Efficacy of biological agents administered as monotherapy in rheumatoid arthritis: a Bayesian mixed-treatment comparison analysis

Figures & data

Figure 1 Selection process for studies included in meta-analysis.

Abbreviations: INIST, Institut de l’Information Scientifique et Technique; MTX, methotrexate; RA, rheumatoid arthritis; RCT, randomized controlled trial.

Table 1 Characteristics of trials included in meta-analysis

Study (year)	ITT	Geographic origin	Drug tested	Comparator	Study duration
Moreland et al^Citation43 (1999)	158	NAM	Etanercept (25 mg, sc, tw)	Placebo	26 weeks
Bathon et al^Citation44 (2000)	424	NAM	Etanercept (25 mg, sc, tw)	MTX (19 mg/week)	24 weeks
Klareskog et al^Citation46 (2004)	451	EUR, AUS, ISR	Etanercept (25 mg, sc, tw)	MTX (17.2 mg/week)	1 year
van de Putte et al^Citation45 (2004)	223	EUR, CAN, AUS	Adalimumab (40 mg, sc, eow)	Placebo	26 weeks
Breedveld et al^Citation47 (2006)	531	EUR, NAM, AUS	Adalimumab (40 mg, sc, eow)	MTX (20 mg/week)	2 years
Maini et al^Citation48 (2006)	102	EUR	Tocilizumab (8 mg, iv, efw)	MTX (10–17.5 mg/week)	16 weeks
Nishimoto et al^Citation49 (2007)	302	JAP	Tocilizumab (8 mg, iv, efw)	DMARDs + MTX (6.9 mg/week)	24 weeks
Jones et al^Citation50 (2010)	524	NAM, ISR	Tocilizumab (8 mg, iv, efw)	MTX (15.5 mg/week)	24 weeks
Nishimoto et al^Citation51 (2009)	125	JAP	Tocilizumab (8 mg, iv, efw)	MTX (8 mg/week)	24 weeks
Gabay et al^Citation23 (2013)	325	NAM, SAM, AUSAS, EUR	Tocilizumab (8 mg, iv, efw)	Adalimumab (40 mg, sc, eow)	24 weeks

Abbreviations: AUS, Australia; AUSAS, Australasia; CAN, Canada; DMARD, disease-modifying antirheumatic drug; efw, every four weeks; eow, every other week; EUR, Europe; ISR, Israel; ITT, intention to treat population; iv, intravenous; JAP, Japan; MTX, methotrexate; NAM, North America; SAM, South America; sc, subcutaneous; tw, twice weekly.

Table 2 Baseline demographic and clinical characteristics

Study (year)	Female (%)	Mean age (years)	Disease duration (years)	MTX naïve	MTX-IR	Mean previous DMARD	DAS-28	ESR (mm/h)	CRP (mg/dL)
Moreland et al^Citation43 (1999)	74	53	11	No	Yes	3.3	N/A	35	4.7
Bathon et al^Citation44 (2000)	74	51±13	1±0.9	Yes	No	0.5±0.7	N/A	N/A	3.3±4
Klareskog et al^Citation46 (2004)	77	52.5±12.4	6.8±5.4	No	Yes	2.3±1.4	5.5±1.2	N/A	2.9±3.3
van de Putte et al^Citation45 (2004)	79.6	52.7±13.3	10.6±6.9	No	Yes	3.8±21.8	7.07±0.86	55.8±27	5.26±3.7
Breedveld et al^Citation47 (2006)	77.4	52.1±13.5	0.7±0.8	Yes	No	2.7± (1–7)	6.4±0.9	N/A	4.1±3.9
Maini et al^Citation48 (2006)	73.1	50.1	0.8	No	Yes	1.2±1.3	6.43	39	2.2
Nishimoto et al^Citation49 (2007)	80.8	52.9±11.6	2.2±1.4	No	Yes	2.7± (1–7)	6.5±0.8	71±25.2	4.9±2.9
Jones et al^Citation50 (2010)	83	50.7±13.1	6.4±7.9	Part	Part	1.2±1.3	6.8±1	49.9±27.9	3.0±3.3
Nishimoto et al^Citation51 (2009)	82.4	52.6±10.6	8.5±8.4	No	Yes	3.3 (1–8)	6.1±0.9	51.9±27.7	3.0±2.0
Gabay et al^Citation23 (2013)	79	54.4±13	7.3±8.1	No	Yes	2±1.1	6.7±0.9	50.5±20.9	2.6±3.1

Note: Data presented as mean ± standard deviation or (range).

Abbreviations: CRP, C-reactive protein; DAS-28, disease activity score in 28 joints; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; MTX, methotrexate; MTX-IR, methotrexate inadequate response patients; N/A, data not available; Part, partial.

Table 3 ACR20/50/70 response in trials included in meta-analysis

Study (year)	Disease duration (years)	ACR20	P-value	ACR50	P-value	ACR70	P-value
Moreland et al^Citation43 (1999)	11	E: 59%, P: 10%	0.0001	E: 40%, P: 5%	0.001	E: 15%, P: 1%	0.031
Bathon et al^Citation44 (2000)	1±0.9	E: ~60%, M: ~60%	NS	E: ~40%, M: ~30%	NS	E: ~20%, M: ~15%	<0.05
Klareskog et al^Citation46 (2004)	6.8±5.4	E: 70%, M: 70%	NS	E: 40%, M: 40%	NS	E: 15%, M: 15%	NS
van de Putte et al^Citation45 (2004)	10.6±6.9	A: 53.4%, P: 19.1%	≤0.001	A: 35%, P: 8.2%	≤0.001	A: 18.4%, P: 1.8%	≤0.001
Breedveld et al^Citation47 (2006)	0.7±0.8	A: 54%, M: 63%	<0.05	A: 41%, M: 46%	NS	A: 26%, M: 28%	NS
Maini et al^Citation48 (2006)	0.8	T: 63%, M: 41%	<0.05	T: 41%, M: 29%	NS	T: 16%, M: 16%	NS
Nishimoto et al^Citation49 (2007)	2.2±1.4	T: 78%, M: 34%	<0.001	T: 64%, M: 13%	<0.001	T: 44%, M: 6%	<0.001
Jones et al^Citation50 (2010)	6.4±7.9	T: 69.9%, M: 52.5%	<0.001	T: 44.1%, M: 33.5%	<0.002	T: 28%, M: 15.1%	<0.001
Nishimoto et al^Citation51 (2009)	8.5±8.4	T: 80.3%, M: 25%	<0.001	T: ~55%, M: ~18%	N/A	T: ~32%, M: ~15%	N/A
Gabay et al^Citation23 (2012)	7.3±8.1	T: 65%, A: 49.4%	0.0038	T: 47.2%, A: 27.8%	0.0002	T: 32.5%, A: 17.9%	0.0023

Note: P-values represent statistically significant differences between the two treatment arms reported in each study.

Abbreviations: A, adalimumab; ACR, American College of Rheumatology; E, etanercept; M, methotrexate; N/A, not available; NS, not statistically significant; P, placebo; T, tocilizumab.

Figure 2 Relative odds of different drug comparisons being the most effective treatment for obtaining improvement in ACR outcome.

Notes: (A) ACR20, (B) ACR50, and (C) ACR70 outcomes. Data presented as odds ratio for different drug comparisons. Solid line denotes mean odds ratio for all treatment comparisons. Black dotted-line denotes an odds ratio of 1. For clarity, each figure is divided into three sections by treatment type vs methotrexate; biologic vs biologic; and vs placebo.
Abbreviations: A, adalimumab; ACR, American College of Rheumatology; E, etanercept; M, methotrexate; P, placebo; T, tocilizumab.

Table 4 Results of mixed-treatment comparison for each drug in being the most effective treatment for obtaining ACR20 improvement

Comparison	Odds ratioa	Lower 95% CrI	Higher 95% CrI	Probability of best treatment for ACR20 (%)	Rank
Tocilizumab vs placebo	0.066	0.035	0.11	100	1
Etanercept vs placebo	0.25	0.13	0.42	0	NR
Adalimumab vs placebo	0.16	0.09	0.26	0	NR
Methotrexate vs placebo	0.21	0.11	0.35	0	NR
Methotrexate vs etanercept	0.85	0.58	1.19	NA	NA
Methotrexate vs adalimumab	1.34	0.82	2.07	NA	NA
Methotrexate vs tocilizumab	3.19	2.46	4.09	NA	NA
Etanercept vs adalimumab	1.62	0.91	2.68	NA	NA
Etanercept vs tocilizumab	3.89	2.46	5.81	NA	NA
Adalimumab vs tocilizumab	2.49	1.61	3.71	NA	NA

Note:

a Odds ratio represents the ratio of being the most effective treatment for one drug compared to another (eg, adalimumab vs tocilizumab, represents a 2.49-fold difference, favoring tocilizumab).

Abbreviations: ACR, American College of Rheumatology; CrI, credible interval; NA, not applicable; NR, not relevant.

Table 5 Results of mixed-treatment comparison for each drug in being the most effective treatment for obtaining ACR50 improvement

Comparison	Odds ratioa	Lower 95% CrI	Higher 95% CrI	Probability of best treatment for ACR50 (%)	Rank
Tocilizumab vs placebo	0.05	0.012	0.13	99.83	1
Etanercept vs placebo	0.11	0.026	0.25	0.14	2
Adalimumab vs placebo	0.12	0.026	0.29	0.023	3
Methotrexate vs placebo	0.16	0.04	0.39	0.003	4
Methotrexate vs etanercept	1.51	1	2.2	NA	NA
Methotrexate vs adalimumab	1.44	0.82	2.33	NA	NA
Methotrexate vs tocilizumab	3.06	2.33	3.97	NA	NA
Etanercept vs adalimumab	0.99	0.49	1.79	NA	NA
Etanercept vs tocilizumab	2.11	1.27	3.31	NA	NA
Adalimumab vs tocilizumab	2.25	1.39	3.47	NA	NA

Note:

a Odds ratio represents the ratio of being the most effective treatment for one drug compared to another (eg, adalimumab vs tocilizumab, represents a 2.25-fold difference, favoring tocilizumab).

Abbreviations: ACR, American College of Rheumatology; CrI, credible interval; NA, not applicable.

Table 6 Results of mixed-treatment comparison for each drug in being the most effective treatment for obtaining ACR70 improvement

Comparison	Odds ratioa	Lower 95% CrI	Higher 95% CrI	Probability of best treatment for ACR70 (%)	Rank
Tocilizumab vs placebo	0.05	0.00008	0.24	98.68	1
Etanercept vs placebo	0.11	0.002	0.45	1.19	2
Adalimumab vs placebo	0.12	0.002	0.54	0.12	3
Methotrexate vs placebo	0.19	0.003	0.81	0.003	4
Methotrexate vs etanercept	1.78	1	2.88	NA	NA
Methotrexate vs adalimumab	1.68	0.86	2.95	NA	NA
Methotrexate vs tocilizumab	3.56	2.51	4.92	NA	NA
Etanercept vs adalimumab	1.01	0.42	2.06	NA	NA
Etanercept vs tocilizumab	2.14	1.11	3.74	NA	NA
Adalimumab vs tocilizumab	2.27	1.32	3.73	NA	NA

Note:

a Odds ratio represents the ratio of being the most effective treatment for one drug compared to another (eg, adalimumab vs tocilizumab, represents a 2.27-fold difference, favoring tocilizumab).

Abbreviations: ACR, American College of Rheumatology; CrI, credible interval; NA, not applicable.

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