Infliximab, methotrexate and their combination for the treatment of
          rheumatoid arthritis: a systematic review and meta-analysis

Costa, Juliana de Oliveira; Lemos, Lívia Lovato Pires de; Machado, Marina Amaral de Ávila; Almeida, Alessandra Maciel; Kakehasi, Adriana Maria; Araújo, Vânia de Eloísa; Cherchiglia, Mariângela Leal; Andrade, Eli Iola Gurgel; Acurcio, Francisco de Assis

doi:10.1016/j.rbr.2014.10.009

Juliana de Oliveira Costa ^**Corresponding author.

Post-Graduate Program in Public Health, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Lívia Lovato Pires de Lemos

Post-Graduate Program in Medications and Pharmaceutical Assistance, School of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Marina Amaral de Ávila Machado

Post-Graduate Program in Public Health, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Alessandra Maciel Almeida

Department of Social Pharmacy, School of Pharmacy, Faculdade de Farmácia, Universidade Federal de Belo Horizonte, Belo Horizonte, MG, Brazila

Adriana Maria Kakehasi

Department of Locomotor System, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Vânia de Eloísa Araújo

Evidence-Based Medicine/PGMIT, Universidade Federal de São Paulo, São Paulo, SP, Brazil

Mariângela Leal Cherchiglia

Department of Preventive and Social Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Eli Iola Gurgel Andrade

Department of Preventive and Social Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Francisco de Assis Acurcio

Department of Social Pharmacy, School of Pharmacy, Faculdade de Farmácia, Universidade Federal de Belo Horizonte, Belo Horizonte, MG, Brazila

*Corresponding author.

Conflicts of interest

The authors declare no conflicts of interest.

Study – follow-up	Patients (n)	Age (years) mean (SD)	Duration of disease (years) mean (SD)	Number of previous DMARD mean (SD)	Number of swollen joints mean (SD)	Number of tender joints mean (SD)	Patients on oral steroid therapy %	Patients on NSAID therapy %
Maini et al. ³³33 Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552–63. – 26 weeks
Placebo + MTX	14	48.8 (12.3)	7.6 (4)	2 (1–3)^b b Median.	17 (12–25)^b b Median.	28 (22–47)^b b Median.	50	NI
IFX IV 3 mg/kg each 4 weeks + MTX	15	58.9 (10)	12.1 (9)	2 (2–4)^b b Median.	16 (13–22)^b b Median.	21 (12–31)^b b Median.	60	NI
IFX IV 3 mg/kg each 4 weeks	14	47 (15)	7.8 (4.3)	2.5 (2–3)^b b Median.	17 (11–32)^b b Median.	31 (23–39)^b b Median.	50	NI
IFX IV 10 mg/kg each 4 weeks + MTX	14	50.4 (13.4)	11.1 (7.4)	2 (2–4)	20 (14–31)^b b Median.	26 (23–37)^b b Median.	28	NI
IFX IV 10 mg/kg each 4 weeks	15	56.3 (9.1)	9.7 (7.4)	2 (1–4)	19 (11–22)^b b Median.	23 (16–35)^b b Median.	60	NI
ATTRACT ³⁵35 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999;354(9194):1932–9. ^, ³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602. – 30 weeks
Placebo + MTX	88	51 (19.0–75.0)^b b Median.	8.9 (0.8–35.0)^b b Median.	2.5 (1.4)	19	24	64	72
IFX IV 3 mg/kg each 8 weeks + MTX	86	56 (25.0–74.0)^b b Median.	8.4 (0.7–45.0)^b b Median.	2.8 (1.5)	19	32	63	79
IFX IV 3 mg/kg each 4 weeks + MTX	86	51 (19.0–78.0)^b b Median.	7.2 (0.5–33.8)^b b Median.	2.6 (1.5)	20	31	53	76
IFX IV 10 mg/kg each 8 weeks + MTX	87	55 (19.0–80.0)^b b Median.	9.0 (0.5–49.9)^b b Median.	2.5 (1.4)	20	30	57	77
IFX IV 10 mg/kg each 4 weeks + MTX	81	52 (23.0–74.0)^b b Median.	8.7 (0.6–47.0)^b b Median.	2.5 (1.3)	23	35	65	68
ASPIRE ²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43. – 52 weeks
Placebo + MTX	282	50 (13)	0.9 (0.7)	NI	22 (11)	34 (15)	38	82
IFX IV 3 mg/kg each 8 weeks + MTX	359	51 (12)	0.8 (0.7)	NI	21 (10)	32 (15)	37	85
IFX IV 6 mg/kg each 8 weeks + MTX	363	50 (13)	0.9 (0.8)	NI	22 (11)	33 (15)	39	82
START ³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86. – 22 weeks
Placebo + MTX	363	52.0 (44–61)^b b Median.	8.4 (4–15)^b b Median.	NI	15 (10–21)^b b Median.	22 (15–32)^b b Median.	59.2^b b Median.	39.4^b b Median.
IFX IV 3 mg/kg each 8 weeks + MTX	360	53.0 (45–61)^b b Median.	7.8 (3–15)^b b Median.	NI	15(11–21)^b b Median.	22 (15–31)^b b Median.	59.2^b b Median.	43.3^b b Median.
IFX IV 10 mg/kg each 8 weeks + MTX	361	52.0 (43–60)^b b Median.	6.3 (3–14)^b b Median.	NI	15 (10–21)^b b Median.	22 (15–30)^b b Median.	59.0^b b Median.	41.3^b b Median.
Abe et al. ³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44. – 14 weeks
Placebo + MTX	47	55.1 (7.6)	7.5 (5.0)	NI	13.5 (7.6)	17.8 (8.7)	89.4	95.7
IFX IV 3 mg/kg each 8 weeks + MTX	49	55.2 (10.9)	9.1 (7.4)	NI	15.1 (9.0)	19.0 (11.8)	85.7	89.8
IFX IV 10 mg/kg each 8 weeks + MTX	51	56.8 (10.5)	7.1 (5.1)	NI	13.2 (6.2)	18.7 (12.3)	92.2	94.1
Zhang et al. ²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30. – 18 weeks
Placebo + MTX	86	48.9 (8.0)	96.0 (74.6)^c c In months.	NI	NI	NI	NI	NI
IFX IV 3 mg/kg + MTX	87	47.9 (10.1)	85.6 (74.0)^c c In months.	NI	NI	NI	NI	NI
Durez et al. ³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27. – 52 weeks
Placebo + MTX	14	53.8 (15.2)	0.45 (0.29)	NI	10.3 (5.5)	11.6 (7.5)	NI	0
IFX IV 3 mg/kg each 8 weeks + MTX	15	50.0 (9.9)	0.36 (0.31)	NI	12.5 (5.4)	15.9 (8.0)	NI	0
ATTEST ²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103. 52 weeks
Placebo + MTX	110	49.4 (11.5)	8.4 (8.6)	NI	20.1 (7.0)	30.3 (11.7)	70.0	84.5
IFX IV 3 mg/kg + MTX^a a Infliximab at days 1, 15, 43, 85 and each 56 days.	165	49.1 (12.0)	7.3 (6.2)	NI	20.3 (8.0)	31.7 (14.5)	71.5	86.1
SWEFOT ³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20. ^, ³¹31 Van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Coster L, Waltbrand E, et al. Addition of infliximab comparedwith addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009;374(9688):459–66. – 104 weeks
SSZ 1000 mg bid + HCQ 400 mg/day + MTX	130	52.9 (13.9)	6.3 (3.6)^c c In months.	NI	NI	NI	8	NI
IFX IV 3 mg/kg each 8 weeks + MTX	128	51.1 (13.3)	6.2 (3.5)^c c In months.	NI	NI	NI	6	NI

Study	Modified Jadad scale									Risk of bias
	Randomisation	Appropriate randomisation method	Inappropriate randomisation method	Concealment	Appropriate Concealment method	Losses to follow-up	ITT analysis	Score	Sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective outcome reporting	Overall risk of bias
ATTRACT³⁵35 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999;354(9194):1932–9.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1	1	0	1	1	1	1	6	L	L	L	L	L	L	L
Maini et al.³³33 Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552–63.	1	0	0	1	1	1	1	5	U	L	L	L	L	H	H
ASPIRE²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.	1	1	0	1	1	1	0	5	L	L	L	L	U	L	U
START³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.	1	0	0	1	1	1	1	5	U	U	L	L	L	L	U
ATTEST²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.	1	0	0	1	1	1	1	5	U	U	L	L	L	L	U
Zhang ²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30.	1	0	0	1	0	1	1	4	U	U	U	U	L	U	U
SWEFOT³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,³¹31 Van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Coster L, Waltbrand E, et al. Addition of infliximab comparedwith addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009;374(9688):459–66.	1	1	0	0	0	1	1	4	U	H	H	H	L	L	H
Abe et al.³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.	1	0	0	0	0	1	1	3	U	U	U	U	L	L	U
Durez et al.³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	1	0	0	0	0	1	1	3	U	U	H	L	L	L	H

Comparison [study]	ACR 20 (RR, 95% CI)	I² (%)^a a I2>40% indicate heterogeneity between studies.	p-Value^b b p-Value<0.10 of χ2 indicates heterogeneity between studies.1	ACR 50 (RR, 95% CI)	I² (%)^a a I2>40% indicate heterogeneity between studies.	p-Value^b b p-Value<0.10 of χ2 indicates heterogeneity between studies.1	ACR 70 (RR, 95% CI)	I² (%)^b b p-Value<0.10 of χ2 indicates heterogeneity between studies.1	p-Value^b b p-Value<0.10 of χ2 indicates heterogeneity between studies.1
Infliximab standard dose according time to follow up
30 weeks²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^–³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁵35 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999;354(9194):1932–9.	1.99 (1.56; 2.55)	68	0.009	2.45 (1.73; 3.48)	54	0.05	2.64 (1.78; 3.91)	12	0.34
52 weeks ²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.^,³¹31 Van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Coster L, Waltbrand E, et al. Addition of infliximab comparedwith addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009;374(9688):459–66.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1.48 (1.11; 1.96)	70	0.02	1.47 (1.25; 1.74)	0	0.49	1.66 (1.31; 2.09)	0	0.48
104 weeks³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.	1.20 (0.87; 1.67)	–	–	1.38 (0.90; 2.10)	–	–	1.18 (0.66; 2.12)	–	–
Infliximab standard dose per patient profile
Insufficient responses to MTX³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1.77 (1.38; 2.26)	74	0.002	2.13 (1.53; 2.97)	61	0.003	2.18 (1.43; 3.34)	43	0.12
MTX-naive²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	1.40 (0.84; 2.34)	64	0.10	1.44 (1.18; 1.76)	0	0.51	1.56 (1.19; 2.04)	0	0.58
Infliximab standard dose according to disease duration
Early RA, disease duration < 1 year³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	1.45 (0.89; 2.36)	51	0.15	1.47 (1.02; 2.14)	0	0.15	1.30 (0.76; 2.23)	0	0.40
Established or late RA, disease duration > 1 year²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^–²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1.75 (1.30; 2.34)	87	<0.00001	2.11 (1.48; 3.01)	74	0.002	2.18 (1.50; 3.15)	45	0.10
Infliximab high doses
Doses higher than 3 mg/kg each 8 weeks versus DMARD²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	2.41 (1.56; 3.73)	92	<0.00001	3.46 (2.01; 5.96)	85	<0.00001	4.56 (2.20; 9.46)	75	=0.001
High doses versus standard dose IFX²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1.07 (0.97; 1.17)	22	0.28	1.17 (1.00; 1.36)	27	0.25	1.19 (1.01; 1.41)	0	0.46

Outcome	Number of evaluated studies [study]	Patients (n)	RR (IC 95%)	I ² ^a a I2>40% indicate heterogeneity between studies.	p-Value^b b p-Value<0.10 of χ2 indicates heterogeneity between studies.
Infections	4	658	1.04 (0.73; 1.47)	66%	0.03
Insufficient responses to MTX	3³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.	629	1.21 (0.75; 1.98)	57%	0.10
MTX-naïve patients	1³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	29	0.81 (0.61; 1.06)	–	–
Serious infections	6	2128	1.19 (0.48; 2.93)	56%	0.08
Insufficient responses to MTX	4³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1428	0.83 (0.33; 2.06)	31%	0.24
MTX-naïve patients	2²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	700	2.80 (1.14; 6.84)	–	–
Serious adverse events	8	2397	1.02 (0.79; 1.33)	0%	0.57
Insufficient responses to MTX	6³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁶36 Lipsky PE, Van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.	1697	0.86 (0.61; 1.21)	0%	0.57
MTX-naïve patients	2²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	700	1.32 (0.87; 1.98)	0%	0.63
Tumours	7	2369	1.87 (0.42; 8.35)	0%	0.92
Insufficient responses to MTX	6³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.^,³⁵35 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet. 1999;354(9194):1932–9.	1698	1.87 (0.42; 8.35)	0%	0.92
MTX-naïve patients	1²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.	671	–	–	–
Tuberculose	5	1928	4.12 (0.47; 36.07)	0%	0.78
Insufficient responses to MTX	4²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,²⁹29 Zhang F-C. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China. Aplar J Rheumatol. 2006;9(2):127–30.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.	1265	2.97 (0.12; 71.81)	–	–
MTX-naïve patients	1²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.	663	5.48 (0.28; 105.67)	–	–
Death	6	2052	1.05 (0.20; 5.42)	0%	0.55
Insufficient responses to MTX	4³3 Van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712–20.^,²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.^,³⁴34 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006;54(4):1075–86.	1352	2.47 (0.26; 23.61)	0%	0.86
MTX-naïve patients	2²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.^,³⁰30 Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56(12):3919–27.	700	0.40 (0.04; 4.38)	–	–
Infusion reactions	3	1042	2.21 (1.63; 2.99)	72%	0.03
Insufficient responses to MTX	2²⁸28 Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–103.^,³²32 Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol. 2006;33(1):37–44.	371	1.52 (1.02; 2.26)	0%	0.40
MTX-naïve patients	1²⁷27 Clair EWS, Van der Heijde D, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis – A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.	671	3.16 (1.98; 5.03)	–	–

[1] *Corresponding author.

Brasil

Brasil

Infliximab, methotrexate and their combination for the treatment of rheumatoid arthritis: a systematic review and meta-analysis^☆ ☆ Institution: School of Medicine, UFMG, Belo Horizonte, MG, Brazil.

Brasil

Brasil

Infliximab, methotrexate and their combination for the treatment of rheumatoid arthritis: a systematic review and meta-analysis☆ ☆ Institution: School of Medicine, UFMG, Belo Horizonte, MG, Brazil.

Infliximab, methotrexate and their combination for the treatment of rheumatoid arthritis: a systematic review and meta-analysis^☆ ☆ Institution: School of Medicine, UFMG, Belo Horizonte, MG, Brazil.