17 [0.04, 0.79]

    6.2 52 weeks
1542Risk Ratio (M-H, Random, 95% CI)0.66 [0.48, 0.89]

    6.3 104 weeks
1151Risk Ratio (M-H, Random, 95% CI)0.35 [0.23, 0.52]

    6.4 156 weeks
1459Risk Ratio (M-H, Random, 95% CI)0.70 [0.59, 0.84]

 7 Withdrawals due to adverse events41241Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.57, 1.00]

    7.1 24 weeks
189Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.10, 10.77]

    7.2 52 weeks
1542Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.50, 1.29]

    7.3 104 weeks
1151Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.41, 3.75]

    7.4 156 weeks
1459Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.45, 0.98]

 8 Serious adverse events41241Risk Ratio (M-H, Random, 95% CI)1.25 [0.74, 2.11]

    8.1 24 weeks
189Risk Ratio (M-H, Random, 95% CI)0.51 [0.08, 3.43]

    8.2 52 weeks
1542Risk Ratio (M-H, Random, 95% CI)0.95 [0.61, 1.49]

    8.3 104 weeks
1151Risk Ratio (M-H, Random, 95% CI)5.69 [1.40, 23.19]

    8.4 156 weeks
1459Risk Ratio (M-H, Random, 95% CI)1.24 [0.87, 1.77]

 9 Serious Infections31152Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.54, 1.55]

   9.1 24 weeks
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.2 52 weeks
1542Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.20, 1.84]

    9.3 104 weeks
1151Risk Ratio (M-H, Fixed, 95% CI)5.5 [0.31, 97.54]

    9.4 156 weeks
1459Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.47, 1.66]

 
Comparison 2. Summary of findings table: etanercept (ET) 25 mg + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD (partial responders to methotrexate (MTX))

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR50189Risk Ratio (M-H, Fixed, 95% CI)11.69 [1.66, 82.47]

    1.1 24 weeks
189Risk Ratio (M-H, Fixed, 95% CI)11.69 [1.66, 82.47]

 2 ACR70189Risk Ratio (M-H, Fixed, 95% CI)9.82 [0.59, 163.15]

    2.1 24 weeks
189Risk Ratio (M-H, Fixed, 95% CI)9.82 [0.59, 163.15]

 3 HAQ (mean reduction from baseline)189Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.62, 0.02]

    3.1 24 weeks
189Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.62, 0.02]

 4 Total withdrawals189Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.04, 0.79]

    4.1 24 weeks
189Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.04, 0.79]

 5 Withdrawals due to adverse events189Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.10, 10.77]

    5.1 24 weeks
189Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.10, 10.77]

 6 Serious adverse events189Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.05, 1.31]

    6.1 24 weeks
189Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.05, 1.31]

 
Comparison 3. Efficacy at six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR202Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)2.66 [1.84, 3.84]

 2 ACR502Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)4.73 [2.42, 9.28]

 3 ACR702Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)11.53 [2.30, 57.86]

 4 DAS1151Mean Difference (IV, Fixed, 95% CI)-1.42 [-1.80, -1.04]

    4.1 Etanercept 25 mg SC twice weekly
1151Mean Difference (IV, Fixed, 95% CI)-1.42 [-1.80, -1.04]

 
Comparison 4. Efficacy at 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR202Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
2958Risk Ratio (M-H, Random, 95% CI)1.20 [1.07, 1.35]

 2 ACR502Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
2958Risk Ratio (M-H, Fixed, 95% CI)1.52 [1.36, 1.70]

 3 ACR702Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
2958Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.59, 2.32]

 4 Remission (DAS < 1.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)2.65 [1.85, 3.81]

 5 Remission (DAS < 2.6)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
2987Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.61, 2.35]

 6 Change in Total Sharp Score (from baseline)2894Mean Difference (IV, Fixed, 95% CI)-2.21 [-2.99, -1.43]

    6.1 Etanercept 25 mg SC twice weekly
2894Mean Difference (IV, Fixed, 95% CI)-2.21 [-2.99, -1.43]

 7 Change in Erosion Score (from baseline)1418Mean Difference (IV, Fixed, 95% CI)-1.63 [-2.41, -0.85]

    7.1 Etanercept 25 mg SC twice weekly
1418Mean Difference (IV, Fixed, 95% CI)-1.63 [-2.41, -0.85]

 8 Change in Joint Space Narrowing Score (from baseline)1418Mean Difference (IV, Fixed, 95% CI)-0.67 [-1.12, -0.22]

    8.1 Etanercept 25 mg SC twice weekly
1418Mean Difference (IV, Fixed, 95% CI)-0.67 [-1.12, -0.22]

 9 No progression of joint damage (TSS ≤ 0.5)2906Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.26, 1.51]

    9.1 Etanercept 25 mg SC twice weekly
2906Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.26, 1.51]

 
Comparison 5. Efficacy at two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR203Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
3871Risk Ratio (M-H, Random, 95% CI)1.48 [1.15, 1.90]

 2 ACR703Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
3871Risk Ratio (M-H, Random, 95% CI)2.22 [1.51, 3.27]

 3 ACR503Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
3871Risk Ratio (M-H, Random, 95% CI)1.93 [1.33, 2.82]

 4 Remission (DAS < 1.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)2.58 [1.84, 3.61]

 5 Remission (DAS < 2.6)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
2720Risk Ratio (M-H, Fixed, 95% CI)2.16 [1.70, 2.74]

 6 Change in Total Sharp Score (from baseline)1419Mean Difference (IV, Fixed, 95% CI)-3.9 [-6.11, -1.69]

    6.1 Etanercept 25 mg SC twice weekly
1419Mean Difference (IV, Fixed, 95% CI)-3.9 [-6.11, -1.69]

 7 Change in Erosion Score (from baseline)1419Mean Difference (IV, Fixed, 95% CI)-2.88 [-4.39, -1.37]

    7.1 Etanercept 25 mg SC twice weekly
1419Mean Difference (IV, Fixed, 95% CI)-2.88 [-4.39, -1.37]

 8 Change in Joint Space Narrowing Score (from baseline)1419Mean Difference (IV, Fixed, 95% CI)-1.03 [-1.89, -0.17]

    8.1 Etanercept 25 mg SC twice weekly
1419Mean Difference (IV, Fixed, 95% CI)-1.03 [-1.89, -0.17]

 9 No progression of joint damage2601Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.18, 1.45]

    9.1 Etanercept 25 mg SC twice weekly
2601Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.18, 1.45]

 10 DAS 281151Mean Difference (IV, Fixed, 95% CI)-2.00 [-2.38, -1.62]

 
Comparison 6. Efficacy at three years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR201Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)1.24 [1.12, 1.38]

 2 ACR501Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.30, 1.85]

 3 ACR701Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etancercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)2.30 [1.73, 3.04]

 4 Remission (DAS < 1.6)1459Risk Ratio (M-H, Fixed, 95% CI)2.32 [1.68, 3.20]

    4.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)2.32 [1.68, 3.20]

 5 Remission (DAS < 2.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)2.13 [1.56, 2.92]

 6 Change in Total Sharp Score (TSS) (from baseline)1427Mean Difference (IV, Fixed, 95% CI)-6.09 [-9.22, -2.96]

    6.1 Etanercept 25 mg SC twice weekly
1427Mean Difference (IV, Fixed, 95% CI)-6.09 [-9.22, -2.96]

 7 Change in Erosion Score (from baseline)1427Mean Difference (IV, Fixed, 95% CI)-3.92 [-5.72, -2.12]

    7.1 Etanercept 25 mg SC twice weekly
1427Mean Difference (IV, Fixed, 95% CI)-3.92 [-5.72, -2.12]

 8 Change in Joint Space Narrowing Score (from baseline)1427Mean Difference (IV, Fixed, 95% CI)-2.17 [-3.78, -0.56]

    8.1 Etanercept 25 mg SC twice weekly
1427Mean Difference (IV, Fixed, 95% CI)-2.17 [-3.78, -0.56]

 9 No progression of joint damage (TSS ≤ 0.5)1427Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.28, 1.74]

    9.1 Etanercept 25 mg SC twice weekly
1427Risk Ratio (M-H, Fixed, 95% CI)1.49 [1.28, 1.74]

 
Comparison 7. Efficacy at six months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR203Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1423Risk Ratio (M-H, Random, 95% CI)1.00 [0.84, 1.19]

    1.2 Etanercept 25 mg SC twice weekly
3814Risk Ratio (M-H, Random, 95% CI)1.35 [0.97, 1.89]

 2 ACR503Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1423Risk Ratio (M-H, Random, 95% CI)1.01 [0.76, 1.34]

    2.2 Etanercept 25 mg SC twice weekly
3814Risk Ratio (M-H, Random, 95% CI)1.55 [1.02, 2.37]

 3 ACR703Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1423Risk Ratio (M-H, Random, 95% CI)0.98 [0.59, 1.61]

    3.2 Etanercept 25 mg SC twice weekly
3814Risk Ratio (M-H, Random, 95% CI)1.97 [1.09, 3.54]

 4 Change in Total Sharp Score (from baseline)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 10 mg SC twice weekly
1425Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.72, 0.22]

    4.2 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)-0.49 [-0.92, -0.06]

 5 Change in Erosion Score (from baseline)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 10 mg SC twice weekly
1425Mean Difference (IV, Fixed, 95% CI)-0.18 [-0.49, 0.13]

    5.2 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)-0.38 [-0.66, -0.10]

 6 Change in Joint Space Narrowing Score (from baseline)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Etanercept 10 mg SC twice weekly
1425Mean Difference (IV, Fixed, 95% CI)-0.07 [-0.35, 0.21]

    6.2 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)-0.11 [-0.35, 0.13]

 7 DAS2177Mean Difference (IV, Random, 95% CI)-0.76 [-2.24, 0.71]

    7.1 Etanercept 25 mg SC twice weekly
2177Mean Difference (IV, Random, 95% CI)-0.76 [-2.24, 0.71]

 
Comparison 8. Efficacy at 12 months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR202Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1423Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.80, 1.11]

    1.2 Etanercept 25 mg SC twice weekly
2874Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.98, 1.16]

 2 ACR502Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1423Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.58, 0.99]

    2.2 Etanercept 25 mg SC twice weekly
2874Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.99, 1.33]

 3 ACR702Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1423Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.49, 1.13]

    3.2 Etanercept 25 mg SC twice weekly
2874Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.95, 1.58]

 4 Remission (DAS < 1.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.81, 1.91]

 5 Remission (DAS < 2.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.53]

 6 Change in Total Sharp Score (TSS) (from baseline)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Etanercept 10 mg SC twice weekly
1425Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.93, 0.85]

    6.2 Etanercept 25 mg SC twice weekly
2832Mean Difference (IV, Fixed, 95% CI)-0.74 [-1.35, -0.13]

 7 Change in Erosion Score (from baseline)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 Etanercept 10 mg SC twice weekly
1425Mean Difference (IV, Fixed, 95% CI)-0.13 [-0.66, 0.40]

    7.2 Etanercept 25 mg SC twice weekly
2832Mean Difference (IV, Fixed, 95% CI)-0.65 [-1.04, -0.27]

 8 Change in Joint Space Narrowing Score (from baseline)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 Etanercept 10 mg SC twice weekly
1425Mean Difference (IV, Fixed, 95% CI)0.09 [-0.42, 0.60]

    8.2 Etanercept 25 mg SC twice weekly
2832Mean Difference (IV, Fixed, 95% CI)-0.11 [-0.43, 0.20]

 9 No progression of joint damage (TSS ≤ 0.5)1424Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.03, 1.38]

    9.1 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.03, 1.38]

 
Comparison 9. Efficacy at two years: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR202Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)1.42 [0.74, 2.73]

 2 ACR502Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)2.33 [0.60, 8.98]

 3 ACR702Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)2.51 [0.52, 12.03]

 4 Remission (DAS < 1.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.01, 2.17]

 5 Remission (DAS < 2.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.83, 1.71]

 6 Change in Total Sharp Score (from baseline)1409Mean Difference (IV, Fixed, 95% CI)-2.24 [-4.61, 0.13]

    6.1 Etanercept 25 mg SC twice weekly
1409Mean Difference (IV, Fixed, 95% CI)-2.24 [-4.61, 0.13]

 7 Change in Erosion Score (from baseline)1409Mean Difference (IV, Fixed, 95% CI)-1.76 [-3.34, -0.18]

    7.1 Etanercept 25 mg SC twice weekly
1409Mean Difference (IV, Fixed, 95% CI)-1.76 [-3.34, -0.18]

 8 Change in Joint Space Narrowing Score (from baseline)1409Mean Difference (IV, Fixed, 95% CI)-0.49 [-1.46, 0.48]

    8.1 Etanercept 25 mg SC twice weekly
1409Mean Difference (IV, Fixed, 95% CI)-0.49 [-1.46, 0.48]

 9 No progression of joint damage1409Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.98, 1.31]

    9.1 Etanercept 25 mg SC twice weekly
1409Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.98, 1.31]

 10 DAS 281153Mean Difference (IV, Fixed, 95% CI)-1.70 [-2.07, -1.33]

 
Comparison 10. Efficacy at three years: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR201Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.93, 1.18]

 2 ACR501Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.32]

 3 ACR701Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.80, 1.58]

 4 Remission (DAS < 1.6)1451Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.84, 1.79]

    4.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.84, 1.79]

 5 Remission (DAS < 2.6)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.75, 1.59]

 6 Change in Total Sharp Score (from baseline)1421Mean Difference (IV, Fixed, 95% CI)-4.34 [-7.56, -1.12]

    6.1 Etanercept 25 mg SC twice weekly
1421Mean Difference (IV, Fixed, 95% CI)-4.34 [-7.56, -1.12]

 7 Change in Erosion Score (from baseline)1421Mean Difference (IV, Fixed, 95% CI)-2.86 [-4.81, -0.91]

    7.1 Etanercept 25 mg SC twice weekly
1421Mean Difference (IV, Fixed, 95% CI)-2.86 [-4.81, -0.91]

 8 Change in Joint Space Narrowing Score (from baseline)1421Mean Difference (IV, Fixed, 95% CI)-1.48 [-3.04, 0.08]

    8.1 Etanercept 25 mg SC twice weekly
1421Mean Difference (IV, Fixed, 95% CI)-1.48 [-3.04, 0.08]

 9 No progression of joint damage (TSS ≤ 0.5)1421Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.01, 1.42]

    9.1 Etanercept 25 mg SC twice weekly
1421Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.01, 1.42]

 
Comparison 11. Efficacy at six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR202346Risk Ratio (M-H, Random, 95% CI)1.19 [0.85, 1.66]

    1.1 Etanercept 25 mg SC twice weekly
2346Risk Ratio (M-H, Random, 95% CI)1.19 [0.85, 1.66]

 2 ACR502346Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.99, 1.49]

    2.1 Etanercept 25 mg SC twice weekly
2346Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.99, 1.49]

 3 ACR702346Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.92, 1.85]

    3.1 Etanercept 25 mg SC twice weekly
2346Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.92, 1.85]

 4 DAS < 3.21142Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.05, 2.33]

    4.1 Etanercept 25 mg SC twice weekly
1142Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.05, 2.33]

 5 Remission (DAS < 2.6)1142Risk Ratio (M-H, Fixed, 95% CI)2.70 [1.22, 5.98]

    5.1 Etanercept 25 mg SC twice weekly
1142Risk Ratio (M-H, Fixed, 95% CI)2.70 [1.22, 5.98]

 6 EULAR - good response1142Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.05, 2.33]

    6.1 Etanercept 25 mg SC twice weekly
1142Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.05, 2.33]

 7 EULAR - moderate response1142Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.78, 1.73]

    7.1 Etanercept 25 mg SC twice weekly
1142Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.78, 1.73]

 8 EULAR - no response1142Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.04, 0.46]

    8.1 Etanercept 25 mg SC twice weekly
1142Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.04, 0.46]

 9 DAS1204Mean Difference (IV, Fixed, 95% CI)0.0 [-0.32, 0.32]

    9.1 ET 25 mg SC twice weekly
1204Mean Difference (IV, Fixed, 95% CI)0.0 [-0.32, 0.32]

 
Comparison 12. Efficacy at 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR201454Risk Ratio (M-H, Fixed, 95% CI)1.12 [1.02, 1.23]

    1.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.12 [1.02, 1.23]

 2 ACR501454Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.22, 1.69]

    2.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.22, 1.69]

 3 ACR701454Risk Ratio (M-H, Fixed, 95% CI)1.77 [1.34, 2.33]

    3.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.77 [1.34, 2.33]

 4 Remission (DAS < 1.6)1454Risk Ratio (M-H, Fixed, 95% CI)2.13 [1.53, 2.96]

    4.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)2.13 [1.53, 2.96]

 5 Remission (DAS < 2.6)1454Risk Ratio (M-H, Fixed, 95% CI)2.18 [1.57, 3.03]

    5.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)2.18 [1.57, 3.03]

 6 Change in Total Sharp Score (from baseline)1414Mean Difference (IV, Fixed, 95% CI)-1.13 [-1.76, -0.50]

    6.1 Etanercept 25 mg SC twice weekly
1414Mean Difference (IV, Fixed, 95% CI)-1.13 [-1.76, -0.50]

 7 Change in Erosion Score (from baseline)1414Mean Difference (IV, Fixed, 95% CI)-0.67 [-1.12, -0.22]

    7.1 Etanercept 25 mg SC twice weekly
1414Mean Difference (IV, Fixed, 95% CI)-0.67 [-1.12, -0.22]

 8 Change in Joint Space Narrowing Score (from baseline)1414Mean Difference (IV, Fixed, 95% CI)-0.46 [-0.74, -0.18]

    8.1 Etanercept 25 mg SC twice weekly
1414Mean Difference (IV, Fixed, 95% CI)-0.46 [-0.74, -0.18]

 9 No progression of joint damage (TSS ≤ 0.5)1430Risk Ratio (M-H, Fixed, 95% CI)1.18 [1.05, 1.32]

    9.1 Etanercept 25 mg SC twice weekly
1430Risk Ratio (M-H, Fixed, 95% CI)1.18 [1.05, 1.32]

 
Comparison 13. Efficacy at two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR202658Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.06, 1.24]

    1.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.06, 1.24]

 2 ACR502663Risk Ratio (M-H, Random, 95% CI)1.47 [1.07, 2.02]

    2.1 Etanercept 25 mg SC twice weekly
2663Risk Ratio (M-H, Random, 95% CI)1.47 [1.07, 2.02]

 3 ACR702658Risk Ratio (M-H, Random, 95% CI)1.45 [0.91, 2.31]

    3.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)1.45 [0.91, 2.31]

 4 Remission (DAS < 1.6)1454Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.31, 2.32]

    4.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.31, 2.32]

 5 Remission (DAS < 2.6)1454Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.42, 2.52]

    5.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.42, 2.52]

 6 Change in Total Sharp Score (TSS) (from baseline)1416Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.76, -0.56]

    6.1 Etanercept 25 mg SC twice weekly
1416Mean Difference (IV, Fixed, 95% CI)-1.66 [-2.76, -0.56]

 7 Change in Erosion Score (from baseline)1416Mean Difference (IV, Fixed, 95% CI)-1.12 [-1.83, -0.41]

    7.1 Etanercept 25 mg SC twice weekly
1416Mean Difference (IV, Fixed, 95% CI)-1.12 [-1.83, -0.41]

 8 Change in Joint Space Narrowing Score (from baseline)1416Mean Difference (IV, Fixed, 95% CI)-0.54 [-1.09, 0.01]

    8.1 Etanercept 25 mg SC twice weekly
1416Mean Difference (IV, Fixed, 95% CI)-0.54 [-1.09, 0.01]

 9 No progression of joint damage (TSS ≤ 0.5)1416Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.02, 1.29]

    9.1 Etanercept 25 mg SC twice weekly
1416Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.02, 1.29]

 10 DAS1204Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.62, 0.02]

 
Comparison 14. Efficacy at three years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR201454Risk Ratio (M-H, Fixed, 95% CI)1.18 [1.07, 1.31]

    1.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.18 [1.07, 1.31]

 2 ACR501454Risk Ratio (M-H, Fixed, 95% CI)1.44 [1.22, 1.71]

    2.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.44 [1.22, 1.71]

 3 ACR701454Risk Ratio (M-H, Fixed, 95% CI)2.04 [1.56, 2.66]

    3.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)2.04 [1.56, 2.66]

 4 Remission (DAS < 1.6)1454Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.41, 2.54]

    4.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.41, 2.54]

 5 Remission (DAS < 2.6)1454Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.44, 2.64]

    5.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.44, 2.64]

 6 Change in Total Sharp Score (TSS) (from baseline)1428Mean Difference (IV, Fixed, 95% CI)-1.75 [-3.27, -0.23]

    6.1 Etanercept 25 mg SC twice weekly
1428Mean Difference (IV, Fixed, 95% CI)-1.75 [-3.27, -0.23]

 7 Change in Erosion Score (from baseline)1428Mean Difference (IV, Fixed, 95% CI)-1.06 [-1.98, -0.14]

    7.1 Etanercept 25 mg SC twice weekly
1428Mean Difference (IV, Fixed, 95% CI)-1.06 [-1.98, -0.14]

 8 Change in Joint Space Narrowing Score (from baseline)1428Mean Difference (IV, Fixed, 95% CI)-0.69 [-1.65, 0.27]

    8.1 Etanercept 25 mg SC twice weekly
1428Mean Difference (IV, Fixed, 95% CI)-0.69 [-1.65, 0.27]

 9 No progression of joint damage (TSS ≤ 0.5)1428Risk Difference (M-H, Fixed, 95% CI)0.15 [0.06, 0.24]

    9.1 Etanercept 25 mg SC twice weekly
1428Risk Difference (M-H, Fixed, 95% CI)0.15 [0.06, 0.24]

 
Comparison 15. Efficacy at six months: etanercept vs. placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR201Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)4.56 [2.37, 8.77]

    1.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)5.24 [2.76, 9.97]

 2 ACR501Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)4.74 [1.68, 13.36]

    2.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)7.95 [2.94, 21.47]

 3 ACR701Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)7.37 [0.93, 58.49]

    3.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)12.31 [1.64, 92.41]

 
Comparison 16. Quality of life at six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HAQ: final value2240Mean Difference (IV, Random, 95% CI)-0.49 [-0.77, -0.21]

 2 EuroQoL VAS1151Mean Difference (IV, Fixed, 95% CI)18.6 [11.76, 25.44]

 
Comparison 17. Quality of life at 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Satisfaction with treatment1458Risk Ratio (M-H, Fixed, 95% CI)1.22 [1.11, 1.34]

    1.1 Etanercept 25 mg SC twice weekly
1458Risk Ratio (M-H, Fixed, 95% CI)1.22 [1.11, 1.34]

 2 HAQ score after treatment2987Mean Difference (IV, Fixed, 95% CI)-0.24 [-0.33, -0.15]

    2.1 Etanercept 25 mg SC twice weekly
2987Mean Difference (IV, Fixed, 95% CI)-0.24 [-0.33, -0.15]

 3 EQ-5D VAS2987Mean Difference (IV, Fixed, 95% CI)7.60 [4.67, 10.54]

    3.1 Etanercept 25 mg SC twice weekly
2987Mean Difference (IV, Fixed, 95% CI)7.60 [4.67, 10.54]

 4 Reduction to normal health assessment (HAQ ≤ 0.5)2956Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.17, 1.58]

    4.1 Etanercept 25 mg SC twice weekly
2956Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.17, 1.58]

 5 Proportion stopping work1205Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.17, 0.73]

    5.1 Etanercept 25 mg SC twice weekly
1205Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.17, 0.73]

 6 SF-36 Physical domain1528Mean Difference (IV, Fixed, 95% CI)2.80 [1.00, 4.60]

    6.1 Etanercept 25 mg SC twice weekly
1528Mean Difference (IV, Fixed, 95% CI)2.80 [1.00, 4.60]

 7 SF-36 Mental domain1528Mean Difference (IV, Fixed, 95% CI)0.60 [-1.35, 2.55]

    7.1 Etanercept 25 mg SC twice weekly
1528Mean Difference (IV, Fixed, 95% CI)0.60 [-1.35, 2.55]

 
Comparison 18. Quality of life at two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Percentage improvement in HAQ (from baseline)1459Mean Difference (IV, Fixed, 95% CI)20.0 [17.45, 22.55]

    1.1 Etanercept 25 mg SC twice weekly
1459Mean Difference (IV, Fixed, 95% CI)20.0 [17.45, 22.55]

 2 HAQ score after treatment2610Mean Difference (IV, Random, 95% CI)-0.49 [-0.69, -0.30]

    2.1 Etanercept 25 mg SC twice weekly
2610Mean Difference (IV, Random, 95% CI)-0.49 [-0.69, -0.30]

 
Comparison 19. Quality of life at six months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HAQ score: final value2Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
2177Mean Difference (IV, Random, 95% CI)-0.06 [-0.83, 0.72]

 2 EuroQoL VAS1153Mean Difference (IV, Fixed, 95% CI)21.30 [14.62, 27.98]

    2.1 Etanercept 25 mg SC twice weekly
1153Mean Difference (IV, Fixed, 95% CI)21.30 [14.62, 27.98]

 
Comparison 20. Quality of life at 12 months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HAQ score after treatment1451Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.25, 0.05]

    1.1 Etanercept 25 mg SC twice weekly
1451Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.25, 0.05]

 2 HAQ score: change from baseline1424Mean Difference (IV, Fixed, 95% CI)0.03 [-0.11, 0.17]

    2.1 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)0.03 [-0.11, 0.17]

 3 Proportion of participants whose HAQ scores improved from baseline1424Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.96, 1.25]

    3.1 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.96, 1.25]

 4 SF-36 score - physical domain: change from baseline1424Mean Difference (IV, Fixed, 95% CI)1.10 [-1.12, 3.32]

    4.1 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)1.10 [-1.12, 3.32]

 5 Proportion of participants whose SF-36 (physical) scores improved from baseline1424Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.92, 1.23]

    5.1 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.92, 1.23]

 6 SF-36 score - mental domain: change from baseline1424Mean Difference (IV, Fixed, 95% CI)-0.50 [-2.72, 1.72]

    6.1 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)-0.50 [-2.72, 1.72]

 7 Proportion of participants whose SF-36 (mental) scores improved from baseline1424Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.70, 1.23]

    7.1 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.70, 1.23]

 8 ASHI: change from baseline1424Mean Difference (IV, Fixed, 95% CI)0.10 [-2.67, 2.87]

    8.1 Etanercept 25 mg SC twice weekly
1424Mean Difference (IV, Fixed, 95% CI)0.10 [-2.67, 2.87]

 9 Proportion of participants whose ASHI scores improved from baseline1424Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.89, 1.24]

    9.1 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.89, 1.24]

 10 EQ-5D VAS1451Mean Difference (IV, Fixed, 95% CI)3.09 [-1.45, 7.63]

    10.1 Etanercept 25 mg SC twice weekly
1451Mean Difference (IV, Fixed, 95% CI)3.09 [-1.45, 7.63]

 11 Satisfaction with treatment1449Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.08, 1.31]

    11.1 Etanercept 25 mg SC twice weekly
1449Risk Ratio (M-H, Fixed, 95% CI)1.19 [1.08, 1.31]

 12 Reduction to normal health assessment (HAQ ≤ 0.5)1451Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.77, 1.29]

    12.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.77, 1.29]

 
Comparison 21. Quality of life at two years: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Percentage improvement in HAQ (from baseline)1451Mean Difference (IV, Fixed, 95% CI)3.0 [0.09, 5.91]

    1.1 Etanercept 25 mg SC twice weekly
1451Mean Difference (IV, Fixed, 95% CI)3.0 [0.09, 5.91]

 2 HAQ score after treatment2604Mean Difference (IV, Random, 95% CI)-0.25 [-0.54, 0.05]

    2.1 Etanercept 25 mg SC twice weekly
2604Mean Difference (IV, Random, 95% CI)-0.25 [-0.54, 0.05]

 
Comparison 22. Quality of life at six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 HAQ score after treatment1142Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.43, 0.03]

    1.1 Etanercept 25 mg SC twice weekly
1142Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.43, 0.03]

 
Comparison 23. Quality of life at 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Satisfaction with treatment1451Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.96, 1.10]

    1.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.96, 1.10]

 2 HAQ score after treatment3800Mean Difference (IV, Fixed, 95% CI)-0.2 [-0.30, -0.10]

    2.1 Etanercept 25 mg SC twice weekly
3800Mean Difference (IV, Fixed, 95% CI)-0.2 [-0.30, -0.10]

 3 EQ-5D VAS2658Mean Difference (IV, Random, 95% CI)1.87 [-6.61, 10.34]

    3.1 Etanercept 25 mg SC twice weekly
2658Mean Difference (IV, Random, 95% CI)1.87 [-6.61, 10.34]

 4 Reduction to normal health assessment (HAQ ≤ 0.5)1454Risk Ratio (M-H, Fixed, 95% CI)1.30 [1.03, 1.64]

    4.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.30 [1.03, 1.64]

 
Comparison 24. Quality of life at two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Percentage improvement in HAQ (from baseline)1454Mean Difference (IV, Fixed, 95% CI)17.0 [14.61, 19.39]

    1.1 Etanercept 25 mg SC twice weekly
1454Mean Difference (IV, Fixed, 95% CI)17.0 [14.61, 19.39]

 2 HAQ score after treatment2658Mean Difference (IV, Fixed, 95% CI)-0.26 [-0.36, -0.15]

    2.1 Etanercept 25 mg SC twice weekly
2658Mean Difference (IV, Fixed, 95% CI)-0.26 [-0.36, -0.15]

 3 Satisfaction with treatment1451Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.96, 1.10]

    3.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.96, 1.10]

 
Comparison 25. Quality of life at six months: etanercept vs. placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 MOS: mental health (change from baseline)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1156Mean Difference (IV, Fixed, 95% CI)8.54 [3.24, 13.84]

    1.2 Etanercept 25 mg SC twice weekly
1158Mean Difference (IV, Fixed, 95% CI)9.47 [4.29, 14.65]

 2 MOS: energy/vitality (change from baseline)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1156Mean Difference (IV, Fixed, 95% CI)12.64 [6.42, 18.86]

    2.2 Etanercept 25 mg SC twice weekly
1158Mean Difference (IV, Fixed, 95% CI)11.61 [5.50, 17.72]

 
Comparison 26. Withdrawals six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARDs

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
189Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.04, 0.79]

 2 Lack of efficacy2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.05, 0.37]

 3 Adverse event2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.09, 1.64]

 4 Death189Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.1 Etanercept 25 mg SC twice weekly
189Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 27. Withdrawals 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total21001Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.48, 0.76]

    1.1 Etanercept 25 mg SC twice weekly
21001Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.48, 0.76]

 2 Lack of efficacy21001Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.18, 0.58]

    2.1 Etanercept 25 mg SC twice weekly
21001Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.18, 0.58]

 3 Adverse events21001Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.55, 1.09]

    3.1 Etanercept 25 mg SC twice weekly
21001Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.55, 1.09]

 4 Death21001Risk Ratio (M-H, Fixed, 95% CI)1.64 [0.22, 12.37]

    4.1 Etanercept 25 mg SC twice weekly
21001Risk Ratio (M-H, Fixed, 95% CI)1.64 [0.22, 12.37]

 
Comparison 28. Withdrawals two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total2610Risk Ratio (M-H, Random, 95% CI)0.47 [0.28, 0.80]

    1.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)0.47 [0.28, 0.80]

 2 Lack of efficacy2610Risk Ratio (M-H, Random, 95% CI)0.19 [0.07, 0.48]

    2.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)0.19 [0.07, 0.48]

 3 Adverse event2610Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.57, 1.19]

    3.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.57, 1.19]

 4 Death1459Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.68]

    4.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.06, 15.68]

 
Comparison 29. Withdrawals three years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.59, 0.84]

 2 Lack of efficacy1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.16, 0.56]

 3 Adverse event1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.45, 0.98]

 4 Death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.18, 21.62]

 
Comparison 30. Withdrawals six months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1238Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.72, 2.88]

 2 Lack of efficacy1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.04 [0.01, 0.30]

 3 Adverse event1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.25, 3.72]

 
Comparison 31. Withdrawals 12 months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.67, 1.42]

    1.2 Etanercept 25 mg SC twice weekly
2875Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.59, 0.97]

 2 Lack of efficacy2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.96 [0.85, 4.52]

    2.2 Etanercept 25 mg SC twice weekly
2875Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.55, 1.54]

 3 Adverse event2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]

    3.2 Etanercept 25 mg SC twice weekly
2875Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.45, 0.99]

 4 Death2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)3.13 [0.13, 76.38]

    4.2 Etanercept 25 mg SC twice weekly
2875Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.23, 12.95]

 
Comparison 32. Withdrawals two years: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total2604Risk Ratio (M-H, Random, 95% CI)0.67 [0.46, 0.97]

    1.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)0.67 [0.46, 0.97]

 2 Lack of efficacy2604Risk Ratio (M-H, Random, 95% CI)0.32 [0.04, 2.48]

    2.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)0.32 [0.04, 2.48]

 3 Adverse event2604Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.55, 1.13]

    3.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.55, 1.13]

 4 Death1451Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.25]

    4.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.06, 16.25]

 
Comparison 33. Withdrawals three years: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.72, 1.00]

 2 Lack of efficacy1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.62, 1.43]

 3 Adverse event1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.53, 1.11]

 4 Death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.19, 22.39]

 
Comparison 34. Withdrawals six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1147Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.92]

    1.1 Etanercept 25 mg SC twice weekly
1147Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.92]

 2 Lack of efficacy2351Risk Ratio (M-H, Random, 95% CI)0.86 [0.03, 24.83]

    2.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Random, 95% CI)0.86 [0.03, 24.83]

 3 Adverse events2351Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.03, 0.86]

    3.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.03, 0.86]

 
Comparison 35. Withdrawals 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1459Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.38, 0.77]

    1.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.38, 0.77]

 2 Lack of efficacy1454Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.14, 0.91]

    2.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.14, 0.91]

 3 Adverse events1454Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.55, 1.57]

    3.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.55, 1.57]

 4 Deaths1454Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.06, 15.34]

    4.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.06, 15.34]

 
Comparison 36. Withdrawals two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total2658Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.62, 1.00]

    1.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.62, 1.00]

 2 Lack of efficacy2658Risk Ratio (M-H, Random, 95% CI)0.54 [0.18, 1.60]

    2.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)0.54 [0.18, 1.60]

 3 Adverse events2658Risk Ratio (M-H, Random, 95% CI)0.78 [0.38, 1.63]

    3.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)0.78 [0.38, 1.63]

 4 Deaths2658Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.08, 4.50]

    4.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.08, 4.50]

 
Comparison 37. Withdrawals three years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1454Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.68, 1.00]

    1.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.68, 1.00]

 2 Lack of efficacy1454Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.17, 0.60]

    2.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.17, 0.60]

 3 Adverse events1454Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.32]

    3.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.57, 1.32]

 4 Deaths1454Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.14, 6.79]

    4.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.14, 6.79]

 
Comparison 38. Withdrawals six months: etanercept vs. placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.33, 0.67]

    1.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.24, 0.55]

 2 Lack of efficacy1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.25, 0.65]

    2.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.17, 0.51]

 3 Adverse event1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)1.75 [0.43, 7.09]

    3.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.12, 3.98]

 
Comparison 39. Adverse events within six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1151Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.94, 1.60]

    1.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.94, 1.60]

 2 Abdominal pain2240Risk Ratio (M-H, Fixed, 95% CI)3.86 [0.72, 20.82]

    2.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)3.86 [0.72, 20.82]

 3 Asthenia2240Risk Ratio (M-H, Fixed, 95% CI)3.75 [0.88, 16.03]

    3.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)3.75 [0.88, 16.03]

 4 Bone pain/arthralgia2240Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.14, 1.28]

    4.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.14, 1.28]

 5 Bronchitis1151Risk Ratio (M-H, Fixed, 95% CI)1.98 [0.23, 17.26]

    5.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.98 [0.23, 17.26]

 6 Diarrhoea1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Etanercept 25 mg SC twice weekly
189Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.22, 1.61]

 7 Dizziness2240Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.44, 3.29]

    7.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.44, 3.29]

 8 Dyspepsia2240Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.50, 10.19]

    8.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.50, 10.19]

 9 Fever1151Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.06, 1.91]

    9.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.06, 1.91]

 10 Flu syndrome1151Risk Ratio (M-H, Fixed, 95% CI)2.48 [0.30, 20.62]

    10.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.48 [0.30, 20.62]

 11 Headache2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.75, 3.04]

 12 Hypertension2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)5.58 [0.73, 42.51]

 13 Increased cough2240Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.21, 1.52]

    13.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.21, 1.52]

 14 Infection2240Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.69, 1.32]

    14.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.69, 1.32]

 15 Injection site reaction2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)6.88 [2.22, 21.34]

 16 Injection site haemorrhage1151Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.21, 3.31]

    16.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.21, 3.31]

 17 Leukopenia1151Risk Ratio (M-H, Fixed, 95% CI)5.5 [0.31, 97.54]

    17.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)5.5 [0.31, 97.54]

 18 Miscellaneous skin infections1151Risk Ratio (M-H, Fixed, 95% CI)2.48 [0.30, 20.62]

    18.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.48 [0.30, 20.62]

 19 Mouth ulcers189Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.08, 3.43]

    19.1 Etanercept 25 mg SC twice weekly
189Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.08, 3.43]

 20 Nausea2240Risk Ratio (M-H, Random, 95% CI)0.89 [0.20, 4.00]

    20.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Random, 95% CI)0.89 [0.20, 4.00]

 21 Pain1151Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.06, 1.91]

    21.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.06, 1.91]

 22 Paraesthesia1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.37, 24.01]

    22.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.37, 24.01]

 23 Pharyngitis (non-infectious)2240Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.15, 1.68]

    23.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.15, 1.68]

 24 Pharyngitis or laryngitis1151Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.21, 3.31]

    24.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.21, 3.31]

 25 Pruritus1151Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.37, 8.04]

    25.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.37, 8.04]

 26 Rash1151Risk Ratio (M-H, Fixed, 95% CI)1.98 [0.44, 8.98]

    26.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.98 [0.44, 8.98]

 27 Rhinitis2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    27.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Random, 95% CI)0.94 [0.06, 15.48]

 28 Trauma/accidental injury2240Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.25, 4.84]

    28.1 Etanercept 25 mg SC twice weekly
2240Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.25, 4.84]

 29 Upper respiratory tract infection1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    29.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.40, 2.96]

 30 Vomiting189Risk Ratio (M-H, Fixed, 95% CI)3.62 [0.19, 67.82]

    30.1 Etanercept 25 mg SC twice weekly
189Risk Ratio (M-H, Fixed, 95% CI)3.62 [0.19, 67.82]

 
Comparison 40. Adverse events within 12 months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Nausea1542Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.73, 1.47]

    1.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.73, 1.47]

 2 Nasopharyngitis1542Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.68, 1.46]

    2.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.68, 1.46]

 3 Serious infections1542Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.20, 1.84]

    3.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.20, 1.84]

 4 Worsening of rheumatoid arthritis1542Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.08, 2.00]

    4.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.08, 2.00]

 5 Breast cancer1542Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.69]

    5.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.69]

 6 Chest pain1542Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.56]

    6.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.56]

 7 Pneumonia1542Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.56]

    7.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.06, 15.56]

 8 Cholelithiasis1542Risk Ratio (M-H, Fixed, 95% CI)4.89 [0.24, 101.40]

    8.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)4.89 [0.24, 101.40]

 9 Invertebral disc protrusion1542Risk Ratio (M-H, Fixed, 95% CI)4.89 [0.24, 101.40]

    9.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)4.89 [0.24, 101.40]

 10 Osteoarthritis1542Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]

    10.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]

 11 Interstitial lung disease1542Risk Ratio (M-H, Fixed, 95% CI)4.89 [0.24, 101.40]

    11.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)4.89 [0.24, 101.40]

 12 Hip arthroplasty1542Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]

    12.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.06]

 13 Malignancy1542Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.25, 3.87]

    13.1 Etanercept 25 mg SC twice weekly
1542Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.25, 3.87]

 
Comparison 41. Adverse events within two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1151Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.98, 1.56]

    1.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.98, 1.56]

 2 Accidental injury2610Risk Ratio (M-H, Random, 95% CI)2.29 [0.25, 21.22]

    2.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)2.29 [0.25, 21.22]

 3 Abdominal pain2610Risk Ratio (M-H, Random, 95% CI)1.85 [0.33, 10.35]

    3.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)1.85 [0.33, 10.35]

 4 Asthenia2610Risk Ratio (M-H, Random, 95% CI)2.44 [0.37, 16.07]

    4.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)2.44 [0.37, 16.07]

 5 Arthralgia2610Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.57, 1.50]

    5.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.57, 1.50]

 6 Back pain2610Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.93, 2.12]

    6.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.93, 2.12]

 7 Bronchitis1151Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.50, 4.37]

    7.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.50, 4.37]

 8 Diarrhoea2610Risk Ratio (M-H, Random, 95% CI)1.49 [0.29, 7.68]

    8.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)1.49 [0.29, 7.68]

 9 Dyspepsia1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.69, 12.77]

    9.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.69, 12.77]

 10 Flu syndrome1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.69, 12.77]

    10.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.69, 12.77]

 11 Gingival/dental infection1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.69, 12.77]

    11.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.97 [0.69, 12.77]

 12 Headache2610Risk Ratio (M-H, Random, 95% CI)1.63 [0.56, 4.73]

    12.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)1.63 [0.56, 4.73]

 13 Hypertension1459Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.87, 3.43]

    13.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.87, 3.43]

 14 Increase in cough2610Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.83, 2.04]

    14.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.83, 2.04]

 15 Infections (total)2610Risk Ratio (M-H, Random, 95% CI)1.14 [0.81, 1.61]

    15.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)1.14 [0.81, 1.61]

 16 Injection site haemorrhage1151Risk Ratio (M-H, Fixed, 95% CI)2.31 [0.70, 7.67]

    16.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)2.31 [0.70, 7.67]

 17 Injection Site Reaction2610Risk Ratio (M-H, Fixed, 95% CI)5.03 [2.29, 11.04]

    17.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)5.03 [2.29, 11.04]

 18 Malignancy2610Risk Ratio (M-H, Fixed, 95% CI)2.47 [0.48, 12.59]

    18.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)2.47 [0.48, 12.59]

 19 Miscellaneous skin infections1151Risk Ratio (M-H, Fixed, 95% CI)12.50 [0.76, 206.93]

    19.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)12.50 [0.76, 206.93]

 20 Nausea2610Risk Ratio (M-H, Random, 95% CI)1.05 [0.42, 2.64]

    20.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Random, 95% CI)1.05 [0.42, 2.64]

 21 Pain1459Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.49, 1.62]

    21.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.49, 1.62]

 22 Paraesthesia1151Risk Ratio (M-H, Fixed, 95% CI)5.45 [0.72, 41.00]

    22.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)5.45 [0.72, 41.00]

 23 Pharyngitis or laryngitis1151Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.48, 5.73]

    23.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.48, 5.73]

 24 Rash2610Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.65, 1.64]

    24.1 Etanercept 25 mg SC twice weekly
2610Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.65, 1.64]

 25 Serious infections1459Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.42, 1.76]

    25.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.42, 1.76]

 26 Sinusitis1151Risk Ratio (M-H, Fixed, 95% CI)3.50 [0.18, 66.47]

    26.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)3.50 [0.18, 66.47]

 27 Upper respiratory tract infection1151Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.76, 2.71]

    27.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.76, 2.71]

 28 Vomiting1459Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.36, 1.05]

    28.1 Etanercept 25 mg SC twice weekly
1459Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.36, 1.05]

 29 Worsening of rheumatoid arthritis1151Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.44, 3.19]

    29.1 Etanercept 25 mg SC twice weekly
1151Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.44, 3.19]

 
Comparison 42. Adverse events within six months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.95, 1.61]

 2 Alopecia1238Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.19, 22.13]

    2.1 Etanercept/Yisaipu (ET/Y) 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.19, 22.13]

 3 Accidental injury1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)6.37 [0.37, 110.97]

 4 Asthenia1153Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.16, 13.65]

    4.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.46 [0.16, 13.65]

 5 Arthralgia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.08, 1.57]

 6 Bronchitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)3.88 [0.50, 30.20]

 7 Chest discomfort1238Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.19, 22.13]

    7.1 ET/Y 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.19, 22.13]

 8 Dyspepsia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)2.43 [0.29, 20.23]

 9 Dizziness2391Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.18, 3.77]

    9.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.18, 3.77]

 10 Oedema1238Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.19]

    10.1 ET/Y 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.19]

 11 Elevation in alanine transaminase1238Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.11, 0.74]

    11.1 ET/Y 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.11, 0.74]

 12 Enlargement of lymph nodes1238Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.19, 22.13]

    12.1 ET/Y 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)2.03 [0.19, 22.13]

 13 Fever1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    13.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.07 [0.00, 1.33]

 14 Gastrointestinal symptoms/abdominal pain2391Risk Ratio (M-H, Random, 95% CI)1.73 [0.23, 13.18]

    14.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Random, 95% CI)1.73 [0.23, 13.18]

 15 Headache1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.17, 2.16]

 16 Increased blood pressure2391Risk Ratio (M-H, Fixed, 95% CI)2.60 [0.41, 16.66]

    16.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Fixed, 95% CI)2.60 [0.41, 16.66]

 17 Increased cough1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.08, 1.57]

 18 Infection at another site/pharyngitis or laryngitis, flu syndrome or miscellaneous skin infections2391Risk Ratio (M-H, Fixed, 95% CI)2.21 [1.14, 4.27]

    18.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Fixed, 95% CI)2.21 [1.14, 4.27]

 19 Injection site haemorrhage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    19.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.20, 3.25]

 20 Injection site reaction3415Risk Ratio (M-H, Fixed, 95% CI)18.24 [4.52, 73.69]

    20.1 ET/Y 25 mg SC twice weekly
3415Risk Ratio (M-H, Fixed, 95% CI)18.24 [4.52, 73.69]

 21 Insomnia1238Risk Ratio (M-H, Fixed, 95% CI)7.12 [0.37, 136.31]

    21.1 ET/Y 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)7.12 [0.37, 136.31]

 22 Leukopenia2391Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.39, 2.28]

    22.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.39, 2.28]

 23 Nausea1153Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.10, 2.32]

    23.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.10, 2.32]

 24 Pain1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    24.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.15, 2.78]

 25 Paraesthesia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    25.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.09, 10.45]

 26 Pharyngitis (non-infectious)1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    26.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.20, 3.25]

 27 Pruritus1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    27.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.02, 2.61]

 28 Rhinitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    28.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 1.06]

 29 Skin rash2391Risk Ratio (M-H, Fixed, 95% CI)2.44 [1.05, 5.63]

    29.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Fixed, 95% CI)2.44 [1.05, 5.63]

 30 Total infectious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    30.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.76 [1.05, 2.93]

 31 Upper respiratory tract infection2391Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.51, 1.76]

    31.1 ET/Y 25 mg SC twice weekly
2391Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.51, 1.76]

 32 Vision disorder1238Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.53]

    32.1 ET/Y 25 mg SC twice weekly
1238Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.53]

 
Comparison 43. Adverse events within 12 months: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Alopecia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.31, 1.09]

    1.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.26, 0.97]

 2 Abdominal pain1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.63, 1.90]

    2.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.54, 1.69]

 3 Asthenia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.42, 1.28]

    3.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.64, 1.73]

 4 Back pain1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.48, 2.27]

    4.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.92 [0.98, 3.78]

 5 Diarrhoea1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.61, 1.66]

    5.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.72, 1.89]

 6 Dizziness1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.22, 0.93]

    6.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.64, 1.88]

 7 Dyspepsia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.59, 1.85]

    7.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.72, 2.16]

 8 Ecchymosis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.44, 1.47]

    8.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.47, 1.55]

 9 Headache1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.67, 1.27]

    9.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.14]

 10 Influenza-like syndrome1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.48, 1.46]

    10.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.65, 1.82]

 11 Injection site haemorrhagia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.88, 2.52]

    11.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.85, 2.46]

 12 Injection site reaction1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)4.11 [2.46, 6.87]

    12.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)5.04 [3.05, 8.35]

 13 Mouth ulcers1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    13.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.24, 0.84]

    13.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.18, 0.70]

 14 Nausea1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    14.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.33, 0.73]

    14.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.41, 0.86]

 15 Rash1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    15.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.46, 1.02]

    15.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.34, 0.81]

 16 Rhinitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.80, 1.95]

    16.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.68, 1.72]

 17 Sinusitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    17.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.51, 1.28]

    17.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.35, 0.97]

 18 Skin infection1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    18.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.60, 1.83]

    18.2 Etanercept 25 mg SC twice weekly
1424Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.79, 2.26]

 19 Upper respiratory tract infection2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    19.1 Etanercept 10 mg SC twice weekly
1425Risk Ratio (M-H, Random, 95% CI)0.71 [0.54, 0.93]

    19.2 Etanercept 25 mg SC twice weekly
2577Risk Ratio (M-H, Random, 95% CI)1.02 [0.68, 1.52]

 
Comparison 44. Adverse events within two years: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1153Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.10, 1.70]

    1.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.10, 1.70]

 2 Abdominal pain2604Risk Ratio (M-H, Random, 95% CI)1.85 [0.21, 16.14]

    2.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)1.85 [0.21, 16.14]

 3 Asthenia2604Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.68, 1.90]

    3.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.68, 1.90]

 4 Accidental injury2604Risk Ratio (M-H, Random, 95% CI)2.04 [0.20, 20.68]

    4.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)2.04 [0.20, 20.68]

 5 Arthralgia2604Risk Ratio (M-H, Random, 95% CI)0.98 [0.39, 2.50]

    5.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)0.98 [0.39, 2.50]

 6 Back pain2604Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.85, 1.95]

    6.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.85, 1.95]

 7 Bronchitis1153Risk Ratio (M-H, Fixed, 95% CI)2.55 [0.92, 7.03]

    7.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)2.55 [0.92, 7.03]

 8 Diarrhoea2604Risk Ratio (M-H, Random, 95% CI)2.32 [0.20, 26.32]

    8.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)2.32 [0.20, 26.32]

 9 Dyspepsia1153Risk Ratio (M-H, Fixed, 95% CI)3.40 [0.80, 14.38]

    9.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)3.40 [0.80, 14.38]

 10 Flu syndrome1153Risk Ratio (M-H, Fixed, 95% CI)4.37 [1.05, 18.10]

    10.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)4.37 [1.05, 18.10]

 11 Gingival/dental infection1153Risk Ratio (M-H, Fixed, 95% CI)1.70 [0.37, 7.88]

    11.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.70 [0.37, 7.88]

 12 Headache2604Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.72, 1.57]

    12.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.72, 1.57]

 13 Hypertension1451Risk Ratio (M-H, Fixed, 95% CI)2.47 [1.29, 4.72]

    13.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)2.47 [1.29, 4.72]

 14 Increased cough2604Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.47, 1.32]

    14.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.47, 1.32]

 15 Infections (total)2604Risk Ratio (M-H, Random, 95% CI)1.26 [0.67, 2.38]

    15.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)1.26 [0.67, 2.38]

 16 Injection site haemorrhage1153Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.35, 2.69]

    16.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.35, 2.69]

 17 Injection site reaction2604Risk Ratio (M-H, Fixed, 95% CI)9.00 [4.21, 19.24]

    17.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)9.00 [4.21, 19.24]

 18 Malignancy2604Risk Ratio (M-H, Fixed, 95% CI)2.53 [0.60, 10.63]

    18.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)2.53 [0.60, 10.63]

 19 Miscellaneous skin infections1153Risk Ratio (M-H, Fixed, 95% CI)19.13 [1.18, 310.46]

    19.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)19.13 [1.18, 310.46]

 20 Nausea2604Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.24, 0.49]

    20.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.24, 0.49]

 21 Pain1451Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.64, 1.96]

    21.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.64, 1.96]

 22 Paraesthesia1153Risk Ratio (M-H, Fixed, 95% CI)1.94 [0.22, 16.92]

    22.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.94 [0.22, 16.92]

 23 Pharyngitis or laryngitis1153Risk Ratio (M-H, Fixed, 95% CI)3.88 [1.23, 12.29]

    23.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)3.88 [1.23, 12.29]

 24 Rash2604Risk Ratio (M-H, Random, 95% CI)1.15 [0.34, 3.95]

    24.1 Etanercept 25 mg SC twice weekly
2604Risk Ratio (M-H, Random, 95% CI)1.15 [0.34, 3.95]

 25 Rheumatoid arthritis1153Risk Ratio (M-H, Fixed, 95% CI)8.25 [2.06, 32.98]

    25.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)8.25 [2.06, 32.98]

 26 Serious infections1451Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.47, 1.93]

    26.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.47, 1.93]

 27 Sinusitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    27.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)12.26 [0.74, 202.98]

 28 Upper respiratory tract infection1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    28.1 Etanercept 25 mg SC twice weekly
1153Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.75, 2.65]

 29 Vomiting1451Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.16, 0.63]

    29.1 Etanercept 25 mg SC twice weekly
1451Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.16, 0.63]

 
Comparison 45. Adverse events within six months: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total2351Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

    1.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

 2 Asthenia1204Risk Ratio (M-H, Fixed, 95% CI)3.40 [0.96, 11.99]

    2.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)3.40 [0.96, 11.99]

 3 Blood and lymphatic system disorders/leukopenia2351Risk Ratio (M-H, Random, 95% CI)1.17 [0.05, 29.43]

    3.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Random, 95% CI)1.17 [0.05, 29.43]

 4 Dizziness1204Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.44, 5.26]

    4.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.44, 5.26]

 5 Fever1204Risk Ratio (M-H, Fixed, 95% CI)5.10 [0.25, 104.89]

    5.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)5.10 [0.25, 104.89]

 6 Flu syndrome1204Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.22, 1.88]

    6.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.22, 1.88]

 7 Gastrointestinal symptoms/abdominal pain/dyspepsia2351Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.63, 2.29]

    7.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.63, 2.29]

 8 Headache1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)3.06 [1.15, 8.10]

 9 Hepatobiliary disorders1147Risk Ratio (M-H, Fixed, 95% CI)1.87 [0.17, 20.16]

    9.1 Etanercept 25 mg SC twice weekly
1147Risk Ratio (M-H, Fixed, 95% CI)1.87 [0.17, 20.16]

 10 Hypertension1204Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.52, 7.93]

    10.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.52, 7.93]

 11 Increased cough1204Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.52, 7.93]

    11.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.52, 7.93]

 12 Infection and infestations/total infectious adverse events2351Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.58, 1.03]

    12.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.58, 1.03]

 13 Injection site reaction/injection site haemorrhage/general disorders and administration site conditions2351Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.37, 0.82]

    13.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.37, 0.82]

 14 Injury, poisoning and procedural complications/accidental Injury2351Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.23, 2.21]

    14.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.23, 2.21]

 15 Malignancy1147Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    15.1 Etanercept 25 mg SC twice weekly
1147Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Metabolism and nutrition disorders1147Risk Ratio (M-H, Fixed, 95% CI)2.81 [0.12, 67.76]

    16.1 Etanercept 25 mg SC twice weekly
1147Risk Ratio (M-H, Fixed, 95% CI)2.81 [0.12, 67.76]

 17 Miscellaneous skin infections1204Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.20, 1.63]

    17.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.20, 1.63]

 18 Musculoskeletal and connective tissue disorders/arthralgia2351Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.36, 4.14]

    18.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.36, 4.14]

 19 Nausea1204Risk Ratio (M-H, Fixed, 95% CI)4.08 [1.19, 14.03]

    19.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)4.08 [1.19, 14.03]

 20 Nervous system disorders/paraesthesia2351Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.61, 6.40]

    20.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.61, 6.40]

 21 Pain1204Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.10, 2.72]

    21.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.10, 2.72]

 22 Pharyngitis (non-infectious)1204Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.23, 2.95]

    22.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.23, 2.95]

 23 Pharyngitis or laryngitis (infectious)1204Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.16, 1.16]

    23.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.16, 1.16]

 24 Reproductive system and breast disorders1147Risk Ratio (M-H, Fixed, 95% CI)2.81 [0.12, 67.76]

    24.1 Etanercept 25 mg SC twice weekly
1147Risk Ratio (M-H, Fixed, 95% CI)2.81 [0.12, 67.76]

 25 Respiratory, thoracic and mediastinal disorders/bronchitis2351Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.22, 1.61]

    25.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.22, 1.61]

 26 Rhinitis1204Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.19, 22.14]

    26.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)2.04 [0.19, 22.14]

 27 Skin and subcutaneous tissue disorders/rash/pruritus2351Risk Ratio (M-H, Random, 95% CI)0.78 [0.20, 2.97]

    27.1 Etanercept 25 mg SC twice weekly
2351Risk Ratio (M-H, Random, 95% CI)0.78 [0.20, 2.97]

 28 Total serious adverse events1147Risk Ratio (M-H, Fixed, 95% CI)1.87 [0.17, 20.16]

    28.1 Etanercept 25 mg SC twice weekly
1147Risk Ratio (M-H, Fixed, 95% CI)1.87 [0.17, 20.16]

 29 Upper respiratory tract infection1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    29.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.50, 2.52]

 
Comparison 46. Adverse events within two years: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total1204Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.80, 1.03]

    1.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.80, 1.03]

 2 Abdominal pain2658Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.83, 1.63]

    2.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.83, 1.63]

 3 Accidental injury2658Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.80, 1.65]

    3.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.80, 1.65]

 4 Arthralgia2658Risk Ratio (M-H, Random, 95% CI)1.00 [0.35, 2.84]

    4.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)1.00 [0.35, 2.84]

 5 Asthenia2658Risk Ratio (M-H, Random, 95% CI)1.76 [0.62, 4.99]

    5.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)1.76 [0.62, 4.99]

 6 Back pain2658Risk Ratio (M-H, Random, 95% CI)1.37 [0.56, 3.31]

    6.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)1.37 [0.56, 3.31]

 7 Bronchitis1204Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.30, 1.12]

    7.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.30, 1.12]

 8 Diarrhoea2658Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.53, 1.33]

    8.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.53, 1.33]

 9 Dyspepsia1204Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.43, 1.80]

    9.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.43, 1.80]

 10 Flu syndrome1204Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.35, 1.34]

    10.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.35, 1.34]

 11 Gingival/dental infection1204Risk Ratio (M-H, Fixed, 95% CI)1.75 [0.72, 4.26]

    11.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)1.75 [0.72, 4.26]

 12 Headache2658Risk Ratio (M-H, Random, 95% CI)1.47 [0.66, 3.29]

    12.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)1.47 [0.66, 3.29]

 13 Hypertension1454Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

    13.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.19]

 14 Increased cough2658Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.05, 2.63]

    14.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.05, 2.63]

 15 Infections (total)2658Risk Ratio (M-H, Random, 95% CI)0.94 [0.71, 1.23]

    15.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)0.94 [0.71, 1.23]

 16 Injection site haemorrhage1204Risk Ratio (M-H, Fixed, 95% CI)1.59 [0.72, 3.50]

    16.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)1.59 [0.72, 3.50]

 17 Injection site reaction2658Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.41, 0.79]

    17.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.41, 0.79]

 18 Malignancy2658Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.24, 2.14]

    18.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.24, 2.14]

 19 Miscellaneous skin infections1204Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.33, 1.26]

    19.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.33, 1.26]

 20 Nausea2658Risk Ratio (M-H, Fixed, 95% CI)2.37 [1.65, 3.40]

    20.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Fixed, 95% CI)2.37 [1.65, 3.40]

 21 Pain1454Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.45, 1.42]

    21.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.45, 1.42]

 22 Paraesthesia1204Risk Ratio (M-H, Fixed, 95% CI)2.80 [0.92, 8.52]

    22.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)2.80 [0.92, 8.52]

 23 Pharyngitis or laryngitis1204Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.84]

    23.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.84]

 24 Rash2658Risk Ratio (M-H, Random, 95% CI)0.93 [0.36, 2.41]

    24.1 Etanercept 25 mg SC twice weekly
2658Risk Ratio (M-H, Random, 95% CI)0.93 [0.36, 2.41]

 25 Rheumatoid arthritis1204Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.55, 2.70]

    25.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.55, 2.70]

 26 Serious infections1454Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.43, 1.86]

    26.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.43, 1.86]

 27 Sinusitis1204Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.07, 0.88]

    27.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.07, 0.88]

 28 Upper respiratory tract infection1204Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.66, 1.58]

    28.1 Etanercept 25 mg SC twice weekly
1204Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.66, 1.58]

 29 Vomiting1454Risk Ratio (M-H, Fixed, 95% CI)1.93 [0.92, 4.03]

    29.1 Etanercept 25 mg SC twice weekly
1454Risk Ratio (M-H, Fixed, 95% CI)1.93 [0.92, 4.03]

 
Comparison 47. Adverse events within six months: etanercept vs. placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Diarrhoea1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)1.68 [0.58, 4.92]

    1.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.23, 2.94]

 2 Headache1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.89, 4.39]

    2.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.60, 3.32]

 3 Injection site reaction1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)3.47 [1.84, 6.55]

    3.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)3.90 [2.09, 7.27]

 4 Rhinitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.44, 2.51]

    4.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.37, 2.24]

 5 Sinusitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.38, 2.30]

    5.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.43, 2.45]

 6 Upper respiratory tract infection1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Etanercept 10 mg SC twice weekly
1156Risk Ratio (M-H, Fixed, 95% CI)1.78 [0.97, 3.28]

    6.2 Etanercept 25 mg SC twice weekly
1158Risk Ratio (M-H, Fixed, 95% CI)2.05 [1.14, 3.69]

 
Comparison 48. Sensitivity analysis: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. DMARD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR2051118Risk Ratio (M-H, Random, 95% CI)2.00 [1.38, 2.88]

    1.1 DMARD naive
1261Risk Ratio (M-H, Random, 95% CI)1.42 [1.22, 1.66]

    1.2 Methotrexate (MTX)-inadequate response
2247Risk Ratio (M-H, Random, 95% CI)3.72 [1.91, 7.24]

    1.3 Non-MTX inadequate response
2610Risk Ratio (M-H, Random, 95% CI)1.63 [0.83, 3.23]

 2 ACR5051118Risk Ratio (M-H, Random, 95% CI)2.82 [1.71, 4.68]

    2.1 DMARD naive
1261Risk Ratio (M-H, Random, 95% CI)1.52 [1.23, 1.89]

    2.2 MTX-inadequate response
2247Risk Ratio (M-H, Random, 95% CI)8.61 [3.55, 20.86]

    2.3 Non-MTX inadequate response
2610Risk Ratio (M-H, Random, 95% CI)2.96 [0.81, 10.81]

 3 ACR7051118Risk Ratio (M-H, Random, 95% CI)2.59 [1.63, 4.12]

    3.1 DMARD naive
2247Risk Ratio (M-H, Random, 95% CI)11.40 [2.21, 58.65]

    3.2 MTX-inadequate response
1261Risk Ratio (M-H, Random, 95% CI)1.77 [1.33, 2.37]

    3.3 Non-MTX inadequate response
2610Risk Ratio (M-H, Random, 95% CI)3.27 [1.19, 8.96]

 
Comparison 49. Sensitivity analysis: etanercept vs. disease-modifying anti-rheumatic drug (DMARD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR2031112Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.99, 1.15]

    1.1 DMARD naive
1423Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.97, 1.30]

    1.2 Methotrexate (MTX)-inadequate response
1238Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.92, 1.26]

    1.3 Non-MTX inadequate response
1451Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.92, 1.13]

 2 ACR5031112Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.02, 1.35]

    2.1 DMARD naive
1423Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.94, 1.47]

    2.2 MTX-inadequate response
1238Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.93, 1.86]

    2.3 Non-MTX inadequate response
1451Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.91, 1.37]

 3 ACR-7031112Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.04, 1.66]

    3.1 DMARD naive
1423Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.82, 1.68]

    3.2 MTX-inadequate response
1238Risk Ratio (M-H, Fixed, 95% CI)1.88 [1.00, 3.51]

    3.3 Non-MTX inadequate response
1451Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.90, 1.83]

 
Comparison 50. Sensitivity analysis: etanercept + disease-modifying anti-rheumatic drug (DMARD) vs. etanercept

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 ACR203800Risk Ratio (M-H, Random, 95% CI)1.21 [1.07, 1.36]

   1.1 DMARD naive
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Methotrexate (MTX)-inadequate response
1142Risk Ratio (M-H, Random, 95% CI)1.42 [1.17, 1.72]

    1.3 Non-MTX inadequate response
2658Risk Ratio (M-H, Random, 95% CI)1.15 [1.06, 1.24]

 2 ACR503805Risk Ratio (M-H, Random, 95% CI)1.44 [1.16, 1.79]

   2.1 DMARD naive
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 MTX-inadequate response
1142Risk Ratio (M-H, Random, 95% CI)1.35 [1.00, 1.82]

    2.3 Non-MTX inadequate response
2663Risk Ratio (M-H, Random, 95% CI)1.47 [1.07, 2.02]

 3 ACR703800Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.27, 1.90]

   3.1 DMARD naive
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 MTX-inadequate response
1142Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.90, 2.41]

    3.3 Non-MTX inadequate response
2658Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.26, 1.96]

 
Summary of findings for the main comparison. Inadequate responders to traditional disease-modifying anti-rheumatic drugs (DMARDs)

Etanercept25 mg + DMARD for the treatment of rheumatoid arthritis

Patient or population: participants with rheumatoid arthritis and with a partial response to DMARDs
Settings: international hospital or clinic settings
Intervention: etanercept 25 mg + DMARD
Comparison: DMARD

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

DMARDET 25 mg + DMARD

ACR50
American College of Rheumatology 50% improvement criteria
Follow-up: 24 to 156 weeks
405 per 1000793 per 1000
(538 to 1000)
RR 1.96
(1.33 to 2.89)1
1198
(4 studies)
⊕⊕⊕⊝
moderate2
Absolute treatment benefit 38% (95% CI 13% to 59%); Relative percent change 96% (95% CI 33% to 189%);
NNTB 3 (95% CI 2 to 8)

 Analysis 1.1

Remission
Achievement of disease activity score < 2.6
Follow-up: 52 and 156 weeks
236 per 1000454 per 1000
(378 to 546)
RR 1.92
(1.6 to 2.31)
987
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 22% (95% CI 17% to 27%);

Relative percent change 122% (95% CI 50% to 229%);

NNTB 5 (95% CI 4 to 8)

 Analysis 1.3

Reduction in disability score
Health Assessment Questionnaire. Scale from: 0 to 3
Follow-up: mean 24 to 156 weeks
The mean reduction in disability score ranged across control groups from
-0.15 to -0.72
The mean reduction in disability score in the intervention groups was
0.36 lower
(0.43 lower to 0.28 lower)
1227
(4 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit -12% (95% CI -16% to -2%);

Relative percent change 57% (95% CI 5% to 76%);

NNTB 5 (95% CI 4 to 6).3

 Analysis 1.4

Radiographic progression
Total Sharp Score Scale from: 0 to 448
Follow-up: 52 and 156 weeks
The mean radiographic progression ranged across control groups from
2.4 to 5.96
The mean radiographic progression in the intervention groups was
3.83 lower
(7.67 lower to 0.01 higher)1,7
903
(2 studies)
⊕⊕⊕⊝
moderate2
Statistically significant for all participants (MD -2.2; 95% CI -3.0 to -1.4);

Absolute treatment benefit -0.49% (95% CI -0.67% to -0.32%);

Relative percent change -92% (95% CI -125% to -59.6%);

NNTB 6 (95% CI 5 to 9)
 Analysis 4.6

Smaller sample size in inadequate responders did not achieve statistical significance. However, the point estimate is very similar (MD -3.83; 95% CI -7.67 to 0.01);

Absolute treatment benefit -0.85% (95% CI -1.7% to 0.002%);

Relative percent change -64% (95% CI -128.9% to 0.17%); NNTB N/A.3

 Analysis 1.5

When we transform the x-ray score to an estimate of irreversible physical disability, etanercept + DMARD treatment would prevent an increase in irreversible disability of 0.45 irreversible HAQ units over 10 years (15%) in addition to the reversible change noted in the disability row above

Withdrawals

due to adverse events

Follow-up: 24 to 156 weeks
158 per 1000118 per 1000

(90 to 158)
RR 0.75 (0.57 to 1.0)11241
(4 studies)
⊕⊕⊕⊝
moderate2
Not statistically significant;

Absolute risk difference -4% (95% CI -8% to 0%);

Relative percent change -25% (95% CI -43% to 0%);

NNTH N/A

 Analysis 1.7

Serious adverse events
Follow-up: 24 to 156 weeks
141 per 1000176 per 1000
(104 to 297)
RR 1.25
(0.74 to 2.11)1
1241
(4 studies)
⊕⊕⊕⊝
moderate2
Not statistically significant;

Absolute risk difference 5% (95% CI -4% to 13%);

Relative percent change 25% (95% CI -26% to 111%);

NNTH N/A

 Analysis 1.8

Serious infections
Follow-up: 52 to 156 weeks
49 per 100045 per 1000
(27 to 77)
RR 0.91
(0.54 to 1.55)
1152
(3 studies)
⊕⊕⊕⊕
high
Not statistically significant;

Absolute risk difference -0.49% (95% CI -3% to 2%);

Relative percent change -9% (95% CI -46% to 55%);

NNTH N/A

 Analysis 1.9

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; N/A: not applicable; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Random-effects model was used.
2 Inconsistency across studies (I2 statistic) was greater than 50% which may represent moderate heterogeneity.
3 Klareskog 2004 (TEMPO) was identified as the most representative study (to calculate baseline mean).
 
Summary of findings 2. Inadequate responders to methotrexate (MTX)

Etanercept25 mg + DMARD for the treatment of rheumatoid arthritis

Patient or population: participants with rheumatoid arthritis and with partial response to MTX
Settings: international hospital or clinic setting
Intervention: etanercept 25 mg + DMARD (disease-modifying anti-rheumatic drug)
Comparison: DMARD

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

DMARDET 25 mg + DMARD

ACR50
American College of Rheumatology improvement criteria
Follow-up: 24 weeks
33 per 1000390 per 1000
(55 to 1000)
RR 11.69
(1.66 to 82.47)
89
(1 study)
⊕⊕⊕⊝
moderate1
Absolute treatment benefit 36% (95% CI 22% to 50%);

Relative percent change 1069% (95% CI 66% to 8147%);

NNTB 3 (95% CI 2 to 6)

 Analysis 2.1

Remission
Disease activity score < 2.6
See commentSee commentNot estimable0
(0)
See commentData not reported

Reduction in disability score
Health Assessment Questionnaire (mean improvement from baseline). Scale from: 0 to 3
Follow-up: 24 weeks
The mean reduction in disability score in the control groups was
-0.4
The mean reduction in disability score in the intervention groups was
0.3 lower
(0.62 lower to 0.02 higher)
89
(1 study)
⊕⊕⊕⊝
moderate1
Absolute treatment benefit -10% (95% CI -21% to 0.6%);
Relative percent change 75% (95% CI 5% to 155%)2

 Analysis 2.3

Radiographic progression
Total Sharp Score
Follow-up: 24 weeks
See commentSee commentNot estimable0
(0)
See commentData not reported

Withdrawals due to adverse events
Follow-up: 24 weeks
33 per 100034 per 1000
(3 to 359)
RR 1.02
(0.1 to 10.77)
89
(1 study)
⊕⊕⊕⊝
moderate1
Not statistically significant;

Absolute risk difference 0.06% (95% CI -8% to 8%);

Relative percent change 2% (95% CI -90% to 977%);

NNTH N/A

 Analysis 2.5

Serious adverse events
Follow-up: 24 weeks
133 per 100033 per 1000
(7 to 175)
RR 0.25
(0.05 to 1.31)
89
(1 study)
⊕⊕⊕⊝
moderate1
Not statistically significant;
Absolute treatment benefit -10% (95% CI -23% to 3%);

Relative percent change -75% (95% CI -95% to 31%); NNTH N/A

 Analysis 2.6

Serious infections
Follow-up: 24 weeks
See commentSee commentNot estimable0
(0)
See commentData not reported

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DMARD: disease-modifying anti-rheumatic drug; N/A: not available; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Evidence derived from 1 study only.
2 Klareskog 2004 (TEMPO) was identified as the most representative study (to calculate baseline mean).
 
Summary of findings 3. ACR50, radiographic progression and serious infections

Etanercept for the treatment of rheumatoid arthritis

Patient or population: participants with rheumatoid arthritis
Intervention: etanercept

OutcomesInterventionComparisonFollow-upIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlEtanercept

ACR50 - American College of Rheumatology Improvement Criteria

Etanercept (25 mg) + DMARDDMARD12 months461 per 1000700 per 1000
(627 to 783)
RR 1.52
(1.36 to 1.7)
958
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 24% (95% CI 18% to 30%);

Relative percent change 52% (95% CI 36% to 70%);

NNTB 5 (95% CI 4 to 7)









Etanercept (10 mg)DMARD12 months392 per 1000298 per 1000
(227 to 388)
RR 0.76
(0.58 to 0.99)
423
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -10% (95% CI -19% to -1%;

Relative percent change 24% (95% CI -42% TO -1%);

NNTB not statistically significant









Etanercept (25 mg) + DMARDEtanercept 12 months480 per 1000686 per 1000
(585 to 811)
RR 1.43
(1.22 to 1.69)
454
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 21% (95% CI 12% to 30%);

Relative percent change 43% (95% CI 22% to 69%);

NNTB 5 (95% CI 4 to 10)









Etanercept (25 mg)PBO6 months50 per 1000398 per 1000
(147 to 1000)
RR 7.95
(2.94 to 21.47)
158
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 35% (95% CI 23% to 47%);

Relative percent change 695% (95% CI 194% to 2047%);

NNTB 3 (95% CI 2 to 8)









Radiographic progression - mean change in Total Sharp Score (from baseline). Scale from: 0 to 448

Etanercept (25 mg) + DMARDDMARD12 months2.4MD -2.21

(-2.99 to -1.43)
894
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.49% (95% CI -0.67% to -0.32%);

Relative percent change -92% (95% CI -125% to -59.6%)









Serious infections

Etanercept (25 mg) + DMARD DMARD12 months30 per 100018 per 1000
(6 to 55)
RR 0.61
(0.2 to 1.84)
542
(1 study)
⊕⊕⊕⊕
high
Absolute risk difference -1% (95% CI -4% to 1%);

Relative percent change -39% (95% CI -80% to 84%);

NNTH not statistically significant.









Etanercept (25 mg) + DMARDEtanercept2 years63 per 100057 per 1000
(27 to 117)
RR 0.9
(0.43 to 1.86)
454
(1 study)
⊕⊕⊕⊕
high
Absolute risk difference -1% (95% CI -5% to 4%); Relative percent change -10% (95% CI -57% to 86%);

NNH not statistically significant









*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DMARD: disease-modifying anti-rheumatic drugs; N/A: not available; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1One study was not blinded.
 
Summary of findings 4. Subgroup analyses: ACR50

Etanercept for rheumatoid arthritis

Patient or population: participants with rheumatoid arthritis
Intervention: etanercept

Outcome:

ACR50 - American College of Rheumatology Improvement Criteria
SubgroupIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlEtanercept

Etanercept + DMARD vs. DMARD
Follow-up: 6-36 months
All combined319 per 1000615 per 1000
(561 to 742)
RR 2.82
(1.71 to 4.68)
1118
(5 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 34% (95% CI 26% to 42%);

Relative percent change 182% (95% CI 71% to 368%);

NNTB 4 (95% CI 3 to 5)

DMARD naive462 per 1000702 per 1000
(568 to 872)
RR 1.52
(1.23 to 1.89)
261
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 24% (95% CI 12% to 36%);

Relative percent change 52% (95% CI 23% to 89%);

NNTB 5 (95% CI 3 to 10)

Methotrexate-inadequate response45 per 1000394 per 1000
(164 to 995)
RR 8.61
(3.55 to 20.86)
247
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 35% (95% CI 26% to 44%);

Relative percent change 761% (95% CI 255% to 1986%;

NNTB 3 (95% CI 2 to 9)

Non-methotrexate inadequate response360 per 1000672 per 1000
(594 to 849)
RR 2.96
(0.81 to 10.81)
610
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 38% (95% CI 19% to 57%);

Relative percent change 196% (95% CI 19% to 981%);

NNTB 3 (95% CI 3 to 5)1,2,3

Etanercept vs. DMARD
Follow-up: 3 to 36 months
All combined389 per 1000457 per 1000
(397 to 526)
RR 1.17
(1.02 to 1.35)
1112
(3 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 7% (95% CI 1% to 13%);

Relative percent change 17% (95% CI 2% to 35%);

NNTB 16 (95% CI 3 to 129)

DMARD naive392 per 1000461 per 1000
(368 to 576)
RR 1.18
(0.94 to 1.47)
423
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 7% (95% CI -2% to 16%);

Relative percent change 18% (95% CI -6% to 47%);

NNTB not statistically significant

Methotrexate-inadequate response308 per 1000407 per 1000
(287 to 574)
RR 1.32
(0.93 to 1.86)
238
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 10% (95% CI -2% to 22%);

Relative percent change 32% (95% CI -7% to 86%);

NNTB 11 not statistically significant

Non-methotrexate inadequate response430 per 1000480 per 1000
(391 to 589)
RR 1.12
(0.91 to 1.37)
451
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 5% (95% CI -4% to 14%);

Relative percent change 12% (95% CI -9% to 37%);

NNTB not statistically significant

Etanercept + DMARD vs. Etanercept
Follow-up: 6 to 36 months
All combined442 per 1000667 per 1000
(584 to 761)
RR 1.44
(1.16 to 1.79)
805
(3 studies)
⊕⊕⊕⊝
moderate4
Absolute treatment benefit 20% (95% CI 8% to 32%);

Relative percent change 44% (95% CI 16% to 79%);

NNTB 5 (95% CI 4 to 8)

DMARD naiveNo dataNo data--No data-

Methotrexate-inadequate response478 per 1000644 per 1000
(478 to 870)
RR 1.35
(1 to 1.82)
142
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 17% (95% CI 0% to 33%);

Relative percent change 35% (95% CI 0% to 82%);

NNTB not statistically significant

Non-methotrexate inadequate response435 per 1000672 per 1000
(583 to 774)
RR 1.47
(1.07 to 2.02)
663
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 21% (95% CI 3% to 39%);

Relative percent change 47% (95% CI 7% to 102%);

NNTB 5 (95% CI 3 to 7)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DMARD: disease-modifying anti-rheumatic drug; N/A: not available; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 
Summary of findings 5. Radiographic outcomes

Etanercept for rheumatoid arthritis

Patient or population: participants with rheumatoid arthritis
Intervention: etanercept

OutcomesInterventionComparisonFollow-upIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlEtanercept

Radiographic progression - mean change in Total Sharp Score (from baseline). Scale from: 0 to 448

Etanercept (25 mg) + DMARDDMARD12 months2.4 MD -2.21

(-2.99 to -1.43)
-894
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.49% (95% CI -0.67% to 0.32%);

Relative percent change -92% (95% CI -125% to -59.6%)


2 years3.34 MD -3.9
(-6.11 to -1.69)
-419
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.87% (95% CI -1.36 to -0.38);

Relative percent change -114.7% (95% CI -180% to -50%)

3 years5.95 MD -6.09
(-9.22 to -2.96)
-427
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -1.36% (95% CI -2.06 to -0.66%);

Relative percent change -102% (95% CI -155% to -49.7%)









Etanercept (10 mg)DMARD6 months1.06 MD -0.25
(-0.72 to 0.22)
-425
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.06% (95% CI -0.16% to 0.05%);

Relative percent change -24% (95% CI -68% to 21%)

12 months1.59 MD -0.04
(-0.93 to 0.85)
-425
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.009% (95% CI -0.21 to 0.19%);

Relative percent change -2.5% (95% CI -58.5% to 53.5%)









Etanercept (25 mg)DMARD6 months1.06 MD -0.49
(-0.92 to -0.06)
-424
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.11% (95% CI -0.21% to -0.01%);

Relative percent change -46% (95% CI -87% to -5.7%)

12 months1.54 MD -0.74
(-1.35 to -0.13)
-832
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.17% (95% CI -0.30 to -0.03%);

Relative percent change -46.5% (95% CI -85% to -8.2%)

2 years3.34 MD -2.24
(-4.61 to 0.13)
-409
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.50% (95% CI -1.03% to 0.03%);

Relative percent change -67.1% (95% CI -138% to 3.89%)

3 years5.95 MD -4.34

(-7.56 to -1.12)
-421
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.97% (95% CI -1.69% to -0.25%);

Relative percent change -72.9% (95% CI -127.0% to -18.8%)









Etanercept (25 mg) + DMARDEtanercept 12 months0.33 MD -1.13
(-1.76 to -0.5)
-414
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.25% (95% CI-0.39% to -0.11%);

Relative percent change -342.4% (95% CI -533.3% to -151.5%)


2 years1.1 MD -1.66
(-2.76 to -0.56)
-416
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.37% (95% CI -0.62% to -0.13%);
Relative percent change -150.9% (95% CI -250.91% to -50.91%)

3 years1.61 MD -1.75
(-3.27 to -0.23)
-428
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.39% (95% CI -0.73% to -0.05%)
Relative percent change -108.7% (95% CI -203.11% to -14.29%)









No progression of joint damage - Total Sharp Score ≤ 0.5 at final visit

Etanercept (25 mg) + DMARDDMARD12 months579 per 1000799 per 1000
(730 to 875)
RR 1.38
(1.26 to 1.51)
906
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 22% (95% CI 16% to 28%);

Relative percent change 38% (95% CI 26% to 51%);

NNTB 5 (95% CI 4 to 7)

2 years623 per 1000816 per 1000
(735 to 903)
RR 1.31
(1.18 to 1.45)
601
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit 19% (95% CI 12% to 26%);

Relative percent change 31% (95% CI 18% to 45%);

NNTB 6 (95% CI 4 to 9)

3 years510 per 1000759 per 1000
(652 to 887)
RR 1.49
(1.28 to 1.74)
427
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 25% (95% CI 16% to 34%);

Relative percent change 49% (95% CI 28% to 74%);

NNTB 5 (95% CI 3 to 8)









Etanercept (25 mg)DMARD12 months571 per 1000679 per 1000
(588 to 788)
RR 1.19
(1.03 to 1.38)
424
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 11% (95% CI 2% to 20%);

Relative percent change 19% (95% CI 3% to 38%);

NNTB 10 (95% CI 59 to 5)

2 years602 per 1000680 per 1000
(590 to 789)
RR 1.13
(0.98 to 1.31)
409
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 8% (95% CI -1% to 17%);

Relative percent change 13% (95% CI -2% to 31%);

NNTB 13 (95% CI 6 to 84)

3 years510 per 1000611 per 1000
(515 to 724)
RR 1.2
(1.01 to 1.42)
421
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 10% (95% CI 1% to 20%);

Relative percent change 20% (95% CI 1% to 42%); NNTB 10 (95% CI 5 to 197)









Etanercept (25 mg) + DMARDEtanercept 12 months679 per 1000802 per 1000
(713 to 897)
RR 1.18
(1.05 to 1.32)
430
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 12% (95% CI 4% to 20%);

Relative percent change 18% (95% CI 5% to 32%);

NNTB 9 (95% CI 5 to 30)

2 years680 per 1000782 per 1000
(693 to 877)
RR 1.15
(1.02 to 1.29)
416
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 10% (95% CI 1% to 18%);

Relative percent change 15% (95% CI 2% to 29%);

NNTB 10 (95% CI 6 to 74)

3 years611 per 1000758 per 1000
(666 to 868)
RR 1.24
(1.09 to 1.42)
428
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 15% (95% CI 6% to 24%);

Relative percent change 24% (95% CI 9% to 42%);

NNTB 7 (95% CI 4 to 19)









Erosions - Change in Sharp Score (from baseline). Scale from: 0 to 280.

Etanercept (25 mg) + DMARDDMARD12 months0.99 MD -1.63
(-2.41 to -0.85)
-418
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.58% (95% CI -0.86% to -0.30%);

Relative percent change -164.65% (95% CI -243.43% to -85.86%)

2 years2.12 MD -2.88
(-4.39 to -1.37)
-419
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -1.03% (95% CI -1.57% to -0.49%);

Relative percent change -86.23% (95% CI -131.44% to -41.02%)

3 years3.25 MD -3.92
(-5.72 to -2.12)
-427
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -1.40% (95% CI -2.04% to -0.76%);

Relative percent change -120.62% (95% CI -176.00% to -65.23%)









Etanercept (10 mg)DMARD6 months0.68 MD -0.18
(-0.49 to 0.13)
-425
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.06% (95% CI -0.18% to 0.05%);

Relative percent change -26.47% (95% CI -72.06% to 19.1%);

NNTB not statistically significant

12 months1.03 MD -0.13
(-0.66 to 0.4)
-425
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.05% (95% CI -0.24% to 0.14%);

Relative percent change -12.62% (95% CI -64.08% to 38.8%);

NNTB not statistically significant









Etanercept (25 mg)DMARD6 months0.68 MD -0.38
(-0.66 to -0.1)
-424
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.14% (95% CI -0.24% to -0.04%);

Relative percent change -55.88% (95% CI -97.06% to -14.7%)

12 months1.0 MD -0.65
(-1.04 to 0.27)
-832
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.23% (95% CI -0.37% to 0.10%);

Relative percent change -65.00% (95% CI -104% to 27%)

2 years2.12 MD -1.76
(-3.34 to -0.18)
-409
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.63% (95% CI -1.19% to -0.06%);

Relative percent change -83.02% (95% CI -157.55% to -8.49%)

3 years3.25 MD -2.86
(-4.81 to -0.91)
-421
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -1.02% (95% CI -1.72% to -0.33%);

Relative percent change -88.00% (95% CI -148% to -28%)









Etanercept (25 mg) + DMARDEtanercept 12 months0.03 MD -0.67
(-1.12 to -0.22)
-414
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.24% (95% CI -0.40% to -0.08%);

Relative percent change -2233.33% (95% CI -3733.3% to -733.3%)

2 years0.36 MD -1.12
(-1.83 to -0.41)
-416
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.40% (95% CI -0.65% to -0.15%);

Relative percent change -311.11% (95% CI -508.3% to -113.89%)

3 years0.39 MD -1.06
(-1.98 to -0.14)
-428
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.38% (95% CI -0.71% to -0.05%);

Relative percent change -271.79% (95% CI -507.69% to -35.9%)









Joint space narrowing Score - change in Total Sharp Score (from baseline). Scale from: 0 to 168

Etanercept (25 mg) + DMARDDMARD12 months0.51 MD -0.67
(-1.12 to -0.22)
-418
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.40% (95% CI -0.67% to -0.13%);

Relative percent change -131.37% (95% CI -219.61% to -43.14%)

2 years1.23 MD -1.03
(-1.89 to 0.17)
-419
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.61% (95% CI -1.13% to 0.10%);

Relative percent change -83.74% (95% CI -153.66% to 13.82%)

3 years2.7 MD -2.17
(-3.78 to -0.56)
-427
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -1.29% (95% CI -2.25 to -0.33%);

Relative percent change -80.37% (95% CI -140.00% to -20.7%)









Etanercept (10 mg)DMARD6 months0.38 MD -0.07
(-0.35 to 0.21)
-425
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.04% (95% CI -0.21% to 0.13%);

Relative percent change -18.42% (95% CI -92.11% to 55.26%)

12 months0.56 MD 0.09
(-0.42 to 0.6)
-425
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit 0.05% (95% CI -0.25% to 0.36%);

Relative percent change 16.07% (95% CI -75.00% to 107.1%)









Etanercept (25 mg)DMARD6 months0.38 MD -0.11
(-0.35 to 0.13)
-424
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.07% (95% CI -0.21% to 0.08%);

Relative percent change -28.95% (95% CI -92.11% to 34.2%)

12 months0.53 MD -0.11
(-0.43 to 0.2)
-832
(2 studies)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.07% (95% CI -0.26% to 0.12%);

Relative percent change -20.75% (95% CI -81.13% to 37.7%)

2 years1.23 MD -0.49
(-1.46 to 0.48)
-409
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.29% (95% CI -0.87% to 0.29%);

Relative percent change -39.84% (95% CI -118.70% to 39%)

3 years2.7 MD -1.48
(-3.04 to 0.08)
-421
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.88% (95% CI -1.81% to 0.05%);

Relative percent change -54.81% (95% CI -112.59% to 2.96%)









Etanercept (25 mg) + DMARDEtanercept 12 months0.3 MD -0.46
(-0.74 to -0.18)
-414
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.27% (95% CI -0.44% to -0.11%);

Relative percent change -153.33% (95% CI -246.67% to -60%)

2 years0.74 MD -0.54
(-1.09 to 0.01)
-416
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.32% (95% CI -0.65% to 0.01%);

Relative percent change -72.97% (95% CI -147.30% to 1.35%)

3 years1.22 MD -0.69
(-1.65 to 0.27)
-428
(1 study)
⊕⊕⊕⊕
high
Absolute treatment benefit -0.41% (95% CI -0.98% to 0.16%);

Relative percent change -56.56% (95% CI -135.25% to 22%)









*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; DMARD: disease-modifying anti-rheumatic drug; MD: mean difference; N/A: not available; NNTB: number needed to treat for an additional beneficial outcome; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 
Table 1. Subgroups - study characteristics

StudyFollow-up (weeks)nGroup 1Group 2Group 3Group 4Group 5Disease durationEligibilityPreviously treated with

Bathon 2000 (ERA)52632ET 10 mgET 25 mg--PBO< 3 yearsMTX-naiveDMARDs

Combe 2006104254-ET 25 mgET 25 mg + SSZSSZ-< 20 years-SSZ

Emery 2008 (COMET)104542--ET 25 mg + MTXMTX-< 2 yearsMTX-naiveDMARDs (4 weeks prior enrolment)

Hu 200924238-ET 25 mg-MTX-NS (mean 7.7 years)-DMARDs

Kameda 2010104151-ET 25 mgET 25 mg + MTX--NS (but subgroups by < 10 and > 10 years)-MTX

Klareskog 2004 (TEMPO)156686-ET 25 mgET 25 mg + MTXMTX-< 20 yearsno MTX 6 months prior enrolmentDMARDs

Marcora 20062426-ET 25 mg-MTX-< 6 monthsDMARDs-naive

Moreland 199926234ET 10 mgET 25 mg--PBONS (mean 12 years)-DMARDs

Weinblatt 19992489--ET 25 mg + MTXMTX-NS (mean 13 years)-MTX

 DMARD: disease-modifying anti-rheumatic drug; ET: etanercept; MTX: methotrexate; NS: not stated; PBO: placebo; SSZ: sulphasalazine.