Certolizumab pegol (CDP870) for rheumatoid arthritis in adults

Vicente Ruiz Garcia; Amanda Burls; Juan B Cabello; Paloma Vela Casasempere; Sylvia Bort‐Marti; José A Bernal

doi:10.1002/14651858.CD007649.pub4

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Figure 1

Update:

Records identified through the databases: (n = 559)

Additional records identified through other sources (Clinicaltrials.gov, ICRTP)
(n = 98)

Flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison 49: Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), outcome: 49.8 Deaths.

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Analysis 1.1

Comparison 1 Efficacy at 12 weeks, any dose, Outcome 1 ACR20.

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Analysis 1.2

Comparison 1 Efficacy at 12 weeks, any dose, Outcome 2 ACR50.

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Analysis 1.3

Comparison 1 Efficacy at 12 weeks, any dose, Outcome 3 ACR70.

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Analysis 2.1

Comparison 2 ACR50 24 weeks, 200 mg certolizumab pegol, Outcome 1 ACR 50.

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Analysis 3.1

Comparison 3 ACR50 at 24 weeks, 400 mg certolizumab, Outcome 1 ACR 50.

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Analysis 4.1

Comparison 4 ACR50 at 52 weeks, 200 mg certolizumab, Outcome 1 ACR 50.

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Analysis 5.1

Comparison 5 ACR50 at 52 weeks, 400 mg certolizumab, Outcome 1 ACR 50.

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Analysis 6.1

Comparison 6 Mean HAQ‐DI from baseline at week 12, Outcome 1 certolizumab pegol 200 mg sc.

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Analysis 7.1

Comparison 7 Mean HAQ‐DI from baseline at week 24, Outcome 1 certolizumab pegol 200 mg sc.

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Analysis 7.2

Comparison 7 Mean HAQ‐DI from baseline at week 24, Outcome 2 certolizumab 400 mg sc.

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Analysis 8.1

Comparison 8 HAQ‐DI at 24 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 9.1

Comparison 9 HAQ‐DI at 52 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 10.1

Comparison 10 SF‐36 Physical Component Summary (PCS), week 24, Outcome 1 certolizumab pegol 200 mg sc.

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Analysis 10.2

Comparison 10 SF‐36 Physical Component Summary (PCS), week 24, Outcome 2 certolizumab pegol 400 mg sc.

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Analysis 11.1

Comparison 11 SF‐36 Mental Component Summary (MCS), week 24, Outcome 1 certolizumab pegol 200 mg sc.

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Analysis 11.2

Comparison 11 SF‐36 Mental Component Summary (MCS), week 24, Outcome 2 certolizumab pegol 400 mg sc.

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Analysis 12.1

Comparison 12 SF‐36 Physical Component Summary (PCS), week 52, Outcome 1 certolizumab 200 mg sc.

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Analysis 12.2

Comparison 12 SF‐36 Physical Component Summary (PCS), week 52, Outcome 2 certolizumab 400 mg sc.

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Analysis 13.1

Comparison 13 SF‐36 Mental Component Summary (MCS), week 52, Outcome 1 certolizumab pegol 200 mg sc.

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Analysis 13.2

Comparison 13 SF‐36 Mental Component Summary (MCS), week 52, Outcome 2 certolizumab pegol 400 mg sc.

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Analysis 14.1

Comparison 14 SF‐36 Physical Component Summary (PCS) at week 24, any dose, Outcome 1 Change from baseline.

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Analysis 15.1

Comparison 15 SF‐36 Mental Component Summary (MCS) at week 24, any dose, Outcome 1 Change from baseline.

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Analysis 16.1

Comparison 16 SF‐36 Physical Component Summary (PCS) at week 52, any dose, Outcome 1 Change from baseline.

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Analysis 17.1

Comparison 17 SF‐36 Mental Component Summary (MCS) at week 52, any dose, Outcome 1 Change from baseline.

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Analysis 18.1

Comparison 18 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any doses, 12 weeks, Outcome 1 Proportion of participants achieving remission 12 weeks certolizumab 200 mg.

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Analysis 19.1

Comparison 19 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any dose, 24 weeks, Outcome 1 Proportion of participants achieving remission 24 weeks.

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Analysis 20.1

Comparison 20 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any dose, 52 weeks, Outcome 1 Proportion of participants achieving remission 52 weeks.

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Analysis 21.1

Comparison 21 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time, Outcome 1 Proportion of participants achieving remission 12 weeks certolizumab 200 mg.

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Analysis 21.2

Comparison 21 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time, Outcome 2 Proportion of participants achieving remission 24 weeks certolizumab 200 mg.

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Analysis 21.3

Comparison 21 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time, Outcome 3 Proportion of participants achieving remission 24 weeks certolizumab 400 mg.

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Analysis 21.4

Comparison 21 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time, Outcome 4 Proportion of participants achieving remission 52 weeks certolizumab 200 mg.

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Analysis 21.5

Comparison 21 Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time, Outcome 5 Proportion of participants achieving remission 52 weeks certolizumab 400 mg.

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Analysis 22.1

Comparison 22 DAS‐28 at 12 weeks, 200 mg certolizumab, Outcome 1 DAS 28 (ESR) change from baseline.

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Analysis 23.1

Comparison 23 DAS‐28 at 24 weeks, 400 mg certolizumab, Outcome 1 DAS 28 (ESR) change from baseline.

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Analysis 24.1

Comparison 24 DAS‐28 at week 52, certolizumab 200 mg, Outcome 1 DAS 28 (ESR) Change from baseline.

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Analysis 25.1

Comparison 25 DAS‐28 at week 52, certolizumab 400 mg, Outcome 1 DAS 28 (ESR) Change from baseline.

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Analysis 26.1

Comparison 26 DAS‐28 at 24 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 27.1

Comparison 27 DAS‐28 at 52 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 28.1

Comparison 28 DAS‐28 at 24 weeks, 200 mg certolizumab, Outcome 1 DAS 28 (ESR) change from baseline.

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Analysis 29.1

Comparison 29 Erosion score (ES), Outcome 1 Change from the baseline mean ES at week 24, certolizumab pegol 200 mg.

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Analysis 29.2

Comparison 29 Erosion score (ES), Outcome 2 Change from the baseline mean ES at week 24, certolizumab pegol 400 mg.

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Analysis 29.3

Comparison 29 Erosion score (ES), Outcome 3 Change from the baseline mean ES at week 52, certolizumab pegol 200 mg.

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Analysis 29.4

Comparison 29 Erosion score (ES), Outcome 4 Change from the baseline mean ES at week 52, certolizumab pegol 400 mg.

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Analysis 30.1

Comparison 30 Erosion score (ES) at 24 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 31.1

Comparison 31 Erosion score (ES) at 52 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 32.1

Comparison 32 Joint space narrowing (JSN), Outcome 1 Change from the baseline mean JSN 24 weeks, certolizumab pegol 200 mg.

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Analysis 32.2

Comparison 32 Joint space narrowing (JSN), Outcome 2 Change from the baseline mean JSN 24 weeks,certolizumab pegol 400 mg.

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Analysis 32.3

Comparison 32 Joint space narrowing (JSN), Outcome 3 Change from the baseline mean JSN 52 weeks,certolizumab pegol 200 mg.

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Analysis 32.4

Comparison 32 Joint space narrowing (JSN), Outcome 4 Change from the baseline mean JSN 52 weeks, certolizumab pegol 400 mg.

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Analysis 33.1

Comparison 33 Joint space narrowing (JSN) at 24 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 34.1

Comparison 34 Joint space narrowing (JSN) at 52 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 35.1

Comparison 35 Modified Total Sharp Scores (mTSS) at 24 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 36.1

Comparison 36 Modified Total Sharp Scores (mTSS) at 52 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 37.1

Comparison 37 Modified total Sharp scores (mTSS), Outcome 1 Change from the baseline mean mTSS 24 weeks, certolizumab pegol 200 mg.

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Analysis 37.2

Comparison 37 Modified total Sharp scores (mTSS), Outcome 2 Change from the baseline mean mTSS 24 weeks, certolizumab 400 mg.

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Analysis 37.3

Comparison 37 Modified total Sharp scores (mTSS), Outcome 3 Change from the baseline mean mTSS 52 weeks, certolizumab pegol 200 mg.

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Analysis 37.4

Comparison 37 Modified total Sharp scores (mTSS), Outcome 4 Change from the baseline mean mTSS 52 weeks, certolizumab pegol 400 mg.

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Analysis 38.1

Comparison 38 Certolizumab pegol 1mg/kg/day sc, Outcome 1 Headache.

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Analysis 38.2

Comparison 38 Certolizumab pegol 1mg/kg/day sc, Outcome 2 Lower respiratory tract infection.

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Analysis 38.3

Comparison 38 Certolizumab pegol 1mg/kg/day sc, Outcome 3 Adverse events Intensity severe.

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Analysis 38.4

Comparison 38 Certolizumab pegol 1mg/kg/day sc, Outcome 4 Antinuclear antibodies (ANA).

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Analysis 38.5

Comparison 38 Certolizumab pegol 1mg/kg/day sc, Outcome 5 Urinary tract infection.

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Analysis 39.1

Comparison 39 Certolizumab 5 mg/kg/day sc, Outcome 1 Lower respiratory tract infection.

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Analysis 39.2

Comparison 39 Certolizumab 5 mg/kg/day sc, Outcome 2 Urinary tract infection.

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Analysis 40.1

Comparison 40 Certolizumab 20 mg/kg/day sc, Outcome 1 Headache.

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Analysis 40.2

Comparison 40 Certolizumab 20 mg/kg/day sc, Outcome 2 Lower respiratory tract infection.

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Analysis 40.3

Comparison 40 Certolizumab 20 mg/kg/day sc, Outcome 3 Death.

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Analysis 40.4

Comparison 40 Certolizumab 20 mg/kg/day sc, Outcome 4 Antinuclear antibodies (ANA).

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Analysis 40.5

Comparison 40 Certolizumab 20 mg/kg/day sc, Outcome 5 Urinary tract infection.

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Analysis 41.1

Comparison 41 Safety, SAE certolizumab 200 mg, Outcome 1 Serious Adverse Events (SAE).

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Analysis 42.1

Comparison 42 Safety, SAE certolizumab 400 mg, Outcome 1 Serious Adverse Events (SAEs).

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Analysis 43.1

Comparison 43 Withdrawals, Outcome 1 All Withdrawn: any doses any follow‐up.

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Analysis 43.2

Comparison 43 Withdrawals, Outcome 2 Withdrawals due to adverse events.

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Analysis 44.1

Comparison 44 ACR at 24 weeks, any dose, Outcome 1 ACR20.

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Analysis 44.2

Comparison 44 ACR at 24 weeks, any dose, Outcome 2 ACR50.

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Analysis 44.3

Comparison 44 ACR at 24 weeks, any dose, Outcome 3 ACR70.

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Analysis 45.1

Comparison 45 ACR at 52 weeks, any dose, Outcome 1 ACR20.

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Analysis 45.2

Comparison 45 ACR at 52 weeks, any dose, Outcome 2 ACR50.

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Analysis 45.3

Comparison 45 ACR at 52 weeks, any dose, Outcome 3 ACR70.

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Analysis 46.1

Comparison 46 ACR20‐ACR70, 24 weeks, 200 mg certolizumab pegol, Outcome 1 ACR 20.

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Analysis 46.2

Comparison 46 ACR20‐ACR70, 24 weeks, 200 mg certolizumab pegol, Outcome 2 ACR 70.

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Analysis 47.1

Comparison 47 ACR20‐ACR70 at 24 weeks, 400 mg certolizumab, Outcome 1 ACR 20.

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Analysis 47.2

Comparison 47 ACR20‐ACR70 at 24 weeks, 400 mg certolizumab, Outcome 2 ACR 70.

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Analysis 48.1

Comparison 48 ACR20‐ACR70 at 52 weeks, 200 mg certolizumab, Outcome 1 ACR 20.

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Analysis 48.2

Comparison 48 ACR20‐ACR70 at 52 weeks, 200 mg certolizumab, Outcome 2 ACR 70.

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Analysis 49.1

Comparison 49 ACR20‐ACR70 at 52 weeks, 400 mg certolizumab, Outcome 1 ACR 20.

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Analysis 49.2

Comparison 49 ACR20‐ACR70 at 52 weeks, 400 mg certolizumab, Outcome 2 ACR 70.

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Analysis 50.1

Comparison 50 Safety, Outcome 1 Any adverse event certolizumab 200 mg.

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Analysis 50.2

Comparison 50 Safety, Outcome 2 Any adverse events certolizumab 400 mg.

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Analysis 50.3

Comparison 50 Safety, Outcome 3 Adverse events: Intensity mild certolizumab 200 mg.

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Analysis 50.4

Comparison 50 Safety, Outcome 4 Adverse events: Intensity mild certolizumab 400 mg.

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Analysis 50.5

Comparison 50 Safety, Outcome 5 Adverse events: Intensity moderate certolizumab 200 mg.

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Analysis 50.6

Comparison 50 Safety, Outcome 6 Adverse events: Intensity moderate certolizumab 400 mg.

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Analysis 50.7

Comparison 50 Safety, Outcome 7 Adverse events: Intensity severe certolizumab 200 mg.

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Analysis 50.8

Comparison 50 Safety, Outcome 8 Adverse events: Intensity severe certolizumab 400 mg.

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Analysis 50.9

Comparison 50 Safety, Outcome 9 Adverse events related to study drug certolizumab 200 mg.

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Analysis 50.10

Comparison 50 Safety, Outcome 10 Adverse events related to study drug certolizumab 400 mg.

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Analysis 50.11

Comparison 50 Safety, Outcome 11 Serious Infections certolizumab 200 mg.

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Analysis 50.12

Comparison 50 Safety, Outcome 12 Serious infections certolizumab 400 mg.

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Analysis 50.13

Comparison 50 Safety, Outcome 13 Adverse events leading to death certolizumab 200 mg.

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Analysis 50.14

Comparison 50 Safety, Outcome 14 Adverse events leading to death certolizumab 400 mg.

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Analysis 50.15

Comparison 50 Safety, Outcome 15 Adverse events leading to withdrawal certolizumab 200 mg.

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Analysis 50.16

Comparison 50 Safety, Outcome 16 Adverse events leading to withdrawal certolizumab 400 mg.

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Analysis 50.17

Comparison 50 Safety, Outcome 17 Death certolizumab 200 mg.

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Analysis 50.18

Comparison 50 Safety, Outcome 18 Death certolizumab 400 mg.

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Analysis 50.19

Comparison 50 Safety, Outcome 19 Deaths overall.

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Analysis 50.20

Comparison 50 Safety, Outcome 20 Tuberculosis certolizumab 200 mg.

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Analysis 50.21

Comparison 50 Safety, Outcome 21 Tuberculosis certolizumab 400 mg.

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Analysis 50.22

Comparison 50 Safety, Outcome 22 Tuberculosis overall.

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Analysis 50.23

Comparison 50 Safety, Outcome 23 Malignancies included lymphoma certolizumab 200 mg.

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Analysis 50.24

Comparison 50 Safety, Outcome 24 Malignancies included lymphoma certolizumab 400 mg.

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Analysis 50.25

Comparison 50 Safety, Outcome 25 Injection side reactions certolizumab 200 mg.

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Analysis 50.26

Comparison 50 Safety, Outcome 26 Injection side reactions certolizumab 400 mg.

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Analysis 50.27

Comparison 50 Safety, Outcome 27 Antinuclear antibodies (ANA) Anti‐certolizumab pegol antibodies certolizumab 200 mg.

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Analysis 50.28

Comparison 50 Safety, Outcome 28 Anti‐certolizumab pegol antibodies certolizumab 400 mg.

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Analysis 50.29

Comparison 50 Safety, Outcome 29 Systemic lupus erythematosus certolizumab 200 mg.

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Analysis 50.30

Comparison 50 Safety, Outcome 30 Prolonged activated partial thromboplastin time (aPTT) certolizumab 200 mg.

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Analysis 50.31

Comparison 50 Safety, Outcome 31 Prolonged activated partial thromboplastin time (aPTT) certolizumab 400 mg.

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Analysis 50.32

Comparison 50 Safety, Outcome 32 Urinary tract infection certolizumab 200 mg.

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Analysis 50.33

Comparison 50 Safety, Outcome 33 Urinary tract infection certolizumab 400 mg.

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Analysis 50.34

Comparison 50 Safety, Outcome 34 Upper respiratory tract infection certolizumab 200 mg.

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Analysis 50.35

Comparison 50 Safety, Outcome 35 Upper respiratory tract infection certolizumab 400 mg.

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Analysis 50.36

Comparison 50 Safety, Outcome 36 Lower respiratory tract infection/ lung infection certolizumab 200 mg.

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Analysis 50.37

Comparison 50 Safety, Outcome 37 Lower respiratory tract infection/ lung infection certolizumab 400 mg.

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Analysis 50.38

Comparison 50 Safety, Outcome 38 Pneumonia certolizumab 200 mg.

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Analysis 50.39

Comparison 50 Safety, Outcome 39 Pneumonitis certolizumab 400 mg.

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Analysis 50.40

Comparison 50 Safety, Outcome 40 Headache certolizumab 200 mg.

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Analysis 50.41

Comparison 50 Safety, Outcome 41 Headache certolizumab 400 mg.

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Analysis 50.42

Comparison 50 Safety, Outcome 42 Bacteriuria certolizumab 200 mg.

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Analysis 50.43

Comparison 50 Safety, Outcome 43 Bacteriuria certolizumab 400 mg.

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Analysis 50.44

Comparison 50 Safety, Outcome 44 Nasopharyngitis/Pharyngitis certolizumab 200 mg.

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Analysis 50.45

Comparison 50 Safety, Outcome 45 Nasopharyngitis/Pharyngitis certolizumab 400 mg.

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Analysis 50.46

Comparison 50 Safety, Outcome 46 Injection site pain certolizumab 200 mg.

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Analysis 50.47

Comparison 50 Safety, Outcome 47 Injection site pain certolizumab 400 mg.

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Analysis 50.48

Comparison 50 Safety, Outcome 48 Hypertension certolizumab 200 mg.

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Analysis 50.49

Comparison 50 Safety, Outcome 49 Hypertension certolizumab 400 mg.

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Analysis 50.50

Comparison 50 Safety, Outcome 50 Hematuria certolizumab 200 mg.

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Analysis 50.51

Comparison 50 Safety, Outcome 51 Haematuria certolizumab 400 mg.

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Analysis 50.52

Comparison 50 Safety, Outcome 52 Hepatic enzyme increased certolizumab 200 mg.

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Analysis 50.53

Comparison 50 Safety, Outcome 53 Hepatic enzyme increased certolizumab 400 mg.

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Analysis 50.54

Comparison 50 Safety, Outcome 54 AST increased certolizumab 200 mg.

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Analysis 50.55

Comparison 50 Safety, Outcome 55 AST increased certolizumab 400 mg.

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Analysis 50.56

Comparison 50 Safety, Outcome 56 ALT increased certolizumab 200 mg.

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Analysis 50.57

Comparison 50 Safety, Outcome 57 ALT increased certolizumab 400 mg.

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Analysis 50.58

Comparison 50 Safety, Outcome 58 Diarrhoea certolizumab 200 mg.

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Analysis 50.59

Comparison 50 Safety, Outcome 59 Gastroenteritis certolizumab 200 mg.

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Analysis 50.60

Comparison 50 Safety, Outcome 60 Gastrointestinal disorders certolizumab 400 mg.

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Analysis 50.61

Comparison 50 Safety, Outcome 61 Back pain certolizumab 200 mg.

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Analysis 50.62

Comparison 50 Safety, Outcome 62 Back pain certolizumab 400 mg.

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Analysis 50.63

Comparison 50 Safety, Outcome 63 Hematologic abnormalities certolizumab 200 mg.

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Analysis 50.64

Comparison 50 Safety, Outcome 64 Haematologic abnormalities certolizumab 400 mg.

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Analysis 50.65

Comparison 50 Safety, Outcome 65 Herpes viral infection certolizumab 200 mg.

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Analysis 50.66

Comparison 50 Safety, Outcome 66 Herpes viral infection certolizumab 400 mg.

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Analysis 50.67

Comparison 50 Safety, Outcome 67 Bacterial peritonitis certolizumab 200 mg.

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Analysis 50.68

Comparison 50 Safety, Outcome 68 Bacterial peritonitis certolizumab 400 mg.

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Analysis 50.69

Comparison 50 Safety, Outcome 69 Opportunistic infections certolizumab 200 mg.

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Analysis 50.70

Comparison 50 Safety, Outcome 70 Opportunistic infections certolizumab 400 mg.

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Analysis 50.71

Comparison 50 Safety, Outcome 71 Infections and infestations certolizumab 200 mg.

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Analysis 50.72

Comparison 50 Safety, Outcome 72 Infections and infestations certolizumab 400 mg.

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Analysis 50.73

Comparison 50 Safety, Outcome 73 Decreased haemoglobin certolizumab 200 mg.

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Analysis 50.74

Comparison 50 Safety, Outcome 74 Decreased haemoglobin certolizumab 400 mg.

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Analysis 50.75

Comparison 50 Safety, Outcome 75 Increased platelet count certolizumab 200 mg.

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Analysis 50.76

Comparison 50 Safety, Outcome 76 Increased platelet count certolizumab 400 mg.

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Analysis 50.77

Comparison 50 Safety, Outcome 77 Cerebral haemorrhage including subarachnoid certolizumab 200 mg.

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Analysis 50.78

Comparison 50 Safety, Outcome 78 Ischaemic stroke certolizumab 400 mg.

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Analysis 50.79

Comparison 50 Safety, Outcome 79 Nausea/vomiting certolizumab 200 mg.

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Analysis 50.80

Comparison 50 Safety, Outcome 80 Vomiting certolizumab 400 mg.

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Analysis 50.81

Comparison 50 Safety, Outcome 81 Acute miocardial infarction certolizumab 200 mg.

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Analysis 50.82

Comparison 50 Safety, Outcome 82 Acute myocardial infarction certolizumab 400 mg.

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Analysis 50.83

Comparison 50 Safety, Outcome 83 Abdominal pain/discomfort/dyspepsia certolizumab 200 mg.

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Analysis 50.84

Comparison 50 Safety, Outcome 84 Constipation certolizumab 200 mg.

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Analysis 50.85

Comparison 50 Safety, Outcome 85 Skin and subcutaneous tissue disorders certolizumab 200 mg.

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Analysis 50.86

Comparison 50 Safety, Outcome 86 Skin and subcutaneous tissue disorders certolizumab 400 mg.

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Analysis 50.87

Comparison 50 Safety, Outcome 87 Cough certolizumab 200 mg.

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Analysis 50.88

Comparison 50 Safety, Outcome 88 Pruritus certolizumab 200 mg.

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Analysis 50.89

Comparison 50 Safety, Outcome 89 Fatigue certolizumab 200 mg.

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Analysis 50.90

Comparison 50 Safety, Outcome 90 Fatigue certolizumab 400 mg.

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Analysis 50.91

Comparison 50 Safety, Outcome 91 Periodontitis certolizumab 200 mg.

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Analysis 50.92

Comparison 50 Safety, Outcome 92 Arthritis bacterial certolizumab 400 mg.

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Analysis 50.93

Comparison 50 Safety, Outcome 93 Mastitis certolizumab 400 mg.

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Analysis 50.94

Comparison 50 Safety, Outcome 94 Benign tumour certolizumab 400 mg.

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Analysis 50.95

Comparison 50 Safety, Outcome 95 Dizziness postural certolizumab 400 mg.

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Analysis 50.96

Comparison 50 Safety, Outcome 96 Menorrhagia certolizumab 400 mg.

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Analysis 50.97

Comparison 50 Safety, Outcome 97 Corneal perforation certolizumab 400 mg.

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Analysis 50.98

Comparison 50 Safety, Outcome 98 Conjunctivitis allergic certolizumab 400 mg.

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Analysis 50.99

Comparison 50 Safety, Outcome 99 Periodontitis certolizumab 400 mg.

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Analysis 51.1

Comparison 51 Participant's assessment of arthritis pain (VAS score 0 to 100 mm), Outcome 1 Mean change at 24 weeks certolizumab pegol 200 mg.

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Analysis 51.2

Comparison 51 Participant's assessment of arthritis pain (VAS score 0 to 100 mm), Outcome 2 Mean change at 24 weeks certolizumab pegol 400 mg.

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Analysis 51.3

Comparison 51 Participant's assessment of arthritis pain (VAS score 0 to 100 mm), Outcome 3 Mean change at 52 weeks certolizumab pegol 200 mg.

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Analysis 51.4

Comparison 51 Participant's assessment of arthritis pain (VAS score 0 to 100 mm), Outcome 4 Mean change at 52 weeks certolizumab pegol 400 mg.

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Analysis 52.1

Comparison 52 Participant's assessment of arthritis pain (VAS score 0 to 100 mm) at 24 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 53.1

Comparison 53 Participant's assessment of arthritis pain (VAS score 0 to 100 mm) at 52 weeks, any dose, Outcome 1 Change from baseline.

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Analysis 54.1

Comparison 54 Withdrawals Withdrawn due to lack of efficacy: any doses any follow‐up, Outcome 1 Withdrawn due to lack of efficacy: any doses any follow‐up.

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Analysis 55.1

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 1 ACR 50 200 mg certolizumab 24 weeks.

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Analysis 55.2

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 2 HAQ change from baseline 200 mg certolizumab 24 weeks.

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Analysis 55.3

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 3 Serious adverse events certolizumab 200 mg sc.

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Analysis 55.4

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 4 Proportion of participants achieving remission 24 weeks certolizumab 200 mg.

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Analysis 55.5

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 5 Radiological changes: Erosion Scores (ES) certolizumab 200 mg sc.

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Analysis 55.6

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 6 All Withdrawals:.

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Analysis 55.7

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 7 Withdrawals due to adverse events.

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Analysis 55.8

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 8 Deaths.

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Analysis 55.9

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 9 Tuberculosis.

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Analysis 55.10

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 10 Upper respiratory tract infections.

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Analysis 55.11

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 11 Lower respiratory tract infections.

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Analysis 55.12

Comparison 55 Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX), Outcome 12 Malignancies including lymphoma.

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Analysis 56.1

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 1 Doses.

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Analysis 56.2

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 2 Size.

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Analysis 56.3

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 3 Use of MTX.

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Analysis 56.4

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 4 Population.

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Analysis 56.5

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 5 Duration of previous disease.

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Analysis 56.6

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 6 Published vs unpublished studies.

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Analysis 56.7

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 7 Imputing to ACR50 200 mg from 24 missing values with same proportion as reported outcomes.

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Analysis 56.8

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 8 Imputing to ACR50 200 mg from 24 weeks 50 % of missing outcomes.

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Analysis 56.9

Comparison 56 Analysis of sensitivity ACR50 24 weeks, Outcome 9 Imputing to ACR50 200 mg from 24 weeks: the worst case.

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Analysis 57.1

Comparison 57 Analysis of sensitivity ACR50 52 weeks, Outcome 1 Doses.

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Analysis 57.2

Comparison 57 Analysis of sensitivity ACR50 52 weeks, Outcome 2 Size.

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Analysis 57.3

Comparison 57 Analysis of sensitivity ACR50 52 weeks, Outcome 3 Use of MTX.

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Analysis 57.4

Comparison 57 Analysis of sensitivity ACR50 52 weeks, Outcome 4 Population.

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Analysis 57.5

Comparison 57 Analysis of sensitivity ACR50 52 weeks, Outcome 5 Duration of previous disease.

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Summary of findings for the main comparison. Certolizumab pegol 200 mg sc (with or without MTX) versus placebo (with or without MTX) for rheumatoid arthritis in adults

Certolizumab pegol 200 mg sc (with or without MTX) versus placebo (with or without MTX) for rheumatoid arthritis in adults
Patient or population: patients with rheumatoid arthritis in adults Settings: adults (18 years old or more) who have persistent disease activity Intervention: certolizumab pegol 200 mg sc (with or without MTX) versus placebo (with or without MTX)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Summary of findings certolizumab pegol 200 mg sc (with or without MTX) versus placebo (with or without MTX)
ACR 50% improvement Follow‐up: mean 24 weeks 200 mg sc certolizumab pegol	87 per 1000	359 per 1000 (328 to 391)	RR 3.80 (2.42 to 5.95)	1445 (5 studies)	⊕⊕⊕⊕ high	Absolute risk difference = 25% (95% CI 20% to 33%). Relative per cent change = 280% (142% to 495%). NNTB = 4 (3 to 5)
HAQ change from baseline Scale from: 0 to 3. Follow‐up: mean 24 weeks (lower scores means better function) 200 mg sc certolizumab pegol	The mean HAQ change from baseline in the control groups was ‐0.13	The mean HAQ change from baseline in the intervention groups was 0.35 lower (0.43 to 0.26 lower)	MD ‐0.35 (‐0.43 to ‐0.26)	1268 (4 studies)	⊕⊕⊕⊝ moderate¹	Absolute risk difference = ‐12% (95% CI ‐9% to ‐14%). Relative per cent change = ‐21% (‐15% to ‐25%). NNT = 8 (7 to 11)
Proportion of patients achieving DAS < 2.6 (remission) Follow‐up: mean 24 weeks 200 mg sc certolizumab pegol	123 per 1000	216 per 1000 (194 to 247)	RR 2.94 (1.64 to 5.28)	2420 (6 studies)	⊕⊕⊕⊕ high	Absolute risk difference = 10% (95% CI 8% to 16%). Relative per cent change = 194% (64% to 428%) NNT = 8 (6 to 12)
Radiological changes: Erosion Scores (ES) Scale from: 0 to 230 Follow‐up: 24 weeks 200 mg sc certolizumab pegol	The mean radiological changes: Erosion Scores (ES) in the control groups was 0.7	The mean Radiological changes: Erosion Scores (ES) in the intervention groups was 0.67 lower (0.96 to 0.38 lower)	MD ‐0.67 (‐0.96 to ‐0.28)	714 (2 studies)	⊕⊕⊕⊝ moderate¹	Absolute risk difference = ‐0.29% (95% CI ‐0.42% to ‐0.17%). Relative per cent change = ‐ 2.90% (‐4.16% to ‐1.65%) NNT = 6 (4 to 10)
Serious adverse events Follow‐up: 12 to 24 weeks 200 mg sc certolizumab pegol	58 per 1000	85 per 1000 (59 to 120)	Peto OR 1.47 (1.13 to 1.91)	3927 (9 studies)	⊕⊕⊕⊕ high	Absolute risk difference = 3% (95% CI 1% to 4%). Relative per cent change = 47% (13% to 91%). NNTH = 33 (25 to 100)
All Withdrawals: All doses of certolizumab pegol vs placebo Follow‐up: 0 to 52 weeks	524 per 1000	231 per 1000 (203 to 291)	RR 0.47 (0.39 to 0.56)	5200 (13 studies)	⊕⊕⊕⊝ moderate²	Absolute risk difference = ‐29% (95% CI ‐16% to ‐42%). Relative per cent change= ‐53% (‐44% to ‐61%). NNTH = 3 (2 to 6)
Withdrawals due to adverse events All doses of certolizumab pegol versus placebo Follow‐up: 0 to 52 weeks	38 per 1000	52 per 1000 (40 to 73)	Peto OR 1.45 (1.09 to 1.94)	5236 (12 studies)	⊕⊕⊕⊕ high	Absolute risk difference = 2% (95% CI 0% to 3%). Relative per cent change = 45% (9% to 94%). NNTH = 58 (28 to 329)
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; RR: Risk ratio; OR: Odds ratio; NNTB: number needed to treat for an additional beneficial outcome
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.
¹We downgraded the quality of evidence by one level for risk of bias due to attrition bias analysed per protocol. We have rated all the trials at low risk for attrition bias since reasons for attrition/exclusions were reported in most of them, and reasons were similar. However, for HAQ‐DI and radiological changes we can only conduct a per protocol analysis, as these are continuous outcomes that count the average number of participants still in the trials. For DAS remission, ACR50, SAEs, all withdrawals and withdrawals due to AEs we conducted an ITT analysis, which is a more conservative approach, not requiring downgrading. ²We downgraded the quality of evidence by one level for inconsistency, due to heterogeneity (not all the confidence intervals overlap, and I² is 79% ).

Summary of findings for the main comparison. Certolizumab pegol 200 mg sc (with or without MTX) versus placebo (with or without MTX) for rheumatoid arthritis in adults

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Table 1. Contribution of trials

	Update 2014		Update 2016
	Benefit (B)	Harm (H)	Benefit (B)	Harm (H)
Atsumi 2016	‐	‐	B	H
CDP870‐004 2001	B	H	B	‐
Choy 2002	‐	H	‐	H
Choy 2012	B	H	B	H
Emery 2015	‐	‐	B	H
Fleischmann 2009	B	H	B	H
Keystone 2008	B	H	B	H
NCT00993317	B	H	B	H
Smolen 2009	B	H	B	H
Smolen 2015	B	H	B	H
Weinblatt 2012	B	H	B	H
Yamamoto (a) 2014	B	H	B	H
Yamamoto (b) 2014	B	H	B	H
Østergaard 2015	‐	‐	‐	H
Total trials	10	11	12	14
Total pooled	9	9	11	13
The data from the two phase II studies (CDP870‐004 2001; Choy 2002) were not pooled with the rest of the studies due to the different follow‐ups and doses used.

Table 1. Contribution of trials

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Table 2. Demographic and disease characteristics of the included Phase III trials

Study

Atsumi 2016

n = 319

Choy 2012n = 247

Emery 2015 n = 879

Fleischmann 2009n = 220

Keystone 2008n = 982

NCT00993317 n = 127

Smolen 2009 n = 619

Smolen 2015n = 194

Weinblatt 2012n = 1063

Yamamoto (a) 2014n = 230

Yamamoto (b) 2014n = 316

Østergaard 2015n = 41

Age (years) Mean ± (SD)

CZP 200 mg plus MTX 49.4 (10.6) Placebo plus MTX <49.0(10.3)

CZP 400 mg plus MTX 53 (12.0) Placebo plus MTX 55.6 (11.7)

CZP 200mg plus MTX 50.4(13.6) Placebo plus MTX 51.2(13)

53.8 (12.2) CZP 400 mg 52.7 (12.7) Placebo 54.0 (11.6)

52.0 (11.6) CZP 200 mg plus MTX 51.4 (11.6) CZP 400 mg plus MTX 52.4 (11.7) Placebo plus MTX 52.2 (11.2)

CZP 200 mg plus MTX 18 ‐ 65 years = 72; > 65 years = 13 Placebo plus MTX 18 ‐ 65 years = 38; > 65 years = 4

51.9 (11.5) CZP 200 mg plus MTX 52.2 (11.1) CZP 400 mg plus MTX 51.9 (11.8) Placebo plus MTX 51.5 (11.8)

CZP 200 mg 53.6 (11.9) Placebo 54.0 (12.4)

55.1 (12.49) CZP 200 mg 55.4 (12.4) Placebo 53.9 (12.7)

55.7 (10.0) CZP 200 mg 56.0 (10.2) Placebo 55.4 (9.8)

Total 53.0 (11.0)

CZP 100 mg plus MTX 54.3 (10.6)

CZP 200 mg plus MTX 50.6 (11.4) CZP 400 mg plus MTX 55.4 (10.3)

Placebo plus MTX51.9 (11.1)

CZP 400 mg 51.3(12.6) Placebo 48.3 (14.4)

Follow‐up

24 and 52 weeks

24 weeks

52 weeks

24 weeks

52 weeks

24 weeks

12 weeks

12 and 24 weeks

2 weeks

Women n (%)

CZP 200 mg plus MTX 129 (81.1%) Placebo plus MTX 127 (80.9%)

CZP 400mg plus MTX 72% Placebo plus MTX 66.1%

CZP 200 mg plus MTX 497 (75.9%)

Placebo plus MTX 170 (79.8%)

184 (83.6%)

817 (83.2%) CZP 200 mg 324 (82.4%) CZP 400 mg 326 (83.6%) Placebo 167 (83.9%)

112 (88.2%) CZP 200 mg 75 (59.1%)

Placebo 37 (29.13%)

505 (81.6%) CZP 200 mg 206 (83.7%) CZP 400 mg 192 (78%) Placebo 107 (84.3%)

156 (80.4%) CZP 200 mg 81 (41.8%) Placebo 75 (38.7%)

829 (78%) CZP 200 mg 660 (62.1%) Placebo 169 (15.9%)

171 (74.3%) CZP 200 mg 83 (36.1%) Placebo 88 (38.3%)

CZP 100 mg plus MTX58 (18.4%)

CZP 200 mg plus MTX69 (21.8%) CZP 400 mg plus MTX69 (21.8%)

Placebo plus MTX66 (20.9%)

CZP 400 mg 81.5% Placebo 76.9%

Disease duration (years) Mean (SD)

Months CZP 200 mg plus MTX 4 ± 2.9

Placebo plus MTX 4.3 ± 2.8

CZP plus MTX 9.4 (7.5) Placebo plus MTX 9.9 (7.8)

Months CZP 200 mg plus MTX 2.9 (4.6) Placebo plus MTX 2.9 (2.9)

9.5 (NC)CZP 400 mg 8.7 (8.2)

Placebo 10.4 (9.6)

6.1 (4.3) CZP 200 mg 6.1 (4.2)

CZP 400 mg 6.2 (4.4) Placebo 6.2 (4.4)

CZP 200 mg 6.4 (4.2) Placebo 6 (5.1)

6.2 (4.2)

CZP 200 mg 6.1 (4.1) CZP 400 mg 6.5 (4.3) Placebo 5.6 (3.9)

‐

6.2 (4.2)

CZP 200 mg 8.6 (8.8)

Placebo 8.9 (9.1)

‐

CZP 400 mg 4.8 (3.8)

Placebo 5.9 (5.1)

RF positive (³ 14 IU/ml) (%)

CZP 200 mg plus MTX 153 (96.2%)

Placebo plus MTX 146 (93%)

78%

CZP 200 mg plus MTX 634 (96.8) Placebo plus MTX 206 (96.7)

100% CZP 400 mg 110 (99.9%)

Placebo 109 (100%)

81.8% CZP 200 mg 312 (79.6%)

CZP 400 mg 326 (83.6%) Placebo 164 (82.8%)

‐

76.9% CZP 200 mg 186 (77.5%)

CZP 400 mg 179 (75.5%)

Placebo 97 (78.2%)

‐

CZP 200 mg 555 (73.9%)

Placebo 137 (78.2%)

‐

MTX concomitant dose (mg/week) Mean(SD)

CZP 200 mg plus MTX 11.6 (3)

Placebo plus MTX 11.6 (2.7)

CZP plus MTX 16.9 (3.9) Placebo plus MTX 16.6 (3.6)

‐

N/A

13.6 CZP 200mg 13.6 (4.3)

CZP 400 mg 13.6 (4) Placebo 13.4 (4.2)

CZP 200 mg 13.4 (2.5)

Placebo 13.6 (2.8)

12.5 CZP 200 mg 12.5 (3.6)

CZP 400 mg 12.6 (3.7) Placebo 12.2 (3.3)

N/A

CZP 200 mg 17.2 (5.7) Placebo 16.3 (5.3)

N/A

Only percentage of concomitant use CZP 400 mg 85.2% Placebo 92.3%

Number of previous DMARDS Mean (SD)

MTX‐naïve CZP 200 mg plus MTX 31 (19.5%)

Placebo plus MTX 19 (18.5%)

1.3

DMARDS‐naïve

2.0 CZP 400 mg 2.0 (1.2) Placebo 2.0 (1.3)

1.3 CZP 200 mg 1.3 (1.3)

CZP 400 mg 1.3 (1.3) Placebo 1.4 (1.4)

1.2 CZP 200 mg 3.3 (1.3)

Placebo 3.2 (1.5)

1.2 CZP 200 mg 1.2 (1.3) CZP 400 mg 1.3 (1.2)

Placebo 1.2 (1.2)

‐

Tender Joint count Mean (0 ‐ 66) (SD)

CZP 200 mg plus MTX 8.4 ± 6.1

Placebo plus MTX 8.9 ± 6.5

CZP plus MTX 29 (11.6)

Placebo plus MTX 31 (12.9)

CZP 200 mg plus MTX 15.6 (6.5)

Placebo plus MTX 16.2 (6.5)

29.0 (13.13)

30.7 (12.9)

CZP 200 mg 25.04 (14.94)

Placebo 25.05 (14.61)

30.2 (14.0)

CZP 200 mg 14.7 (6.6)

Placebo 14.7 (6.6)

CZP 400 mg 13 (7.8)

Placebo 13.8 (7.4)

Swollen Joint Count Mean (0 ‐ 66) (SD)

‐

CZP plus MTX 22.8 (9.4)

Placebo plus MTX 22.2 (9.6)

CZP 200 mg plus MTX 12.4 (5.5)

Placebo plus MTX 13 (5.6)

20.5 (9.67)

21.5 (9.8)

CZP 200 mg 15.96 (8.86) Placebo 17.31 (11.18)

21.0 (9.8)

‐

CZP 200 mg 11.8 (5.6)

Placebo 11.1 (5.2)

‐

CZP 400 mg 10 (6.4)

Placebo 9.9 (6.3)

HAQ‐DI mean (SD)

CZP 200 mg plus MTX 1.0 ± 0.6

Placebo plus MTX 1.1 ± 0.7

CZP plus MTX 1.4 (0.6) Placebo plus MTX 1.5 (0.7)

CZP 200 mg plus MTX 1.6 (0.6)

Placebo plus MTX 1.7 (0.7)

1.5 (0.64)

1.7 (0.60)

CZP 200 mg 1.43 (0.67) Placebo 1.53 (0.74)

1.6 (0.59)

‐

CZP 200 mg 1.5 (0.6)

Placebo 1.6 (0.6)

‐

CZP 400 mg 1.2 (0.6)

Placebo 1.4 (0.5)

CRP (mg/L) Geometric mean (CV)

‐

CZP plus MTX 11.9

Placebo plus MTX 13.1

Median (min, max) CZP 200 mg plus MTX 11.1 (0.2, 231.1)

Placebo plus MTX 10.5 (0.3, 243.2)

11.5 (NC)

14.7 (144.2)

‐

13.6 (180.9)

‐

CZP 200 mg 9

Placebo 10

‐

CZP 400mg3.8 (171)

Placebo 6.2 (247.5)

DAS‐28 (ESR) Mean (SD)

‐

6.2 (0.99)

CZP 200 mg plus MTX 6.7 (0.9)

Placebo plus MTX 6.8 (0.9)

6.3 (1.00)

6.9 (0.8)

‐

6.8 (0.83)

‐

CZP 200 mg 6.4 (0.9)

Placebo 6.4 (0.9)

‐

CZP 400mg 5.1 (1.1)

Placebo 5.3(1.2)

Notes: All randomised participants; the actual numbers vary slightly across parameters

CZP: certolizumab pegol
CV: coefficient of variation
DAS: disease activity score
DMARD: disease‐modifying anti‐rheumatic drug
ESR: erythrocyte sedimentation rate
IU: international units
L: litre
mg: milligrams
mL: millilitres
N/A: not applicable
NC: not calculated
RF: rheumatoid factor
SD: standard deviation
Y: years

Table 2. Demographic and disease characteristics of the included Phase III trials

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Table 3. Flow of participants in the included Phase III trials

Study	Placebo	Certolizumab pegol 100 mg	Certolizumab pegol 200 mg	Certolizumab pegol 400 mg
Atsumi 2016	ITT n = 158Safety n = 157	‐	ITT n = 161Safety n = 159	‐
	Discontinued n = 15 (%) Consent withdrawn = 3 (2% ) Lack of efficacy = 1 (0.06%) Adverse event = 6 (4%)Other reasons = 5 (3%) Moved to rescue = 70 (44%)	‐	Discontinued n = 12 (7,45%) Consent withdrawn = 2 (1% ) Lack of efficacy = 0 Adverse event = 9 (5%) Other reasons = 1 (0,5%) Moved to rescue = 36 (22%)	‐
	Completed n= 73 (46.20%)	‐	Completedn = 111( 69%)	‐
Choy 2012	ITT n = 121^a Safety n = 119	‐	‐	ITT n = 126 Safety n = 124
	All withdrawn n = 56 (46.3%) Lack of efficacy = 45 (37.2%) Adverse event = 6 (5%) Other reasons = 5 (4.1%)	‐	‐	All withdrawn n = 28 (22.2%) Lack of efficacy = 16 (12.7%) Adverse event = 7 (5.6%) Other reasons = 5 (4%)
	Completed n = 65 (53.7%)	‐	‐	Completed n = 98 (77.8%)
	ITT n = 121^a Safety n = 119	‐	ITT n = 126^a Safety n = 124
Emery 2015	ITT n = 219 Safety n = 217	‐	ITT n = 660 Safety n = 659	‐
	All withdrawn n = 76 (35%) Lack of efficacy = 14 (6%) Adverse event = 17 (8%) Protocol violation = 6 ( 3%) Lost to follow‐up = 6 (3%) Consent withdrawn = 15 (7%) Other reasons = 18 (8%)	‐	All withdrawn n = 160 (24%) Lack of efficacy = 19 (3%) Adverse event = 51 (8%) Protocol violation = 18 (3%) Lost to follow‐up = 14 (2%) Consent withdrawn = 35 (5%) Other reasons = 23 (3%)	‐
	Completed n = 143 (65%)	‐	Completed n = 500 (76%)	‐
Fleischmann 2009	ITT n = 109 Safety n = 109	‐	‐	ITT n = 111 Safety n = 111
	All withdrawn n = 81 (74%) Lack of efficacy = 75 (68.8%) Adverse event = 2 (1.8%) Protocol violation = 1 (0.9%) Lost to follow‐up = 3 (2.8%)	‐	‐	All withdrawn n = 35 (31.5%) Lack of efficacy = 24 (21.6%) Adverse event = 5 (4.5%) Protocol violation = 4 (3.6%) Consent withdrawn = 2 (1.8%)
	Completed n = 28 (25.7%)	‐	‐	Completed n = 76 (68.5%)
Keystone 2008	ITT n = 199 Safety n = 199	‐	ITT n = 393 Safety n = 392^b	ITT n = 390 Safety n = 389^b
	Withdrawn at week 16 due to lack of efficacy n = 125 (62.8%)	‐	Withdrawn at week 16 due to lack of efficacy n = 83 (21.1%)	Withdrawn at week 16 due to lack of efficacy n = 68 (17.4%)
	All withdrawn n = 156 (78.4%)	‐	All withdrawn n = 138 (35.1%)	All withdrawn n = 116 (39.7%)
	Completed n = 43 (21.6%)	‐	Completed n = 255 (64.9%)	Completed n = 274 (70.3%)
NCT00993317	ITT n = 42 Safety n = 42	‐	ITT n = 85 Safety n = 85	‐
	All withdrawn n = 21 (50%) Lack of efficacy = 18 (42%) Adverse event = 2 (4.76%) Other reasons = 1 (2.38%)	‐	All withdrawn n = 25 (29.41%) Lack of efficacy = 18 (21.8%) Adverse event = 4 (4.70%) Other reasons = 3 (3.52%)	‐
	Completed n = 21 (50%)	‐	Completed n = 60 (70.58%)	‐
Smolen 2009	ITT n = 127 Safety n = 125	‐	ITT n = 246 Safety n = 248^c	ITT n = 246 Safety n = 246
	Withdrawn at week 16 due to lack of efficacy n = 103 (81%)	‐	Withdrawn at week 16 due to lack of efficacy n = 52 (21.1%)	Withdrawn at week 16 due to lack of efficacy n = 52 (21.1%)
	All withdrawn n = 110 (86%)	‐	All withdrawn n = 72 (29.3%)	All withdrawn n = 65 (26.4%)
	Completed n = 17 (13.4%)	‐	Completed n = 174 (70.7%)	Completed n = 181 (73.6%)
Smolen 2015	ITT n = 98Safety n = 98	‐	ITT n = 96Safety n = 96	‐
	All withdrawnn = 18 (18.36%) Lack of efficacy = 7 (7.14%) Adverse event = 6 (6.12 %) Other reasons = 5 (5.10%)	‐	All withdrawnn = 12 (12.5%) Lack of efficacy = 2 (2.08 %) Adverse event = 6 (6.25%) Other reasons = 4 (4.16%)	‐
	Completed n = 80 (81.63%)	‐	Completedn = 84 (87.5%)	‐
Weinblatt 2012	ITT n = 212 Safety n = 209	‐	ITT n = 851 Safety n = 846	‐
	All withdrawn n = 28 (13.20%) Lack of efficacy = 6 (2.83%) Adverse event = 6 (2.83%) Other reasons = 16 (7.54%)	‐	All withdrawn n = 80 (9.41%) Lack of efficacy = 6 (0.70%) Adverse event = 33 (3.87%) Other reasons = 41 (4.81%)	‐
	Completed n = 184 (86.79%)	‐	Completed n = 771 (90.59%)	‐
Yamamoto (a) 2014	ITT n = 114Safety n = 114	‐	ITT n = 116Safety n = 116	‐
	All withdrawnn = 96 (84.2%) Lack of efficacy = 2 (1.75%) Adverse event = 2 (1.75%) Other reasons (protocol planned n = 88) = 94 (82%)	‐	All withdrawnn = 34 (29.31%) Lack of efficacy = 0 (0%) Adverse event = 8 (6.9%) Other reasons (protocol planned n = 24) = 26 (22.4%)	‐
	Completed n = 18 (15.8%)	‐	Completedn = 82 (70.69%)
Yamamoto (b) 2014	ITT n = 77 Safety n = 77	ITT n = 72 Safety n = 72	ITT n = 82 Safety n = 82	ITT n = 85 Safety n = 85
	All withdrawn n = 52 (67.53%) Lack of efficacy = 2 (2.98%) Adverse event = 3 (3.90%) Other reasons (Protocol planned withdrawal = 45) = 47 (61.04%)	All withdrawn n = 21 (29.17%) Lack of efficacy = 3 (4.17%) Adverse event = 0 (0%) Other reasons (Protocol planned withdrawal = 14) = 18 (25%)	All withdrawn n = 16 (19.51%) Lack of efficacy = 1 (1.22%) Adverse event = 3 (3.66%) Other reasons (Protocol planned withdrawal = 11) = 12 (14.63%)	All withdrawn n = 20 (23.53%) Lack of efficacy = 0 (0%) Adverse event = 7 (8.23%) Other reasons (Protocol planned withdrawal = 11) = 13 (15.29%)
	Completed n = 25 (32.47%)	Completed n = 51 (70.83%)	Completed n = 66 (80.49%)	Completed n = 65 (76.47%)
Østergaard 2015	ITT n = 13 Safety at 12 weeks n = 13	‐	ITT n = 27 Safety at 12 weeks n = 27	‐
Østergaard 2015	Only the data obtained at week 2 were usable		Only the data obtained at week 2 were usable
^a Manufacturers reported efficacy calculations from placebo n = 119 and certolizumab pegol n = 124. ^b Two participants in each treatment group did not take study medication. ^cTwo participants in the placebo group received certolizumab pegol and were included for safety in the 200 mg group. (d)

Table 3. Flow of participants in the included Phase III trials

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Table 4. Beneficial ACR50

	Follow‐up	Doses/study	Response rate certolizumab pegol	Response rate placebo	RR (CI 95%)	% RD	NNTB
ACR50
Analysis 2.1	24 weeks	200 mg: Smolen 2015; Yamamoto (b) 2014; NCT00993317; Keystone 2008; Smolen 2009	36%	9%	3.80 (2.42 to 5.95)	27 (20 to 33)	4 (3 to 8)
Analysis 3.1	24 weeks	400 mg: Choy 2012; Fleischmann 2009; Yamamoto (b) 2014; Keystone 2008; Smolen 2009	34%	7%	4.65 (3.09 to 6.99)	27 (17 to 34)	4 (3 to 7)
Analysis 4.1	52 weeks	200 mg: Atsumi 2016; Emery 2015; Keystone 2008	55%	36%	1.54 (1.38 to 1.73)	20 (15 to 24)	5 (3 to 7)
Analysis 5.1	52 weeks	400 mg: Keystone 2008	40%	8%	5.27 (3.19 to 8.71)	32 (26 to 38)	3 (2 to 6)

Table 4. Beneficial ACR50

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Table 5. Health‐related quality of life

	Follow‐up	Doses/study	Mean differences
HAQ (0 ‐ 3) (Best = 0; Worst = 3)
Analysis 7.1	24 weeks	200 mg/ Smolen 2015; NCT00993317; Keystone 2008; Smolen 2009	‐0.35 (‐0.43 to ‐0.26)
Analysis 7.2	24 weeks	400 mg/ Choy 2012; Fleischmann 2009; Keystone 2008; Smolen 2009	‐0.38 (‐0.48 to ‐0.28)
Analysis 9.1.1	52 weeks	200 mg/ Emery 2015; Keystone 2008	‐0.27 (‐0.35 to ‐0.20)
Analysis 9.1.2	52 weeks	400 mg/ Keystone 2008	‐0.45 (‐0.57 to ‐0.33)
SF‐36 PCS (0 ‐ 100) (Worst = 0; Best = 100)
Analysis 10.1	24 weeks	200 mg/ Smolen 2015; Keystone 2008; Smolen 2009	5.03 (3.90 to 6.16)
Analysis 10.2	24 weeks	400 mg/ Choy 2012; Keystone 2008; Smolen 2009	5.54 (4.11 to 6.97)
SF‐36 MCS (0 ‐ 100) (Worst = 0; Best = 100)
Analysis 11.1	24 weeks	200 mg/ Keystone 2008; Smolen 2009	4.18 (2.70 to 5.66)
Analysis 11.2	24 weeks	400 mg/ Choy 2012; Keystone 2008; Smolen 2009	4.05 (2.77 to 5.34)
SF‐36 PCS
Analysis 12.1	52 weeks	200 mg/ Keystone 2008	6.06 (4.59 to 7.53)
Analysis 12.2	52 weeks	400 mg/ Keystone 2008	6.88 (5.42 to 8.34)
SF‐36 MCS (0 ‐ 100) (Worst = 0; Best = 100)
	52 weeks	200 mg/ Keystone 2008	4.3 (2.4 to 6.2)
	52 weeks	400 mg/ Keystone 2008	4.3 (2.4 to 6.2)
Participants' VAS score (0 ‐ 100)
Analysis 52.1	24 weeks	200 mg/ Keystone 2008; Smolen 2009	‐20.48 (‐24.26 to ‐16.69)
Analysis 52.1	24 weeks	400 mg/ Fleischmann 2009; Keystone 2008; Smolen 2009	‐21.35 (‐25.08 to ‐17.61)
Analysis 53.1	52 weeks	200 mg/ Keystone 2008	‐22.20 (‐27.37 to ‐17.03)
Analysis 53.1	52 weeks	400 mg/ Keystone 2008	‐24.70 (‐29.73 to ‐19.67)
DAS‐28 remission (< 2.6)
Analysis 21.2	24 weeks	200 mg/ Smolen 2015; Yamamoto (a) 2014; Atsumi 2016; Emery 2015; Keystone 2008; Smolen 2009	3.79 (1.90 to 7.56)
Analysis 21.3	24 weeks	400 mg/ Choy 2012; Keystone 2008; Smolen 2009	7.18 (3.12 to 16.50)
Analysis 21.4	52 weeks	200 mg/ Atsumi 2016; Emery 2015; Keystone 2008	1.83 (1.53 to 2.18)
Analysis 21.5	52 weeks	400 mg/ Keystone 2008	12.49 (3.99 to 39.12)

Table 5. Health‐related quality of life

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Table 6. Radiological changes

	Follow‐up	Doses/study	Mean differences
Modified Total Sharp Scores (mTTS) is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 ‐ 398
Analysis 37.1	24 weeks	200 mg/ Keystone 2008; Smolen 2009	‐1.06 (‐1.58 to ‐0.55)
Analysis 37.2	24 weeks	400 mg/ Keystone 2008; Smolen 2009	‐1.32 (‐1.85 to ‐0.78)
Analysis 36.1.1	52 weeks	200 mg/ Keystone 2008; Emery 2015	‐2.4 (‐4.11 to ‐0.69)
Analysis 36.1.2	52 weeks	400 mg/ Keystone 2008	‐2.6 (‐4.29 to ‐0.91)
Erosion Score is the sum of joint scores collected for 46 joints and has a range of 0 to 230
Analysis 29.1	24 weeks	200 mg/ Keystone 2008; Smolen 2009	‐0.35 (‐0.50 to ‐0.21)
Analysis 29.2	24 weeks	400 mg/ Keystone 2008; Smolen 2009	‐0.76 (‐1.14 to ‐0.37)
Analysis 29.3	52 weeks	200 mg/ Keystone 2008; Emery 2015	‐1.14 (‐1.54 to ‐0.74)
Analysis 29.4	52 weeks	400 mg/ Keystone 2008	‐1.5 (‐2.20 to ‐0.80)
Joint space narrowing (JSN) is the sum of joint scores collected for 42 joints and has a range of 0 to 168
Analysis 32.1	24 weeks	200 mg/ Keystone 2008; Smolen 2009	‐0.45 (‐0.77 to ‐0.13)
Analysis 32.2	24 weeks	400 mg/ Keystone 2008; Smolen 2009	‐0.55 (‐ 0.86 to ‐0.24)
Analysis 32.3	52 weeks	200 mg/ Keystone 2008	‐1 (‐1.85 to ‐0.15)
Analysis 32.4	52 weeks	400 mg/ Keystone 2008	‐1.2 (‐1.98 to ‐0.42)

Table 6. Radiological changes

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Table 7. Adverse events

	Studies	Response rate in % (number of events) certolizumab pegol	Response rate in % (number of events) placebo	RR (95% CI)	% RD	NNTH
Serious adverse events (doses)				Peto OR
Analysis 41.1 200 mg certolizumab pegol	Smolen 2015; Yamamoto (a) 2014; Yamamoto (b) 2014; NCT00993317; Keystone 2008; Smolen 2009; Weinblatt 2012; Atsumi 2016; Emery 2015	8.4% (228)	5,8% (72)	1.47 (1.13 to 1.91)	3 (1 to 4)	33 (25o 100)
Analysis 42.1 400 mg certolizumab pegol	Choy 2012; Fleischmann 2009; Yamamoto (b) 2014; Keystone 2008; Smolen 2009; Østergaard 2015	10% (95)	4% (31)	1.98 (1.36 to 2.9)	5 (2 to 7)	28 (15 to 74)
Adverse events leading to withdrawal				Peto OR
Analysis 50.15 200 mg certolizumab pegol	Emery 2015; Keystone 2008; NCT00993317; Smolen 2009; Smolen 2015; Weinblatt 2012; Yamamoto (a) 2014; Yamamoto (b) 2014	6% (147)	4% (46)	1.32 (0.95 to 1.84)	1 (0 to 3)	NS
Analysis 50.16 400 mg certolizumab pegol	Choy 2012; Fleischmann 2009; Yamamoto (b) 2014; Keystone 2008; Smolen 2009	5% (48)	2% (16)	2.01 (1.20 to 3.36)	3 (1 to 5)	52 (23 to 257)
Death				Peto OR
Analysis 50.17; 200 mg certolizumab pegol	Emery 2015; Keystone 2008; Smolen 2009; Smolen 2015; Weinblatt 2012; Yamamoto (a) 2014	0.03% (8)	0.1% (1)	2.66 (0.63 to 11.16)	0 (‐1 to 1)	NS
Analysis 50.18 400 mg certolizumab pegol	Choy 2012; Fleischmann 2009; Keystone 2008; Smolen 2009; Østergaard 2015	0.5% (5)	0% (1)	1.87 (0.31 to 11.34)	0 (‐1 to 1)	NS
Tuberculosis				Peto OR
Analysis 50.20; 200 mg certolizumab pegol	Emery 2015; Keystone 2008; NCT00993317; Smolen 2009; Smolen 2015; Weinblatt 2012	0.4% (7)	0% (0)	1.90 (0.55 to 6.58)	Not calculated	NS
Analysis 50.21 400 mg certolizumab pegol	Fleischmann 2009; Keystone 2008; Smolen 2009	0.6% (5)	0% (0)	4.55 (0.71 to 29.11)	Not calculated	NS
Malignancies (neoplasias including lymphoma)				Peto OR
Analysis 50.23 200 mg certolizumab pegol	Atsumi 2016; Emery 2015; Keystone 2008; NCT00993317; Smolen 2009; Smolen 2015; Weinblatt 2012; Yamamoto (a) 2014	0.7% (19)	0.7% (9)	0.92 (0.40 to 2.11)	0 (‐1 to 1)	NS
Analysis 50.24 400 mg certolizumab pegol	Fleischmann 2009; Keystone 2008; Smolen 2009	0.6 % (5)	0.4% (2)	1.26 (0.26 to 6.08)	0 (‐1 to 1)	NS
Infections and infestations				RR
Analysis 50.71 200 mg certolizumab pegol	Atsumi 2016; Emery 2015; Keystone 2008; NCT00993317; Smolen 2009; Smolen 2015; Weinblatt 2012; Yamamoto (a) 2014; Yamamoto (b) 2014	35% (891)	29% (389)	1.27 (1.10 to 1.46)	7 (1 to 13)	14 (8 to 58)
Analysis 50.72 400 mg certolizumab pegol	Choy 2012; Keystone 2008; Smolen 2009; Yamamoto (b) 2014; Østergaard 2015	34% (298)	21% (183)	1.43 (1.03 to 1.98)	10 (1 to 20)	10 (5 to 44)

Table 7. Adverse events

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Comparison 1. Efficacy at 12 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR20 Show forest plot	6	2902	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.79, 1.63]

1.1 certolizumab 50 mg sc	1	47	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.13, 0.57]
1.2 certolizumab 100 mg sc	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.09, 7.05]
1.3 certolizumab 200 mg sc	6	2456	Risk Ratio (M‐H, Random, 95% CI)	1.66 [0.97, 2.85]
1.4 certolizumab 400 mg sc	2	161	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.38, 5.23]
1.5 certolizumab 600 mg sc	1	47	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.51, 0.90]
1.6 certolizumab 800 mg sc	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.66, 1.04]
2 ACR50 Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 certolizumab 50 mg sc	1	47	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.09, 27.88]
2.2 certolizumab 100 mg sc	1	48	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.06, 20.96]
2.3 certolizumab 200 mg sc	4	2118	Risk Ratio (M‐H, Random, 95% CI)	1.89 [1.06, 3.37]
2.4 certolizumab 400 mg sc	1	50	Risk Ratio (M‐H, Random, 95% CI)	7.33 [0.48, 110.96]
3 ACR70 Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 certolizumab 50 mg sc	1	47	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.06, 21.47]
3.2 certolizumab 100 mg sc	1	48	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.03, 14.89]
3.3 certolizumab 200 mg sc	4	2118	Risk Ratio (M‐H, Random, 95% CI)	2.78 [1.20, 6.41]
3.4 certolizumab 400 mg sc	1	50	Risk Ratio (M‐H, Random, 95% CI)	5.23 [0.34, 80.54]

Comparison 1. Efficacy at 12 weeks, any dose

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Comparison 2. ACR50 24 weeks, 200 mg certolizumab pegol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 50 Show forest plot	5	1445	Risk Ratio (M‐H, Random, 95% CI)	3.80 [2.42, 5.95]

Comparison 2. ACR50 24 weeks, 200 mg certolizumab pegol

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Comparison 3. ACR50 at 24 weeks, 400 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 50 Show forest plot	5	1591	Risk Ratio (M‐H, Random, 95% CI)	4.65 [3.09, 6.99]

Comparison 3. ACR50 at 24 weeks, 400 mg certolizumab

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Comparison 4. ACR50 at 52 weeks, 200 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 50 Show forest plot	3	1790	Risk Ratio (M‐H, Fixed, 95% CI)	1.54 [1.38, 1.73]

Comparison 4. ACR50 at 52 weeks, 200 mg certolizumab

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Comparison 5. ACR50 at 52 weeks, 400 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 50 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 5. ACR50 at 52 weeks, 400 mg certolizumab

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Comparison 6. Mean HAQ‐DI from baseline at week 12

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 certolizumab pegol 200 mg sc Show forest plot	1	1063	Mean Difference (IV, Fixed, 95% CI)	‐0.22 [‐0.23, ‐0.21]

Comparison 6. Mean HAQ‐DI from baseline at week 12

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Comparison 7. Mean HAQ‐DI from baseline at week 24

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 certolizumab pegol 200 mg sc Show forest plot	4	1268	Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.43, ‐0.26]

2 certolizumab 400 mg sc Show forest plot	4	1425	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.48, ‐0.28]

Comparison 7. Mean HAQ‐DI from baseline at week 24

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Comparison 8. HAQ‐DI at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	5	2246	Mean Difference (IV, Random, 95% CI)	‐0.36 [‐0.43, ‐0.29]

1.1 certolizumab pegol 200 mg sc	3	985	Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.44, ‐0.23]
1.2 certolizumab pegol 400 mg sc	4	1261	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.48, ‐0.27]

Comparison 8. HAQ‐DI at 24 weeks, any dose

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Comparison 9. HAQ‐DI at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	1837	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.39, ‐0.26]

1.1 certolizumab pegol 200 mg sc	2	1348	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.35, ‐0.20]
1.2 certolizumab pegol 400 mg sc	1	489	Mean Difference (IV, Fixed, 95% CI)	‐0.45 [‐0.57, ‐0.33]

Comparison 9. HAQ‐DI at 52 weeks, any dose

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Comparison 10. SF‐36 Physical Component Summary (PCS), week 24

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 certolizumab pegol 200 mg sc Show forest plot	3	1129	Mean Difference (IV, Random, 95% CI)	5.03 [3.90, 6.16]

2 certolizumab pegol 400 mg sc Show forest plot	3	1205	Mean Difference (IV, Random, 95% CI)	5.54 [4.11, 6.97]

Comparison 10. SF‐36 Physical Component Summary (PCS), week 24

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Comparison 11. SF‐36 Mental Component Summary (MCS), week 24

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 certolizumab pegol 200 mg sc Show forest plot	2	965	Mean Difference (IV, Random, 95% CI)	4.18 [2.70, 5.66]

2 certolizumab pegol 400 mg sc Show forest plot	3	1205	Mean Difference (IV, Random, 95% CI)	4.05 [2.77, 5.34]

Comparison 11. SF‐36 Mental Component Summary (MCS), week 24

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Comparison 12. SF‐36 Physical Component Summary (PCS), week 52

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 certolizumab 200 mg sc Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2 certolizumab 400 mg sc Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 12. SF‐36 Physical Component Summary (PCS), week 52

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Comparison 13. SF‐36 Mental Component Summary (MCS), week 52

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 certolizumab pegol 200 mg sc Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2 certolizumab pegol 400 mg sc Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 13. SF‐36 Mental Component Summary (MCS), week 52

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Comparison 14. SF‐36 Physical Component Summary (PCS) at week 24, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	3	1765	Mean Difference (IV, Random, 95% CI)	5.29 [4.37, 6.21]

1.1 certolizumab pegol 200 mg sc	3	967	Mean Difference (IV, Random, 95% CI)	4.99 [3.79, 6.20]
1.2 certolizumab pegol 400 mg sc	2	798	Mean Difference (IV, Random, 95% CI)	5.62 [3.70, 7.54]

Comparison 14. SF‐36 Physical Component Summary (PCS) at week 24, any dose

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Comparison 15. SF‐36 Mental Component Summary (MCS) at week 24, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	4	2012	Mean Difference (IV, Random, 95% CI)	4.01 [2.94, 5.08]

1.1 certolizumab pegol 200 mg sc	3	971	Mean Difference (IV, Random, 95% CI)	4.11 [2.62, 5.61]
1.2 certolizumab pegol 400 mg sc	3	1041	Mean Difference (IV, Random, 95% CI)	3.91 [2.38, 5.44]

Comparison 15. SF‐36 Mental Component Summary (MCS) at week 24, any dose

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Comparison 16. SF‐36 Physical Component Summary (PCS) at week 52, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 certolizumab pegol 200 mg sc	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 certolizumab pegol 400 mg sc	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 16. SF‐36 Physical Component Summary (PCS) at week 52, any dose

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Comparison 17. SF‐36 Mental Component Summary (MCS) at week 52, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 certolizumab pegol 200 mg sc	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 certolizumab pegol 400 mg sc	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 17. SF‐36 Mental Component Summary (MCS) at week 52, any dose

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Comparison 18. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any doses, 12 weeks

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants achieving remission 12 weeks certolizumab 200 mg Show forest plot	2	1942	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [1.44, 2.61]

Comparison 18. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any doses, 12 weeks

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Comparison 19. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any dose, 24 weeks

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants achieving remission 24 weeks Show forest plot	7	3462	Risk Ratio (M‐H, Random, 95% CI)	3.27 [1.96, 5.46]

1.1 certolizumab pegol 200 mg sc	6	2420	Risk Ratio (M‐H, Random, 95% CI)	2.94 [1.64, 5.28]
1.2 certolizumab pegol 400 mg sc	3	1042	Risk Ratio (M‐H, Random, 95% CI)	4.46 [1.95, 10.21]

Comparison 19. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any dose, 24 weeks

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Comparison 20. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any dose, 52 weeks

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants achieving remission 52 weeks Show forest plot	3	2175	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [1.55, 2.21]

1.1 certolizumab pegol 200 mg sc	3	1689	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [1.43, 2.04]
1.2 certolizumab pegol 400 mg sc	1	486	Risk Ratio (M‐H, Fixed, 95% CI)	6.31 [2.03, 19.59]

Comparison 20. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any dose, 52 weeks

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Comparison 21. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants achieving remission 12 weeks certolizumab 200 mg Show forest plot	2	1942	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [1.44, 2.76]

2 Proportion of participants achieving remission 24 weeks certolizumab 200 mg Show forest plot	6	2579	Risk Ratio (M‐H, Random, 95% CI)	3.79 [1.90, 7.56]

3 Proportion of participants achieving remission 24 weeks certolizumab 400 mg Show forest plot	3	1201	Risk Ratio (M‐H, Random, 95% CI)	7.18 [3.12, 16.50]

4 Proportion of participants achieving remission 52 weeks certolizumab 200 mg Show forest plot	3	1785	Risk Ratio (M‐H, Fixed, 95% CI)	1.83 [1.53, 2.18]

5 Proportion of participants achieving remission 52 weeks certolizumab 400 mg Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 21. Disease Activity Score (DAS‐28) (ESR) remission (< 2.6), any time

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Comparison 22. DAS‐28 at 12 weeks, 200 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DAS 28 (ESR) change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 22. DAS‐28 at 12 weeks, 200 mg certolizumab

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Comparison 23. DAS‐28 at 24 weeks, 400 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DAS 28 (ESR) change from baseline Show forest plot	2	593	Mean Difference (IV, Random, 95% CI)	‐1.46 [‐2.49, ‐0.42]

Comparison 23. DAS‐28 at 24 weeks, 400 mg certolizumab

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Comparison 24. DAS‐28 at week 52, certolizumab 200 mg

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DAS 28 (ESR) Change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 24. DAS‐28 at week 52, certolizumab 200 mg

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Comparison 25. DAS‐28 at week 52, certolizumab 400 mg

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DAS 28 (ESR) Change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 25. DAS‐28 at week 52, certolizumab 400 mg

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Comparison 26. DAS‐28 at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	839	Mean Difference (IV, Random, 95% CI)	‐1.59 [‐2.10, ‐1.08]

1.1 certolizumab pegol 200 mg sc	1	310	Mean Difference (IV, Random, 95% CI)	‐1.77 [‐2.08, ‐1.46]
1.2 certolizumab pegol 400 mg sc	2	529	Mean Difference (IV, Random, 95% CI)	‐1.45 [‐2.49, ‐0.41]

Comparison 26. DAS‐28 at 24 weeks, any dose

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Comparison 27. DAS‐28 at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	1838	Mean Difference (IV, Fixed, 95% CI)	‐0.78 [‐0.93, ‐0.63]

1.1 certolizumab pegol 200 mg sc	2	1349	Mean Difference (IV, Fixed, 95% CI)	‐0.71 [‐0.88, ‐0.53]
1.2 certolizumab pegol 400 mg sc	1	489	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐1.29, ‐0.71]

Comparison 27. DAS‐28 at 52 weeks, any dose

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Comparison 28. DAS‐28 at 24 weeks, 200 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DAS 28 (ESR) change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 28. DAS‐28 at 24 weeks, 200 mg certolizumab

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Comparison 29. Erosion score (ES)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from the baseline mean ES at week 24, certolizumab pegol 200 mg Show forest plot	2	859	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐0.50, ‐0.21]

2 Change from the baseline mean ES at week 24, certolizumab pegol 400 mg Show forest plot	2	869	Mean Difference (IV, Random, 95% CI)	‐0.76 [‐1.14, ‐0.37]

3 Change from the baseline mean ES at week 52, certolizumab pegol 200 mg Show forest plot	2	1235	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.54, ‐0.74]

4 Change from the baseline mean ES at week 52, certolizumab pegol 400 mg Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 29. Erosion score (ES)

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Comparison 30. Erosion score (ES) at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	1437	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.98, ‐0.42]

1.1 certolizumab pegol 200 mg sc	2	714	Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.06, ‐0.28]
1.2 certolizumab pegol 400 mg sc	2	723	Mean Difference (IV, Random, 95% CI)	‐0.73 [‐1.14, ‐0.32]

Comparison 30. Erosion score (ES) at 24 weeks, any dose

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Comparison 31. Erosion score (ES) at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	1599	Mean Difference (IV, Fixed, 95% CI)	‐1.16 [‐1.56, ‐0.77]

1.1 certolizumab pegol 200 mg sc	2	1146	Mean Difference (IV, Fixed, 95% CI)	‐1.09 [‐1.52, ‐0.65]
1.2 certolizumab pegol 400 mg sc	1	453	Mean Difference (IV, Fixed, 95% CI)	‐1.5 [‐2.44, ‐0.56]

Comparison 31. Erosion score (ES) at 52 weeks, any dose

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Comparison 32. Joint space narrowing (JSN)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from the baseline mean JSN 24 weeks, certolizumab pegol 200 mg Show forest plot	2	861	Mean Difference (IV, Random, 95% CI)	‐0.45 [‐0.77, ‐0.13]

2 Change from the baseline mean JSN 24 weeks,certolizumab pegol 400 mg Show forest plot	2	869	Mean Difference (IV, Random, 95% CI)	‐0.55 [‐0.86, ‐0.24]

3 Change from the baseline mean JSN 52 weeks,certolizumab pegol 200 mg Show forest plot	2	1239	Mean Difference (IV, Fixed, 95% CI)	‐0.67 [‐1.02, ‐0.32]

4 Change from the baseline mean JSN 52 weeks, certolizumab pegol 400 mg Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 32. Joint space narrowing (JSN)

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Comparison 33. Joint space narrowing (JSN) at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	1439	Mean Difference (IV, Random, 95% CI)	‐0.50 [‐0.79, ‐0.21]

1.1 certolizumab pegol 200 mg sc	2	716	Mean Difference (IV, Random, 95% CI)	‐0.46 [‐0.87, ‐0.04]
1.2 certolizumab pegol 400 mg sc	2	723	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐0.96, ‐0.13]

Comparison 33. Joint space narrowing (JSN) at 24 weeks, any dose

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Comparison 34. Joint space narrowing (JSN) at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	2	1602	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐1.04, ‐0.36]

1.1 certolizumab pegol 200 mg sc	2	1149	Mean Difference (IV, Fixed, 95% CI)	‐0.64 [‐1.00, ‐0.28]
1.2 certolizumab pegol 400 mg sc	1	453	Mean Difference (IV, Fixed, 95% CI)	‐1.2 [‐2.27, ‐0.13]

Comparison 34. Joint space narrowing (JSN) at 52 weeks, any dose

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Comparison 35. Modified Total Sharp Scores (mTSS) at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	3	1753	Mean Difference (IV, Random, 95% CI)	‐0.86 [‐1.19, ‐0.53]

1.1 certolizumab pegol 200 mg sc	3	1029	Mean Difference (IV, Random, 95% CI)	‐0.74 [‐1.11, ‐0.37]
1.2 certolizumab pegol 400 mg sc	2	724	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐1.99, ‐0.60]

Comparison 35. Modified Total Sharp Scores (mTSS) at 24 weeks, any dose

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Comparison 36. Modified Total Sharp Scores (mTSS) at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	3	1915	Mean Difference (IV, Fixed, 95% CI)	‐1.63 [‐2.13, ‐1.13]

1.1 certolizumab pegol 200 mg sc	3	1462	Mean Difference (IV, Fixed, 95% CI)	‐1.54 [‐2.06, ‐1.01]
1.2 certolizumab pegol 400 mg sc	1	453	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐4.29, ‐0.91]

Comparison 36. Modified Total Sharp Scores (mTSS) at 52 weeks, any dose

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Comparison 37. Modified total Sharp scores (mTSS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from the baseline mean mTSS 24 weeks, certolizumab pegol 200 mg Show forest plot	2	859	Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.58, ‐0.55]

2 Change from the baseline mean mTSS 24 weeks, certolizumab 400 mg Show forest plot	2	869	Mean Difference (IV, Random, 95% CI)	‐1.32 [‐1.85, ‐0.78]

3 Change from the baseline mean mTSS 52 weeks, certolizumab pegol 200 mg Show forest plot	1	545	Mean Difference (IV, Fixed, 95% CI)	‐2.4 [‐3.68, ‐1.12]

4 Change from the baseline mean mTSS 52 weeks, certolizumab pegol 400 mg Show forest plot	1	544	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐3.84, ‐1.36]

Comparison 37. Modified total Sharp scores (mTSS)

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Comparison 38. Certolizumab pegol 1mg/kg/day sc

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Headache Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

2 Lower respiratory tract infection Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

3 Adverse events Intensity severe Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

4 Antinuclear antibodies (ANA) Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

5 Urinary tract infection Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

Comparison 38. Certolizumab pegol 1mg/kg/day sc

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Comparison 39. Certolizumab 5 mg/kg/day sc

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Lower respiratory tract infection Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

2 Urinary tract infection Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

Comparison 39. Certolizumab 5 mg/kg/day sc

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Comparison 40. Certolizumab 20 mg/kg/day sc

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Headache Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Lower respiratory tract infection Show forest plot	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.32, 27.83]

3 Death Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

4 Antinuclear antibodies (ANA) Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

5 Urinary tract infection Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

Comparison 40. Certolizumab 20 mg/kg/day sc

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Comparison 41. Safety, SAE certolizumab 200 mg

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serious Adverse Events (SAE) Show forest plot	9	3927	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.47 [1.13, 1.91]

Comparison 41. Safety, SAE certolizumab 200 mg

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Comparison 42. Safety, SAE certolizumab 400 mg

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serious Adverse Events (SAEs) Show forest plot	6	1624	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.98 [1.36, 2.90]

Comparison 42. Safety, SAE certolizumab 400 mg

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Comparison 43. Withdrawals

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All Withdrawn: any doses any follow‐up Show forest plot	13	5200	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.39, 0.56]

2 Withdrawals due to adverse events Show forest plot	12	5236	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.45 [1.09, 1.94]

Comparison 43. Withdrawals

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Comparison 44. ACR at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR20 Show forest plot	8	2935	Risk Ratio (M‐H, Random, 95% CI)	2.76 [2.29, 3.33]

1.1 certolizumab 100 mg sc	1	98	Risk Ratio (M‐H, Random, 95% CI)	2.65 [1.28, 5.47]
1.2 certolizumab 200 mg sc	6	1462	Risk Ratio (M‐H, Random, 95% CI)	2.92 [2.17, 3.95]
1.3 certolizumab 400 mg sc	5	1375	Risk Ratio (M‐H, Random, 95% CI)	2.65 [1.98, 3.56]
2 ACR50 Show forest plot	7	2705	Risk Ratio (M‐H, Random, 95% CI)	2.95 [2.37, 3.68]

2.1 certolizumab 100 mg sc	1	98	Risk Ratio (M‐H, Random, 95% CI)	2.89 [1.13, 7.38]
2.2 certolizumab 200 mg sc	5	1232	Risk Ratio (M‐H, Random, 95% CI)	2.76 [2.02, 3.78]
2.3 certolizumab 400 mg sc	5	1375	Risk Ratio (M‐H, Random, 95% CI)	3.18 [2.29, 4.41]
3 ACR70 Show forest plot	7	2705	Risk Ratio (M‐H, Random, 95% CI)	4.15 [2.68, 6.42]

3.1 certolizumab 100 mg sc	1	98	Risk Ratio (M‐H, Random, 95% CI)	6.86 [0.97, 48.72]
3.2 certolizumab 200 mg sc	5	1232	Risk Ratio (M‐H, Random, 95% CI)	4.29 [2.36, 7.77]
3.3 certolizumab 400 mg sc	5	1375	Risk Ratio (M‐H, Random, 95% CI)	4.04 [1.37, 11.90]

Comparison 44. ACR at 24 weeks, any dose

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Comparison 45. ACR at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR20 Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.46 [1.11, 1.93]

1.1 certolizumab 200 mg sc	3	1691	Risk Ratio (M‐H, Random, 95% CI)	1.30 [1.03, 1.65]
1.2 certolizumab 400 mg sc	1	489	Risk Ratio (M‐H, Random, 95% CI)	2.08 [1.48, 2.93]
2 ACR50 Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]

2.1 certolizumab 200 mg sc	3	1691	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.11, 1.96]
2.2 certolizumab 400 mg sc	1	489	Risk Ratio (M‐H, Random, 95% CI)	2.62 [1.62, 4.25]
3 ACR70 Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.89 [1.44, 2.48]

3.1 certolizumab 200 mg sc	3	1691	Risk Ratio (M‐H, Random, 95% CI)	1.71 [1.39, 2.11]
3.2 certolizumab 400 mg sc	1	489	Risk Ratio (M‐H, Random, 95% CI)	3.26 [1.56, 6.82]

Comparison 45. ACR at 52 weeks, any dose

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Comparison 46. ACR20‐ACR70, 24 weeks, 200 mg certolizumab pegol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 20 Show forest plot	6	1675	Risk Ratio (M‐H, Random, 95% CI)	3.71 [2.68, 5.13]

2 ACR 70 Show forest plot	5	1445	Risk Ratio (M‐H, Random, 95% CI)	7.26 [3.83, 13.76]

Comparison 46. ACR20‐ACR70, 24 weeks, 200 mg certolizumab pegol

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Comparison 47. ACR20‐ACR70 at 24 weeks, 400 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 20 Show forest plot	5	1591	Risk Ratio (M‐H, Random, 95% CI)	3.73 [2.43, 5.72]

2 ACR 70 Show forest plot	5	1591	Risk Ratio (M‐H, Random, 95% CI)	7.20 [2.25, 23.03]

Comparison 47. ACR20‐ACR70 at 24 weeks, 400 mg certolizumab

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Comparison 48. ACR20‐ACR70 at 52 weeks, 200 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 20 Show forest plot	3	1790	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [1.30, 1.58]

2 ACR 70 Show forest plot	3	1790	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.41, 1.90]

Comparison 48. ACR20‐ACR70 at 52 weeks, 200 mg certolizumab

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Comparison 49. ACR20‐ACR70 at 52 weeks, 400 mg certolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 20 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 ACR 70 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 49. ACR20‐ACR70 at 52 weeks, 400 mg certolizumab

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Comparison 50. Safety

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any adverse event certolizumab 200 mg Show forest plot	9	3927	Risk Ratio (M‐H, Random, 95% CI)	1.16 [1.03, 1.31]

2 Any adverse events certolizumab 400 mg Show forest plot	6	1624	Risk Ratio (M‐H, Random, 95% CI)	1.19 [1.05, 1.34]

3 Adverse events: Intensity mild certolizumab 200 mg Show forest plot	4	2249	Risk Ratio (M‐H, Random, 95% CI)	1.18 [1.00, 1.41]

4 Adverse events: Intensity mild certolizumab 400 mg Show forest plot	5	1462	Risk Ratio (M‐H, Random, 95% CI)	1.25 [1.06, 1.47]

5 Adverse events: Intensity moderate certolizumab 200 mg Show forest plot	4	2249	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.86, 1.32]

6 Adverse events: Intensity moderate certolizumab 400 mg Show forest plot	5	1462	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.99, 1.47]

7 Adverse events: Intensity severe certolizumab 200 mg Show forest plot	4	2249	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.14 [0.78, 1.65]

8 Adverse events: Intensity severe certolizumab 400 mg Show forest plot	5	1462	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.23 [0.83, 1.81]

9 Adverse events related to study drug certolizumab 200 mg Show forest plot	2	964	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.27, 1.99]

10 Adverse events related to study drug certolizumab 400 mg Show forest plot	4	1219	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.20, 1.80]

11 Serious Infections certolizumab 200 mg Show forest plot	3	1283	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.99, 3.80]

12 Serious infections certolizumab 400 mg Show forest plot	4	1422	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.25 [1.65, 6.39]

13 Adverse events leading to death certolizumab 200 mg Show forest plot	6	3322	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.63 [0.41, 6.47]

14 Adverse events leading to death certolizumab 400 mg Show forest plot	3	1179	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.16 [0.40, 11.79]

15 Adverse events leading to withdrawal certolizumab 200 mg Show forest plot	8	3608	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.32 [0.95, 1.84]

16 Adverse events leading to withdrawal certolizumab 400 mg Show forest plot	6	1624	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.01 [1.20, 3.36]

17 Death certolizumab 200 mg Show forest plot	6	3320	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.66 [0.63, 11.16]

18 Death certolizumab 400 mg Show forest plot	5	1462	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [0.31, 11.34]

19 Deaths overall Show forest plot	10	4745	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.63 [0.78, 8.91]

19.1 Certolizumab pegol 200 mg	7	3266	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.10 [0.44, 10.08]
19.2 Certolizumab pegol 400 mg	5	1349	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.53 [0.40, 31.39]
19.3 Other doses	2	130	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.48 [0.07, 286.49]
20 Tuberculosis certolizumab 200 mg Show forest plot	7	3538	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.90 [0.55, 6.58]

21 Tuberculosis certolizumab 400 mg Show forest plot	3	1179	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.55 [0.71, 29.11]

22 Tuberculosis overall Show forest plot	7	4074	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.91 [0.61, 5.96]

22.1 Certolizumab pegol 200 mg	6	3058	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.53 [0.40, 5.77]
22.2 Certolizumab pegol 400 mg	3	1016	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.52 [0.40, 31.33]
23 Malignancies included lymphoma certolizumab 200 mg Show forest plot	8	3768	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.40, 2.11]

24 Malignancies included lymphoma certolizumab 400 mg Show forest plot	3	1179	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.26 [0.26, 6.08]

25 Injection side reactions certolizumab 200 mg Show forest plot	5	2497	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.34 [1.85, 6.06]

26 Injection side reactions certolizumab 400 mg Show forest plot	5	1584	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.34 [0.20, 0.56]

27 Antinuclear antibodies (ANA) Anti‐certolizumab pegol antibodies certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

28 Anti‐certolizumab pegol antibodies certolizumab 400 mg Show forest plot	2	591	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.70 [2.18, 20.55]

29 Systemic lupus erythematosus certolizumab 200 mg Show forest plot	2	567	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.50 [0.07, 286.06]

30 Prolonged activated partial thromboplastin time (aPTT) certolizumab 200 mg Show forest plot	2	500	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.73 [0.98, 7.61]

31 Prolonged activated partial thromboplastin time (aPTT) certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

32 Urinary tract infection certolizumab 200 mg Show forest plot	6	3219	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.68, 1.40]

33 Urinary tract infection certolizumab 400 mg Show forest plot	2	959	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.87 [0.50, 1.52]

34 Upper respiratory tract infection certolizumab 200 mg Show forest plot	8	3608	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.68 [1.28, 2.20]

35 Upper respiratory tract infection certolizumab 400 mg Show forest plot	4	1364	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.77, 2.61]

36 Lower respiratory tract infection/ lung infection certolizumab 200 mg Show forest plot	6	2356	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.12 [0.76, 5.95]

37 Lower respiratory tract infection/ lung infection certolizumab 400 mg Show forest plot	3	993	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.11 [0.75, 5.95]

38 Pneumonia certolizumab 200 mg Show forest plot	6	2804	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.45, 1.97]

39 Pneumonitis certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

40 Headache certolizumab 200 mg Show forest plot	6	3251	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.33 [0.94, 1.87]

41 Headache certolizumab 400 mg Show forest plot	4	1364	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.30 [0.76, 2.20]

42 Bacteriuria certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

43 Bacteriuria certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

44 Nasopharyngitis/Pharyngitis certolizumab 200 mg Show forest plot	7	2553	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.37 [1.01, 1.84]

45 Nasopharyngitis/Pharyngitis certolizumab 400 mg Show forest plot	4	1364	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.98 [1.26, 3.11]

46 Injection site pain certolizumab 200 mg Show forest plot	3	1091	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.85 [0.49, 6.92]

47 Injection site pain certolizumab 400 mg Show forest plot	3	1179	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.74 [0.41, 7.42]

48 Hypertension certolizumab 200 mg Show forest plot	4	1353	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.09 [1.64, 5.84]

49 Hypertension certolizumab 400 mg Show forest plot	3	1121	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.35 [1.80, 6.20]

50 Hematuria certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

51 Haematuria certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

52 Hepatic enzyme increased certolizumab 200 mg Show forest plot	3	851	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.84 [0.56, 1.27]

53 Hepatic enzyme increased certolizumab 400 mg Show forest plot	2	533	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.69 [0.25, 1.92]

54 AST increased certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

55 AST increased certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

56 ALT increased certolizumab 200 mg Show forest plot	2	1252	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.85 [0.48, 1.50]

57 ALT increased certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

58 Diarrhoea certolizumab 200 mg Show forest plot	3	1200	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.25, 2.03]

59 Gastroenteritis certolizumab 200 mg Show forest plot	2	785	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.97 [0.33, 2.87]

60 Gastrointestinal disorders certolizumab 400 mg Show forest plot	2	831	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.05 [0.54, 2.03]

61 Back pain certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

62 Back pain certolizumab 400 mg Show forest plot	2	831	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.11 [1.48, 6.55]

63 Hematologic abnormalities certolizumab 200 mg Show forest plot	2	821	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.02 [0.27, 15.21]

64 Haematologic abnormalities certolizumab 400 mg Show forest plot	2	750	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.21, 6.07]

65 Herpes viral infection certolizumab 200 mg Show forest plot	2	821	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.80 [0.34, 100.23]

66 Herpes viral infection certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

67 Bacterial peritonitis certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

68 Bacterial peritonitis certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

69 Opportunistic infections certolizumab 200 mg Show forest plot	4	2070	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.33 [0.46, 117.85]

70 Opportunistic infections certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

71 Infections and infestations certolizumab 200 mg Show forest plot	9	3910	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.10, 1.46]

72 Infections and infestations certolizumab 400 mg Show forest plot	5	1404	Risk Ratio (M‐H, Random, 95% CI)	1.43 [1.03, 1.98]

73 Decreased haemoglobin certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

74 Decreased haemoglobin certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

75 Increased platelet count certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

76 Increased platelet count certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

77 Cerebral haemorrhage including subarachnoid certolizumab 200 mg Show forest plot	2	321	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.27 [0.12, 13.50]

78 Ischaemic stroke certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

79 Nausea/vomiting certolizumab 200 mg Show forest plot	4	2447	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.84, 1.54]

80 Vomiting certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

81 Acute miocardial infarction certolizumab 200 mg Show forest plot	2	1073	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.79 [0.04, 351.89]

82 Acute myocardial infarction certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

83 Abdominal pain/discomfort/dyspepsia certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

84 Constipation certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

85 Skin and subcutaneous tissue disorders certolizumab 200 mg Show forest plot	4	1395	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.83 [1.46, 5.48]

86 Skin and subcutaneous tissue disorders certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

87 Cough certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

88 Pruritus certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

89 Fatigue certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

90 Fatigue certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

91 Periodontitis certolizumab 200 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

92 Arthritis bacterial certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

93 Mastitis certolizumab 400 mg Show forest plot	1	220	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.26 [0.14, 365.79]

94 Benign tumour certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

95 Dizziness postural certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

96 Menorrhagia certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

97 Corneal perforation certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

98 Conjunctivitis allergic certolizumab 400 mg Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

99 Periodontitis certolizumab 400 mg Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 50. Safety

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Comparison 51. Participant's assessment of arthritis pain (VAS score 0 to 100 mm)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean change at 24 weeks certolizumab pegol 200 mg Show forest plot	2	965	Mean Difference (IV, Random, 95% CI)	‐20.49 [‐23.43, ‐17.55]

2 Mean change at 24 weeks certolizumab pegol 400 mg Show forest plot	3	1182	Mean Difference (IV, Random, 95% CI)	‐22.69 [‐25.53, ‐19.84]

3 Mean change at 52 weeks certolizumab pegol 200 mg Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4 Mean change at 52 weeks certolizumab pegol 400 mg Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 51. Participant's assessment of arthritis pain (VAS score 0 to 100 mm)

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Comparison 52. Participant's assessment of arthritis pain (VAS score 0 to 100 mm) at 24 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	4	2064	Mean Difference (IV, Random, 95% CI)	‐21.07 [‐23.59, ‐18.55]

1.1 certolizumab pegol 200 mg sc	2	803	Mean Difference (IV, Random, 95% CI)	‐20.48 [‐24.26, ‐16.69]
1.2 certolizumab pegol 400 mg sc	4	1261	Mean Difference (IV, Random, 95% CI)	‐21.35 [‐25.08, ‐17.61]

Comparison 52. Participant's assessment of arthritis pain (VAS score 0 to 100 mm) at 24 weeks, any dose

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Comparison 53. Participant's assessment of arthritis pain (VAS score 0 to 100 mm) at 52 weeks, any dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.1 certolizumab pegol 200 mg sc	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 certolizumab pegol 400 mg sc	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 53. Participant's assessment of arthritis pain (VAS score 0 to 100 mm) at 52 weeks, any dose

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Comparison 54. Withdrawals Withdrawn due to lack of efficacy: any doses any follow‐up

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Withdrawn due to lack of efficacy: any doses any follow‐up Show forest plot	8	3433	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.26, 0.37]

Comparison 54. Withdrawals Withdrawn due to lack of efficacy: any doses any follow‐up

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Comparison 55. Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACR 50 200 mg certolizumab 24 weeks Show forest plot	5	1445	Risk Ratio (M‐H, Random, 95% CI)	3.80 [2.42, 5.95]

2 HAQ change from baseline 200 mg certolizumab 24 weeks Show forest plot	4	1268	Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.43, ‐0.26]

3 Serious adverse events certolizumab 200 mg sc Show forest plot	9	3927	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.47 [1.13, 1.91]

4 Proportion of participants achieving remission 24 weeks certolizumab 200 mg Show forest plot	4	1381	Risk Ratio (M‐H, Random, 95% CI)	8.47 [4.15, 17.28]

5 Radiological changes: Erosion Scores (ES) certolizumab 200 mg sc Show forest plot	2	859	Mean Difference (IV, Random, 95% CI)	‐0.67 [‐0.96, ‐0.38]

5.1 certolizumab 200 mg sc 24 weeks	2	859	Mean Difference (IV, Random, 95% CI)	‐0.67 [‐0.96, ‐0.38]
6 All Withdrawals: Show forest plot	10	3962	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.36, 0.50]

7 Withdrawals due to adverse events Show forest plot	9	3998	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.66 [1.15, 2.37]

8 Deaths Show forest plot	10	4745	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.63 [0.78, 8.91]

8.1 Certolizumab pegol 200 mg	7	3266	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.10 [0.44, 10.08]
8.2 Certolizumab pegol 400 mg	5	1349	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.53 [0.40, 31.39]
8.3 Other doses	2	130	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.48 [0.07, 286.49]
9 Tuberculosis Show forest plot	7	4074	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.91 [0.61, 5.96]

9.1 Certolizumab pegol 200 mg	6	3058	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.53 [0.40, 5.77]
9.2 Certolizumab pegol 400 mg	3	1016	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.52 [0.40, 31.33]
10 Upper respiratory tract infections Show forest plot	8	3692	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.86, 1.59]

10.1 Certolizumab pegol 200 mg	7	2528	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.28 [0.91, 1.80]
10.2 Certolizumab pegol 400 mg	4	1164	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.81 [0.41, 1.61]
11 Lower respiratory tract infections Show forest plot	7	3073	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.66 [0.77, 3.58]

11.1 Certolizumab pegol 200 mg	6	2218	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.81 [0.62, 5.26]
11.2 Certolizumab pegol 400 mg	3	855	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.50, 4.59]
12 Malignancies including lymphoma Show forest plot	7	3749	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.90 [0.39, 2.08]

12.1 Certolizumab pegol 200 mg	6	2570	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.79 [0.29, 2.12]
12.2 Certolizumab pegol 400 mg	3	1179	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.26 [0.26, 6.08]

Comparison 55. Summary of findings: certolizumab (with or without MTX) versus placebo (with or without MTX)

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Comparison 56. Analysis of sensitivity ACR50 24 weeks

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Doses Show forest plot	8	3768	Risk Ratio (M‐H, Random, 95% CI)	2.89 [2.38, 3.51]

1.1 certolizumab 100 mg sc	1	98	Risk Ratio (M‐H, Random, 95% CI)	2.89 [1.13, 7.38]
1.2 certolizumab 200 mg sc	6	2295	Risk Ratio (M‐H, Random, 95% CI)	2.73 [2.13, 3.51]
1.3 certolizumab 400 mg sc	5	1375	Risk Ratio (M‐H, Random, 95% CI)	3.18 [2.29, 4.41]
2 Size Show forest plot	8	3768	Risk Ratio (M‐H, Random, 95% CI)	2.89 [2.38, 3.51]

2.1 certolizumab < 200 patients	2	321	Risk Ratio (M‐H, Random, 95% CI)	2.44 [1.45, 4.10]
2.2 certolizumab > 200 patients	6	3447	Risk Ratio (M‐H, Random, 95% CI)	2.97 [2.41, 3.67]
3 Use of MTX Show forest plot	8	3768	Risk Ratio (M‐H, Random, 95% CI)	2.89 [2.38, 3.51]

3.1 With MTX	5	3038	Risk Ratio (M‐H, Random, 95% CI)	2.77 [2.21, 3.46]
3.2 Without MTX	3	730	Risk Ratio (M‐H, Random, 95% CI)	3.32 [2.23, 4.95]
4 Population Show forest plot	8	3768	Risk Ratio (M‐H, Random, 95% CI)	2.89 [2.38, 3.51]

4.1 Asian trials	2	443	Risk Ratio (M‐H, Random, 95% CI)	2.66 [1.77, 4.00]
4.2 Other trials	6	3325	Risk Ratio (M‐H, Random, 95% CI)	2.96 [2.37, 3.70]
5 Duration of previous disease Show forest plot	6	3258	Risk Ratio (M‐H, Random, 95% CI)	2.87 [2.31, 3.57]

5.1 Long previous disease duration (9 years or more)	2	467	Risk Ratio (M‐H, Random, 95% CI)	4.02 [2.02, 7.98]
5.2 Short previous disease duration (less than 7 years)	4	2791	Risk Ratio (M‐H, Random, 95% CI)	2.75 [2.18, 3.47]
6 Published vs unpublished studies Show forest plot	8	3768	Risk Ratio (M‐H, Random, 95% CI)	2.89 [2.38, 3.51]

6.1 Published studies	5	3131	Risk Ratio (M‐H, Random, 95% CI)	2.97 [2.36, 3.73]
6.2 Unpublished studies	3	637	Risk Ratio (M‐H, Random, 95% CI)	2.71 [1.89, 3.90]
7 Imputing to ACR50 200 mg from 24 missing values with same proportion as reported outcomes Show forest plot	5	1445	Risk Ratio (M‐H, Fixed, 95% CI)	3.34 [2.68, 4.17]

7.1 Imputing missing values with same proportion as reported outcomes	5	1445	Risk Ratio (M‐H, Fixed, 95% CI)	3.34 [2.68, 4.17]
8 Imputing to ACR50 200 mg from 24 weeks 50 % of missing outcomes Show forest plot	5	1445	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [1.04, 1.32]

8.1 Imputing the 50 % of missing outcomes	5	1445	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [1.04, 1.32]
9 Imputing to ACR50 200 mg from 24 weeks: the worst case Show forest plot	5	1445	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.43, 0.52]

9.1 Analysis in the worst case. All missing values did not reach ACR50 in certolizumab group and did in placebo group	5	1445	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.43, 0.52]

Comparison 56. Analysis of sensitivity ACR50 24 weeks

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Comparison 57. Analysis of sensitivity ACR50 52 weeks

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Doses Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]

1.1 certolizumab 200 mg sc	3	1691	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.11, 1.96]
1.2 certolizumab 400 mg sc	1	489	Risk Ratio (M‐H, Random, 95% CI)	2.62 [1.62, 4.25]
2 Size Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]

2.1 certolizumab <200 patients	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 certolizumab >200 patients	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]
3 Use of MTX Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]

3.1 Use of MTX	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]
3.2 Without MTX	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Population Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]

4.1 Asian trials	1	319	Risk Ratio (M‐H, Random, 95% CI)	1.41 [1.17, 1.68]
4.2 Other trials	2	1861	Risk Ratio (M‐H, Random, 95% CI)	1.94 [1.01, 3.72]
5 Duration of previous disease Show forest plot	3	2180	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.22, 2.33]

5.1 Long previous disease duration (6 years or more)	1	982	Risk Ratio (M‐H, Random, 95% CI)	2.58 [1.83, 3.62]
5.2 Short previous disease duration (less than 1 year)	2	1198	Risk Ratio (M‐H, Random, 95% CI)	1.29 [1.10, 1.50]

Comparison 57. Analysis of sensitivity ACR50 52 weeks

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