Table 3.
Characteristics of included combination therapy studies
| Study | Disease severity | Treatment and dose | Treatment group for analysis | Number of patients randomized | Mean age, years | Mean disease duration, years | Withdrawals, % |
|---|---|---|---|---|---|---|---|
| Abe et al58 | Active disease despite MTX | INF 3 mg/kg + MTX | INF 3 mg/kg/8 weeks + DMARD (MTX) | 49 | 55.2 | 9.1 | 2 |
| INF 10 mg/kg + MTX | INF 10 mg/kg/8 weeks + DMARD (MTX) | 51 | 56.8 | 7.1 | 7.8 | ||
| MTX | DMARD (MTX) | 47 | 55.1 | 7.5 | 10.6 | ||
| Chen et al59 | Active disease despite MTX DAS28 6.54 (median) Range 5.63–7.37 | ADA 40 mg every other week + MTX | ADA 40 mg/2 weeks + DMARD (MTX) | 35 | 53 (median) | 6.2 (median) | 8.6 (AEs leading to discontinuation) |
| MTX | DMARD (MTX) | 12 | 53 (median) | 8.3 (median) | 0 (AEs leading to discontinuation) | ||
| Combe et al42 | Active RA despite SUL Mean baseline DAS28 5.1, 5.0, 5.2 | ETN 25 mg twice weekly | ETN 2 × 25 mg/week | 103 | 51.3 | 7.1 | 37 at 2 years |
| SUL 2, 2.5, or 3 g daily | DMARD (SUL) | 50 | 53.3 | 5.6 | 68 at 2 years | ||
| ETN 25 mg twice weekly + SUL 2–3 g daily | ETN 2 × 25 mg/week + DMARD (SUL) | 101 | 50.6 | 6.5 | 24 at 2 years | ||
| Durez et al60 | RA > 1 year Severe, active disease despite MTX | IFN, 3 mg/kg IV infusion weeks 0, 2, and 6 + MTX | INF 3 mg/kg/8 weeks + DMARD (MTX) | 12 | 48 | 10 | NR |
| MP, 1 g, single infusion week 0 + MTX | MP 1 mg + DMARD (MTX) | 15 | 56 | 12 | |||
| Edwards et al81 | Active disease despite MTX DAS mean 6.8 or 6.9 | RTX 1000 mg IV day 1 and 15 | RTX 2 × 1000 mg | 40 | 54 | 9 | 5 at week 24 90 at year 2 |
| RTX 1000 mg iv day 1 and 15, cyclophosphamide 750 mg IV day 3 and 17 | RTX 2 × 1000 mg + CYC | 41 | 53 | 10 | 7.3 at week 24 78 at year 2 |
||
| RTX 1000 mg IV day 1 and 15 with MTX | RTX 2 × 1000 mg + DMARD (MTX) | 40 | 54 | 12 | 2.5 at week 24 55 at year 2 |
||
| MTX | DMARD (MTX) | 40 | 54 | 11 | 82.5 at week 24 85 at year 2 |
||
| Emery et al61 | Active disease despite MTX Mean DAS28 ESR 6.4–6.54 across groups | RTX 2 × 500 mg IV infusion day 1 and 15 + MTX | RTX 2 × 500 mg + DMARD (MTX) | 168 | 51.9 | 7.1 | 3.0 at week 24 |
| RTX 2 × 1000 mg IV infusion day 1 and 15 + MTX | RTX 2 × 1000 mg + DMARD (MTX) | 170 | 51.3 | 6.6 | 2.4 at week 24 | ||
| MTX | DMARD (MTX) | 172 | 52.2 | 7.5 | 7.6 at week 24 | ||
| Genovese et al48 | Active RA despite MTX | ETN 25 mg twice weekly + MTX (mean) 16.1 mg/week | ETN 2 × 25 mg/week + DMARD (MTX) | 80 | 54.4 | 9.7 | 7 |
| ETN 25 mg twice weekly + ANA 100 mg/day + MTX (mean) 15.7 mg/week | ETN 2 × 25 mg/week + ANA + DMARD (MTX) | 81 | 55.7 | 10.6 | 20 | ||
| ETN 25 mg once weekly + ANA 100 mg/day + MTX (mean) 16.2 mg/week | ETN 1 × 25 mg/week + ANA + DMARD (MTX) | 81 | 53.8 | 9.5 | 22 | ||
| Genovese et al43 | Active, moderate to severe RA, despite conventional antirheumatic therapy DAS 28 6.6–6.7. | TOC 8 mg/kg IV every 4 weeks + cDMARD | TOC 8 mg/kg/4 weeks + DMARD (any traditional) | 805 | 53 | 9.8 | 7 (withdrawn from initial treatment) 2 (rescue therapy) |
| cDMARD | DMARD (any traditional) | 415 | 54 | 9.8 | 10 (withdrawn from initial treatment) 11 (rescue therapy) |
||
| Huang et al62 | Active disease despite MTX | ADA 40 mg every other week + MTX | ADA 40 mg/2 weeks + DMARD (MTX) | 121 | NR | NR | NR |
| ADA 80 mg every other week + MTX | ADA 80 mg/2 weeks + DMA RD (MTX) | 121 | NR | NR | NR | ||
| MTX | DMARD (MTX) | 60 | NR | NR | NR | ||
| Kameda et al46 | Active RA despite MTX | ETN 25 mg twice weekly (MTX discontinued) | ETN 2 × 25 mg/week | 74 | 58.1 | 10.6 | 16 |
| ETN 25 mg twice weekly + MTX 6–8 mg/week | ETN 2 × 25 mg/week + DMARD (MTX) | 77 | 56.5 | 8.1 | 5 | ||
| Kay et al63 | Active disease despite MTX | GOL 100 mg SC every 4 weeks + MTX (≥10 mg/week) | GOL 100 mg/4 weeks + DMARD (MTX) | 34 | 57.5 | 6.3 | 12.4 at week 16 |
| GOL 100 mg SC every 2 weeks + MTX (≥10 mg/week) | GOL 100 mg/2 weeks + DMARD (MTX) | 34 | 53.5 | 9 | |||
| GOL 50 mg SC every 4 weeks + MTX (≥10 mg/week) | GOL 50 mg/4 weeks + DMARD (MTX) | 35 | 57 | 8.2 | |||
| GOL 50 mg SC every 2 weeks + MTX (≥10 mg/week) | GOL 50 mg/2 weeks + DMARD (MTX) | 34 | 48 | 8.2 | |||
| MTX (≥10 mg/week) | DMARD (MTX) | 35 | 52 | 5.6 | 17.1 at week 16 | ||
| Keystone et al44 | Active disease despite MTX DAS28 using ESR at baseline median range 6.9–7.0 | CZP 200 mg + MTX (mean) 13.6 mg/week | CZP 200 mg/2 weeks + DMARD (MTX) | 393 | 51.4 | 6.1 | 35.1 at week 52 |
| CZP 400 mg + MTX (mean) 13.6 mg/week | CZP 400 mg/2 weeks + DMARD (MTX) | 390 | 52.4 | 6.2 | 29.7 at week 52 | ||
| MTX (mean) 13.4 mg/week | DMARD (MTX) | 199 | 52.2 | 6.2 | 78.4 at week 52 | ||
| Keystone et al64 | Moderate–severe active disease despite MTX | ADA 40 mg every other week + MTX (mean) 16.7 mg/week | ADA 40 mg/2 weeks + DMARD (MTX) | 207 | 56.1 | 11 | 22 at week 52 |
| ADA 20 mg every other week + MTX (mean) 16.3 mg/week | ADA 20 mg/2 weeks + DMARD (MTX) | 212 | 57.3 | 11 | |||
| MTX (mean) 16.7 mg/week | DMARD (MTX) | 200 | 56.1 | 10.9 | 30 | ||
| Keystone et al82 | Active disease despite MTX Median DAS28 using ESR at baseline Range 5.9–6.1 | GOL, 100 mg, injection every 4 weeks | GOL 100 mg/4 weeks | 133 | 51 (median) | 5.9 (median) | NR |
| GOL 100 mg injection every 4 weeks + MTX | GOL 100 mg/4 weeks + DMARD (MTX) | 89 | 50 (median) | 6.7 (median) | |||
| GOL 50 mg injection every 4 weeks + MTX | GOL 50 mg/4 weeks + DMARD (MTX) | 89 | 52 (median) | 4.5 (median) | |||
| MTX | DMARD (MTX) | 133 | 52 (median) | 6.5 (median) | |||
| Kim et al65 | NR | ADA 40 mg every other week + MTX (mean) 16.6 mg/week | ADA 40 mg/2 weeks + DMARD (MTX) | 65 | 48.5 | 6.8 | 21.5 at week 24 |
| MTX (mean) 16.3 mg/week | DMARD (MTX) | 63 | 49.8 | 6.9 | 36.5 at week 24 | ||
| Kremer et al50 | Moderate–severe active disease despite MTX for at least 3 months | GOL 2 mg/kg every 12 weeks | GOL 2 mg/kg | 128 | 49.9 | 7.4 | 80–90 at week 48 |
| GOL 4 mg/kg every 12 weeks | GOL 4 mg/kg | 129 | 48.4 | 8.4 | |||
| GOL 2 mk/kg every 12 weeks + MTX | GOL 2 mg/kg + DMARD (MTX) | 129 | 49.7 | 8.1 | |||
| GOL 4 mg/kg every 12 weeks + MTX | GOL 4 mg/kg + DMARD (MTX) | 128 | 49.6 | 9.4 | |||
| MTX | DMARD (MTX) | 129 | 50.2 | 7.4 | |||
| Kremer et al49 | Active disease despite DMARD A high degree of baseline activity based on number of tender and swollen joints | ABA 2 mg/kg, day 1, 15, and 30, and then monthly + MTX 10–30 mg/week | ABA 2 mg/kg/4 weeks + DMARD (MTX) | 105 | 54.4 | 9.6 | 22 |
| ABA 10 mg/kg, day 1, 15 and 30 and then monthly + MTX 10–30 mg/week | ABA 10 mg/kg/4 weeks + DMARD (MTX) | 115 | 55.8 | 9.7 | 14 | ||
| MTX 10–30 mg/week | DMARD (MTX) | 119 | 54.7 | 8.9 | 34 | ||
| Kremer et al66 | Active RA despite MTX DAS28 6.4 for both groups | ABA −10 mg/kg on day 1, 15, 29, and monthly + MTX ≥10 mg/week | ABA 10 mg/kg/4 weeks + DMARD (MTX) | 433 | 51.5 | 8.5 | 11 |
| MTX ≥ 10 mg/week | DMARD (MTX) | 219 | 50.4 | 8.9 | 26 | ||
| Lan et al67 | Active disease despite previous MTX | ETN 25 mg twice weekly + MTX 12.5–20 mg/week | ETN 2 × 25 mg/week + DMARD (MTX) | 29 | 47.6 | >1 | 7 |
| MTX 12.5–20 mg/week | DMARD (MTX) | 29 | 50.8 | 7 | |||
| Maini et al68 | Active disease despite MTX A considerable level of disease activity | INF 3 mg/kg every 8 weeks + MTX | INF 3 mg/kg/8 weeks + DMARD (MTX) | 86 | 56 | 8.4 | 9–18 |
| INF 3 mg/kg every 4 weeks + MTX | INF 3 mg/kg/4 weeks + DMARD (MTX) | 86 | 51 | 7.2 | |||
| INF 10 mg/kg every 8 weeks + MTX | INF 10 mg/kg/8 weeks + DMARD (MTX) | 87 | 55 | 9 | |||
| INF 10 mg/kg every 4 weeks + MTX | INF 10 mg/kg/4 weeks + DMARD (MTX) | 81 | 52 | 8.7 | |||
| MTX | DMARD (MTX) | 88 | 51 | 8.9 | 36 | ||
| Maini et al51 | Active disease despite MTX DAS28 ESR range 6.34–6.75 | TOC, 2 mg/kg every 4 weeks | TOC 2 mg/kg/4 weeks | 53 | 52.2 | 9.19 mo | 22.6 |
| TOC, 4 mg/kg every 4 weeks | TOC 4 mg/kg/4 weeks | 54 | 49.3 | 9.79 mo | 20 | ||
| TOC, 8 mg/kg every 4 weeks | TOC 8 mg/kg/4 weeks | 52 | 50.1 | 9.21 mo | 15 | ||
| TOC, 2 mg/kg every 4 weeks + MTX | TOC 2 mg/kg/4 weeks + DMARD (MTX) | 52 | 49.2 | 9.33 mo | 11.5 | ||
| TOC, 4 mg/kg every 4 weeks + MTX | TOC 4 mg/kg/4 weeks + DMARD (MTX) | 49 | 50.2 | 7.82 mo | 14 | ||
| TOC, 8 mg/kg every 4 weeks + MTX | TOC 8 mg/kg/4 weeks + DMARD (MTX) | 50 | 50.1 | 10.62 mo | 14 | ||
| MTX | DMARD (MTX) | 49 | 50.9 | 11.24 mo | 18 | ||
| Schiff et al69 | Active disease despite MTX DAS28 6.8–6.9 | ABA −10 mg/kg on day 1, 15, 29, and monthly + MTX | ABA 10 mg/kg/4 weeks + DMARD (MTX) | 156 | 49 | 7.9 | 5.8 |
| INF 3 mg/kg every 8 weeks + MTX | INF 3 mg/kg/8 weeks + DMARD (MTX) | 165 | 49.1 | 7.3 | 7.9 | ||
| MTX | DMARD (MTX) | 110 | 49.4 | 8.4 | 2.7 | ||
| Smolen et al52 | Moderate–severe active RA despite prior MTX DAS 6.8 | TOC 4 mg/kg IV every 4 weeks + MTX 10–25 mg/week (mean) 14.7 mg | TOC 4 mg/kg/4 weeks + DMARD (MTX) | 214 | 51.4 | 7.4 | 13 |
| TOC 8 mg/kg IV every 4 weeks + MTX 10–25 mg/week (mean) 14.5 mg | TOC 8 mg/kg/4 weeks + DMARD (MTX) | 205 | 50.8 | 7.5 | 6.8 | ||
| MTX (mean) 14.8 mg/week | DMARD (MTX) | 204 | 50.6 | 7.8 | 7.4 | ||
| Smolen et al45 | Active disease despite prior MTX DAS28 ESR 6.8–6.85 | CZP 200 mg SC + MTX (mean) 12.5 mg/week | CZP 200 mg/2 weeks + DMARD (MTX) | 246 | 52.2 | 6.1 | 29.3 at week 24 |
| CZP 400 mg SC + MTX (mean) 12.6 mg/week | CZP 400 mg/2 weeks + DMARD (MTX) | 246 | 51.9 | 6.5 | 26.4 at week 24 | ||
| MTX (mean) 12.2 mg/week | DMARD (MTX) | 127 | 51.5 | 5.6 | 86.6 at week 24 | ||
| van Riel et al47 | Active RA despite MTX Mean baseline DAS28 6.2–6.3 | ETN 25 mg twice weekly | ETN 2 × 25 mg/week | 160 | 53 | 10 | 10.7 |
| ETN 25 mg twice weekly + MTX ≥ 12.5 mg/week | ETN 2 × 25 mg/week + DMARD (MTX) | 155 | 54 | 9.8 | 8.4 | ||
| Weinblatt et al71 | Active disease despite prior MTX | ADA 20 mg every other week + MTX (mean) 16.9 mg/week | ADA 20 mg/2 weeks + DMARD (MTX) | 69 | 53.5 | 13.1 | NR |
| ADA 40 mg every other week + MTX (mean) 16.4 mg/week | ADA 40 mg/2 weeks + DMARD (MTX) | 67 | 57.2 | 12.2 | NR | ||
| ADA 80 mg every other week + MTX (mean) 17.2 mg/week | ADA 80 mg/2 weeks + DMARD (MTX) | 73 | 55.5 | 12.8 | NR | ||
| MTX (mean) 16.5 mg/week | DMARD (MTX) | 62 | 56.0 | 11.1 | NR | ||
| Weinblatt et al70 | Active disease despite MTX | ETN 25 mg twice weekly + MTX (mean) 19 mg/week | ETN 2 × 25 mg/week + DMARD (MTX) | 59 | 48 | 13 | 3 |
| MTX (mean) 18 mg/week | DMARD (MTX) | 30 | 53 | 13 | 20 | ||
| Westhovens et al72 | Moderate–severe active disease despite MTX Mean DAS28 5.1 | INF 3 mg/kg + MTX | INF 3 mg/kg/8 weeks + DMARD (MTX) | 360 | 53 | 7.8 (median) | 7.2 at week 22 |
| INF 10 mg/kg + MTX | INF 10 mg/kg/8 weeks + DMARD (MTX) | 361 | 52 | 6.3 (median) | 8.9 at week 22 | ||
| Placebo + MTX | DMARD (MTX) | 363 | 52 | 8.4 (median) | 6.3 at week 22 | ||
| Zhang53 | Active RA despite MTX (definition of active RA was ≥3 swollen joints and ≥8 joints) | INF, 3 mg/kg IV infusion weeks 0, 2, 6, and 14 + MTX | INF 3 mg/kg/8 weeks + DMARD (MTX) | 87 | 47.9 | 85.6 mo | 10.3 |
| Placebo + MTX | DMARD (MTX) | 86 | 48.9 | 96.0 mo | 17.4 |
Notes: Treatments in bold are treatments of interest (licensed doses); DMARD is the reference treatment.
Abbreviations: ABA, Abatacept; ADA, Adalimumab; AE, adverse event; ANA, anakinra; CZP, certolizumab pegol; DMARD, disease-modifying antirheumatic drug; ETN, etanercept; GOL, golimumab; INF, infliximab; mo, months; MP, methyl prednisolone; MTX, methotrexate; NR, not reported; RA, rheumatoid arthritis; RTX, rituximab; SUL, sulfasalazine; TOC, tocilizumab.