Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate?

Figures & data

Table 1 Radiographic outcomes reported in clinical trials for biologic combination therapy with methotrexate or as monotherapy at baseline and at 52 weeks

	Baseline X-ray score		Mean change in X-ray score		P value
	MTX	Biologic + MTX	MTX	Biologic + MTX
Agent + methotrexate
Infliximab^Citation13	82	75	4.0	0.25	<0.001
Infliximab^Citation14	–	–	25.0	−1.57	<0.001
Adalimumab^Citation11	66.4	72.1	2.7	0.1	<0.001
Etanercept^Citation6	26.8	21.8	2.8	−0.54	<0.0001
Adalimumab^Citation12	21.9	18.1	5.7	1.3	<0.001
Abatacept^Citation20	44.9	44.5	2.3	1.2	0.012
Certolizumab^Citation10	46.5	39.6	1.2	0.2	<0.01
Abatacept^Citation21	6.7	7.5	0.63	1.06	0.04
Rituximab^Citation16	32.5	30.6	2.81	1.14	<0.0001
Golimumab^Citation15,*	19.7	18.7	1.37	0.74	0.015
Golimumab^Citation15,*	36.7	29.7	1.1	0.93	0.855
Tocilizumab^Citation19	28.5	28.8	1.13	0.29	<0.0001
Rituximab^Citation17	7.4	7.7	0.74	0.23	<0.001
	MTX	Biologic	MTX	Biologic
Monotherapy
Etanercept^Citation5	12.9	2.4	1.59	1.00	0.11
Etanercept^Citation22	26.8	21.8	2.8	0.52	0.0469
Adalimumab^Citation12	21.9	18.8	5.7	3.0	<0.001
Tocilizumab^Citation18	30.6	28.3	6.1	2.3	<0.01
Golimumab^Citation15,*	19.7	20.4	1.37	1.25	0.266
Golimumab^Citation15,*	36.7	37.4	1.10	0.89	0.967

Notes:

* First line of data is from GO-BEFORE and the second is from GO-FORWARD. Not all trials reported data in this format.

Abbreviation: MTX, methotrexate.

Table 2 Biologic plus methotrexate versus methotrexate for total X-ray score in rank order

Medication	Reference	Follow-up period	Number	SMD (95% CI)
Infliximab	Lipsky et al^Citation13	54 weeks	173	−0.63 (−0.87 to −0.38)
Adalimumab	Keystone et al^Citation11	12 months	299	−0.45 (−0.68 to −0.22)
	Breedveld et al^Citation14	12 months	372	−0.45 (−0.65 to −0.24)
	Pooled			−0.45 (−0.60 to −0.29)
Rituximab	Tak et al^Citation17	12 months	443	−0.46 (−0.65 to −0.28)
	Cohen et al^Citation16	24 months	468	−0.41 (−0.59 to −0.22)
	Pooled			−0.44 (−0.58 to −0.30)
Etanercept	Emery et al^Citation7	12 months	476	−0.37 (−0.55 to −0.19)
	Klareskog et al^Citation6	12 months	430	−0.36 (−0.55 to −0.17)
	Pooled			−0.37 (−0.50 to −0.23)
Certolizumab pegol	Smolen et al^Citation10	24 weeks	373	−0.29 (−0.51 to −0.08)
Abatacept	Kremer et al^Citation20	12 months	586	−0.21 (−0.39 to −0.04)
	Westhovens et al^Citation21	12 months	459	−0.33 (−0.51 to −0.14)
	Pooled			−0.26 (−0.39 to −0.14)
Golimumab	Emery et al^Citation15	12 months	541	−0.09 (−0.26 to +0.08)

Note: Bold text indicates pooled results for each agent.

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Table 3 Odds of progression of radiographic damage ranked by effect size: therapy plus methotrexate versus methotrexate

Agent	Trial	Treatment*	Placebo*	OR (95% CI)
Infliximab	Breedveld et al^Citation14	24%	83%	0.07 (0.02, 0.29)
	Lipsky et al^Citation13	11%	31%	0.26 (0.14, 0.50)
	Pooled			0.19 (0.09, 0.41)
Etanercept	Klareskog et al^Citation6	20%	43%	0.34 (0.21, 0.54)
	Emery et al^Citation7	20%	41%	0.36 (0.23, 0.56)
	Pooled			0.35 (0.26, 0.47)
Tocilizumab	Kremer et al^Citation19	16%	33%	0.39 (0.25, 0.62)
Adalimumab	Breedveld et al^Citation12	36%	63%	0.33 (0.22, 0.51)
	Keystone et al^Citation11	38%	54%	0.52 (0.33, 0.83)
	Pooled			0.41 (0.27, 0.64)
Certolizumab pegol	Keystone et al^Citation8	31%	48%	0.48 (0.34, 0.69)
	Keystone et al^Citation9	26%	41%	0.51 (0.35, 0.75)
	Pooled			0.50 (0.38, 0.64)
Rituximab	Cohen et al^Citation16	43%	61%	0.48 (0.33, 0.71)
	Tak et al^Citation17	36%	47%	0.64(0.44, 0.93)
	Pooled			0.57 (0.43, 0.76)
Golimumab	Emery et al^Citation15	31%	40%	0.64 (0.44, 0.94)
Abatacept	Westhovens et al^Citation21	39%	47%	0.71 0.49, 1.03)

Note:

* Treatment refers to biologic DMARD plus methotrexate while placebo refers to the methotrexate plus placebo group. Bold text indicates pooled results for each agent.

Abbreviations: CI, confidence interval; DMARD, disease-modifying anti-rheumatic drug; OR, odds ratio.

Table 4 Biologic monotherapy versus methotrexate: standardized mean difference for total X-ray score

Medication	Reference	Follow-up period	Number analyzed	SMD (95% CI)
Tocilizumab	Nishimoto et al^Citation18	12 months	300	−0.43 (−0.65, −0.20)
Etanercept	Bathon et al^Citation5	12 months	395	−0.28 (−0.48, −0.08)
	Klareskog et al^Citation6	12 months	424	−0.24 (−0.43, −0.05)
	Pooled			−0.26 (−0.40, −0.12)
Adalimumab	Breedveld et al^Citation14	12 months	531	−0.23 (−0.40, −0.05)
Golimumab	Emery et al^Citation15 GO-BEFORE^Citation15	12 months	319	−0.02 (−0.24, +0.20)
	Emery et al^Citation15 GO-FORWARD^Citation15	12 months	222	−0.04 (−0.30, +0.23)
	Pooled			−0.03 (−0.20, +0.14)

Note: Bold text indicates pooled results for each agent.

Abbreviations: CI, confidence interval; SMD, standardized mean difference.

Table 5 Odds of progression of radiographic damage ranked by effect size: monotherapy versus methotrexate

Medication	Reference	Patients progressing		OR (95% CI)
		Treatment	Placebo
Tocilizumab	Nishimoto et al^Citation18	44%	61%	0.50 (0.31, 0.82)
Adalimumab	Breedveld et al^Citation14	49%	63%	0.57 (0.37, 0.89)
Etanercept	Klareskog et al^Citation6	32%	43%	0.63 (0.42, 0.93)
	Bathon et al^Citation5	28%	40%	0.58 (0.38, 0.88)
	Pooled			0.61 (0.45, 0.81)
Golimumab	Emery et al^Citation15 GO-BEFORE^Citation15	39%	46%	0.76 (0.98, 1.23)
	Emery et al^Citation15 GO-FORWARD^Citation15	34%	31%	0.89 (0.49, 1.61)
	Pooled			0.81 (0.56, 1.17)

Note: Bold text indicates pooled results for each agent.

Abbreviations: CI, confidence interval; OR, odds ratio.

LipskyPEvan der HeijdeDMSt ClairEWInfliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study groupN Engl J Med20003431594160211096166

 PubMed Web of Science ®Google Scholar

BreedveldFCEmeryPKeystoneEInfliximab in active early rheumatoid arthritisAnn Rheum Dis20046314915514722203

 PubMed Web of Science ®Google Scholar

KeystoneECKavanaughAFSharpJTRadiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trialArthritis Rheum2004501400141115146409

 PubMed Web of Science ®Google Scholar

KlareskogLvan der HeijdeDde JagerJPTherapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trialLancet200436367568115001324

 PubMed Web of Science ®Google Scholar

BreedveldFCWeismanMHKavanaughAFThe PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatmentArthritis Rheum200654263716385520

 PubMed Web of Science ®Google Scholar

KremerJMGenantHKMorelandLWEffects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trialAnn Intern Med200614486587616785475

 PubMed Web of Science ®Google Scholar

SmolenJLandeweRBMeasePEfficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trialAnn Rheum Dis20096879780419015207

 PubMed Web of Science ®Google Scholar

WesthovensRRoblesMXimenesACClinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factorsAnn Rheum Dis2009681870187719124524

 PubMed Web of Science ®Google Scholar

CohenSBKeystoneEGenoveseMCContinued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexateAnn Rheum Dis2010691158116120439295

 PubMed Web of Science ®Google Scholar

EmeryPFleischmannRvan der HeijdeDThe effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapyArthritis Rheum2011631200121021305524

 PubMed Web of Science ®Google Scholar

KremerJMBlancoRBrzoskoMTocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one yearArthritis Rheum20116360962121360490

 PubMed Web of Science ®Google Scholar

TakPPRigbyWFRubbert-RothAInhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trialAnn Rheum Dis201170394620937671

 PubMed Web of Science ®Google Scholar

BathonJMMartinRWFleischmannRMA comparison of etanercept and methotrexate in patients with early rheumatoid arthritisN Engl J Med20003431586159311096165

 PubMed Web of Science ®Google Scholar

van der HeijdeDKlareskogLRodriguez-ValverdeVComparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trialArthritis Rheum2006541063107416572441

 PubMed Web of Science ®Google Scholar

NishimotoNHashimotoJMiyasakaNStudy of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumabAnn Rheum Dis2007661162116717485422

 PubMed Web of Science ®Google Scholar

EmeryPBreedveldFCHallSComparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trialLancet200837237538218635256

 PubMed Web of Science ®Google Scholar

KeystoneEHeijdeDMasonDJrCertolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group studyArthritis Rheum2008583319332918975346

 PubMed Web of Science ®Google Scholar

KeystoneECCurtisJRFleischmannRMRapid improvement in the signs and symptoms of rheumatoid arthritis following certolizumab pegol treatment predicts better longterm outcomes: post-hoc analysis of a randomized controlled trialJ Rheumatol20113899099621362764

 PubMed Web of Science ®Google Scholar