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Defining the optimal biological monotherapy in rheumatoid arthritis: A systematic review and meta-analysis of randomised trials. Tarp et al.

SUPPLEMENTARY DATA

ContentSupplement Table 1: Search Strategies................................................................................................2

PubMed search strategy....................................................................................................................2The Cochrane Central Register of Controlled Trials (CENTRAL) search strategy.........................2EMBASE search strategy.................................................................................................................3Clinicaltrials.gov search strategy.....................................................................................................4

Supplement Table 2: Recommended maintenance dose regime..........................................................5Supplement Table 3: Characteristics of Included Studies (including references) and Outcome Data.6Supplement Table 4: Odds ratios for secondary benefit outcomes....................................................10Supplement Table 5: Odds ratios for secondary harm outcomes.......................................................12Supplement Table 6: Odds ratios for primary benefit/harm outcomes - recommended dose (incl. MTX)..................................................................................................................................................14Supplement Table 7: Odds ratios for primary benefit/harm outcomes – DMARD-IR patients.........15Supplement Table 8: Odds ratios for primary benefit/harm outcomes – DMARD-IR patients (excluding the ADACTA study)........................................................................................................17Supplement Table 9: Odds ratios for primary benefit outcome – imputation method for discontinued patients................................................................................................................................................19Supplement Table 10: Odds ratios for primary benefit/harm outcomes – inclusion of tofacitinib....21Supplement Figure 1: Direct pairwise meta-analysis for ACR50 - compared with placebo.............23Supplement Figure 2: Direct pairwise meta-analysis for ACR50 - compared with methotrexate.....24Supplement Figure 3: Direct pairwise meta-analysis for withdrawal due to adverse events - compared with placebo.......................................................................................................................25Supplement Figure 4: Direct pairwise meta-analysis for withdrawal due to adverse events - compared with methotrexate..............................................................................................................26Supplement Figure 5: Direct pairwise meta-analysis for ACR50 – tofacitinib compared with placebo................................................................................................................................................27Supplement Figure 6: Direct pairwise meta-analysis for ACR50 – tofacitinib compared with methotrexate.......................................................................................................................................27Supplement Figure 7: Direct pairwise meta-analysis for ACR50 – tofacitinib compared with adalimumab........................................................................................................................................27Supplement Figure 8: Direct pairwise meta-analysis for withdrawal due to adverse events – tofacitinib compared with placebo.....................................................................................................27Supplement Figure 9: Direct pairwise meta-analysis for withdrawal due to adverse events – tofacitinib compared with methotrexate.............................................................................................28

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Supplement Figure 10: Direct pairwise meta-analysis for withdrawal due to adverse events – tofacitinib compared with adalimumab..............................................................................................28

Supplement Table 1: Search Strategies

PubMed search strategy(((("Receptors, Tumor Necrosis Factor"[nm] OR TNFR:Fc OR "TNFR-Fc fusion protein"[Supplementary Concept] OR "TNFR-Fc fusion protein"[All Fields] OR "etanercept"[All Fields] OR "enbrel"[All Fields]) OR ("infliximab"[Supplementary Concept] OR "infliximab"[All Fields] OR "remicade"[All Fields] OR "mab ca2"[All Fields] OR "monoclonal antibody ca2"[All Fields]) OR ("adalimumab"[Supplementary Concept] OR "adalimumab"[All Fields] OR "humira"[All Fields]) OR ("interleukin 1 receptor antagonist protein"[MeSH Terms] OR "interleukin 1 receptor antagonist protein"[All Fields] OR "anakinra"[All Fields] OR "kineret"[All Fields] OR "antril"[All Fields]) OR ("abatacept"[Supplementary Concept] OR "abatacept"[All Fields]) OR CTLA4Ig[All Fields] OR "orencia"[All Fields]) OR ("rituximab"[Supplementary Concept] OR "rituximab"[All Fields] OR "rituxan"[All Fields] OR "idec c2b8"[All Fields]) OR ("golimumab"[All Fields] OR "golimumab"[Supplementary Concept] OR "simponi"[All Fields] OR "cnto-148"[All Fields] OR ("cnto"[All Fields] AND "148"[All Fields])) OR ("tocilizumab"[All Fields] OR "tocilizumab"[Supplementary Concept] OR "atlizumab"[All Fields] OR "actemra"[All Fields]) OR ("certolizumab"[All Fields] OR "certolizumab pegol"[Supplementary Concept] OR "CDP870"[All Fields] OR ("cdp"[All Fields] AND "870"[All Fields]) OR "cimzia"[All Fields]) OR ("tofacitinib"[Supplementary Concept] OR "tofacitinib"[All Fields]) OR ("Antibodies, Monoclonal"[Mesh] OR "Monokines"[Mesh] OR "Receptors, Interleukin-1"[Mesh] OR "Receptors, Interleukin-6"[Mesh])) AND ("Randomized Controlled Trial"[ptyp] OR "Controlled Clinical Trial"[ptyp] OR "Multicenter Study"[ptyp] OR "randomized"[tiab] OR "randomised"[tiab] OR "placebo"[tiab] OR "randomly"[tiab] OR "trial"[tiab] OR randomized controlled trials[mh] OR random allocation[mh] OR double-blind method[mh] OR single-blind method[mh]) AND ("Arthritis, Rheumatoid"[MeSH Terms] OR (Rheumatoid[text word] AND arthriti*[text word]))) NOT (animals[mh] NOT human[mh])

The Cochrane Central Register of Controlled Trials (CENTRAL) search strategyID Search#1 MeSH descriptor: [Recombinant Fusion Proteins] explode all trees#2 MeSH descriptor: [Antibodies, Monoclonal] explode all trees#3 MeSH descriptor: [Receptors, Tumor Necrosis Factor] explode all trees#4 MeSH descriptor: [Receptors, Interleukin-1] explode all trees#5 MeSH descriptor: [Receptors, Interleukin-6] explode all trees#6 MeSH descriptor: [Monokines] explode all trees#7 monoclonal antibody ca2#8 TNFR-Fc fusion protein#9 MeSH descriptor: [Interleukin 1 Receptor Antagonist Protein] explode all trees#10 etanercept#11 enbrel#12 infliximab#13 remicade#14 adalimumab#15 humira#16 D2E7#17 anakinra#18 kineret#19 antril#20 abatacept#21 CTLA4Ig#22 orencia#23 rituximab#24 rituxan

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#25 idec c2b8#26 golimumab#27 simponi#28 cnto-148#29 tocilizumab#30 atlizumab#31 actemra#32 roactemra#33 certolizumab#34 CDP870#35 cimzia#36 "TNFR:Fc":ti,ab,kw (Word variations have been searched)#37 tofacitinib:ti,ab,kw (Word variations have been searched)#38 MeSH descriptor: [Janus Kinases] explode all trees#39 Xeljanz:ti,ab,kw (Word variations have been searched)#40 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16

or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39

#41 MeSH descriptor: [Arthritis, Rheumatoid] explode all trees#42 Rheumatoid:ti or Rheumatoid:ab (Word variations have been searched)#43 arthriti*:ti or arthriti*:ab (Word variations have been searched)#44 #42 and #43#45 #41 or #44#46 #40 and #45 in Trials

EMBASE search strategy1 abatacept.mp.2 adalimumab.mp.3 certolizumab.mp.4 etanercept.mp.5 CDP870.mp.6 golimumab.mp.7 infliximab.mp.8 rituximab.mp.9 tocilizumab.mp.10 humira.mp.11 trudexa.mp.12 orencia.mp.13 cimzia.mp.14 enbrel.mp.15 simponi.mp.16 rituxan.mp.17 mabthera.mp.18 actemra.mp.19 RoActemra.mp.20 monoclonal antibodies.mp. or exp Antibodies, Monoclonal/21 exp Monokines/22 exp Receptors, Interleukin-1/23 exp Receptors, Interleukin-6/24 exp Polyethylene Glycols/

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25 exp Immunoglobulin G/26 exp Immunoconjugates/27 immunoglobulin fab fragments.mp. or exp Immunoglobulin Fab Fragments/28 t-lymphocytes.mp. or exp T-Lymphocytes/29 exp tumor necrosis factor inhibitor/30 exp interleukin 1 receptor blocking agent/31 D2E7.mp.32 anakinra.mp.33 kineret.mp.34 antril.mp.35 CTLA4Ig.mp.36 idec c2b8.mp.37 cnto-148.mp.38 atlizumab.mp.39 tofacitinib.mp.40 exp Janus kinase inhibitor/41 *tumor necrosis factor receptor/dt [Drug Therapy]42 or/1-4143 exp Random Allocation/44 exp Single-Blind Method/45 exp Double-Blind Method/46 Placebo.mp.47 Randomi?ed controlled trial$.mp.48 rct.mp.49 Random allocation.mp.50 Randomly allocated.mp.51 Allocated randomly.mp.52 (allocated adj2 random).mp.53 Single blind$.mp.54 Double blind$.mp.55 ((treble or triple) adj blind$).mp.56 Placebo$.mp.57 or/43-5658 rheumatoid.ti,ab.59 *rheumatoid arthritis/60 58 or 5961 42 and 57 and 6062 limit 61 to (book or book series or conference abstract or conference paper or conference proceeding or

"conference review")63 61 not 62

Clinicaltrials.gov search strategyStudy Type (Interventional); Conditions (rheumatoid arthritis); Interventions (abatacept OR 188667 OR CTLA4Ig OR adalimumab OR D2E7 OR anakinra OR certolizumab OR CDP870 OR etanercept OR TNFR:Fc OR golimumab OR CNTO148 OR infliximab OR rituximab OR tocilizumab OR tofacitinib OR CP-690,550).

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Supplement Table 2: Recommended maintenance dose regimeBiological agent Recommended maintenance dose regime

Abatacept iv: 500-1000 mg (depending on weight) or 10 mg/kg every 4th week

sc: 125 mg every week

Adalimumab sc: 40 mg every 2nd week or 20 mg every week

Anakinra sc: 100 mg daily

Certolizumab pegol sc: 200 mg every 2nd week or 400 mg every 4th week

Etanercept sc: 25 mg twice a week or 50 mg every week

Golimumab iv: 2mg/kg every 8th week

sc: 50 mg every 4th week

Infliximab iv: 3 mg/kg every 8th week

Rituximab iv: 1000 mg at weeks 0 and 2

Tocilizumab iv: 8 mg/kg every 4th week

sc: 162 mg every week

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Supplement Table 3: Characteristics of Included Studies (including references) and Outcome DataStudy Information Efficacy outcome data Harm outcome data

Author Year ACRONYM DMARDRisk ofBias* Drug Adm.

Dose(mg)

Rec.Dose

Disease duration (years)

TimeACR

eACR20

eACR50

eACR70

NACR

Timeharm

eWD

NWD

eWDAE

NWDAE

eSAE

NSAE

AB

A Moreland(1)¶ 2002 IR L/L/L/L/L/L

ABA iv 0.5 No 4.2 12 6 0 0 26 12 8 26 2 26 NRABA iv 2 No 3.3 12 14 6 4 32 12 8 32 2 32 NRABA iv 10 No 3.4 12 17 5 2 32 12 4 32 0 32 NRPLA 3.2 12 10 2 0 32 12 12 32 0 32 NR

Emery(2)¶ 2015 AVERT Naïve L/L/L/L/U/L ABA sc 125 Yes 0.6 24 74 43 30 113 52 25 116 8 116 14 116MTX po 15-20 Yes 0.5 24 64 39 21 115 52 20 116 5 116 9 116

AD

A

Breedveld(3)¶ 2006 PREMIER Naïve L/L/L/L/L/L ADA sc 40 Yes 0.7 52 149 113 71 274 104 107 274 26 274 NRMTX po 20 Yes 0.8 52 161 118 70 257 104 88 257 19 257 NR

van de Putte(4)¶ 2004 DE011 IR L/L/L/L/L/L

ADA sc 20 No 9.3 26 38 20 9 106 26 38 106 4 106 11 106ADA sc 20 Yes 11.3 26 44 23 11 112 26 33 112 3 112 18 112ADA sc 40 No 11.9 26 55 36 19 103 26 15 103 3 103 11 103ADA sc 40 Yes 10.6 26 52 25 14 113 26 32 113 6 113 13 113PLA 11.6 26 21 9 2 110 26 62 110 1 110 16 110

Miyasaka(5)¶ 2008 CHANGE IR L/L/L/L/L/L

ADA sc 20 No 10.0 24 25 14 9 87 24 33 87 5 87 10 87ADA sc 80 No 9.5 24 44 28 13 87 24 22 87 3 87 8 87ADA sc 40 Yes 9.9 24 40 22 11 91 24 32 91 12 91 17 91PLA 8.4 24 12 5 1 87 24 51 87 4 87 8 87

van de Putte(6)¶ 2003 IR L/L/L/L/L/L

ADA sc 20 Yes 10.4 12 36 17 8 71 12 10 72 0 72 2 71ADA sc 40 No 10.0 12 40 19 7 70 12 12 70 3 70 5 70ADA sc 80 No 10.1 12 39 14 6 72 12 6 72 2 72 9 72PLA 9.4 12 7 1 0 70 12 23 70 1 70 7 70

Fleischmann(7)¶ 2012 A3921035 IR L/L/L/L/L/L ADA sc 40 Yes 7.7 12 19 10 2 53 12 8 53 2 53 1 53PLA 10.8 12 13 6 2 59 12 13 59 1 59 1 59

Taylor(8)¶ 2014 OSKIRA-4 Naïve L/L/L/L/L/L ADA sc 40 Yes 1.4 6 29 14 4 54 6 NR NR NRPLA 2.0 6 10 2 2 52 6 NR NR NR

AN

A

Bresnihan(9)§ 1998 IR L/L/L/L/L/L

ANA sc 30 No 4.3 24 45 20 5 119 24 24 119 5 119 NRANA sc 75 No 4.2 24 38 13 1 116 24 22 116 7 116 NRANA sc 150 No 3.9 24 44 20 1 116 24 28 116 11 116 NRPLA 3.7 24 30 9 1 121 24 32 121 5 121 NR

CE

R Fleischmann(10)¶ 2009 FAST4WARD IR L/L/L/L/L/L CER sc 400 Yes 8.7 24 50 25 6 111 24 35 111 5 111 8 111PLA 10.4 24 10 4 0 109 24 81 109 2 109 3 109

Weinblatt(11)#¶ 2012 REALISTIC IR L/L/L/L/L/L CER sc 200 Yes 8.6 12 71 34 13 154 12 NR NR NRPLA 8.9 12 10 6 1 47 12 NR NR NR

ETA

Klareskog(12)§ 2004 TEMPO Naïve L/L/L/L/L/L ETA sc 25 Yes 6.3 24 158 89 36 223 52 53 223 25 223 35 223MTX po 20 Yes 6.8 24 166 91 34 228 52 69 228 32 228 37 228

Bathon(13)¶ 2000 ERA Naïve L/L/L/L/L/LETA sc 25 Yes 1.0 26 137 83 43 207 52 31 207 10 207 NRETA sc 10 No 0.9 26 127 71 27 208 52 42 208 9 208 NRMTX po 20 Yes 1.0 26 128 69 30 217 52 45 217 22 217 NR

Moreland(14)¶ 1999 IR L/L/L/L/L/L ETA sc 10 No 13.0 26 39 18 7 76 26 24 76 5 76 NRETA sc 25 Yes 11.0 26 46 31 12 78 26 19 78 2 78 NR

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PLA 12.0 26 9 4 1 80 26 54 80 3 80 NR

Moreland(15)¶ 1997 IR L/L/L/L/L/L

ETA sc 0.25 No NR 12 15 4 NR 46 12 18 46 NR NRETA sc 2 No NR 12 21 10 NR 46 12 10 46 NR NRETA sc 16 No NR 12 33 25 NR 44 12 3 44 NR NRPLA NR 12 6 3 NR 44 12 21 44 NR NR

Takeuchi(16)§ 2012 IR L/L/L/L/L/LETA sc 10 No 2.9 24 148 103 49 192 52 35 192 15 192 8 192ETA sc 25 Yes 3.0 24 141 99 47 182 52 31 182 19 182 11 182MTX po 8 No 3.0 24 99 57 21 176 52 53 176 9 176 10 176

GO

L

Emery(17)¶ 2009 GO-BEFORE Naïve L/L/L/L/L/L GOL sc 100 No 4.1 24 82 52 22 159 24 11 159 2 159 5 157MTX po 20 Yes 2.9 24 79 47 25 160 24 10 160 2 160 11 160

Keystone(18)¶ 2009 GO-FORWARD IR L/L/L/L/L/L GOL sc 100 No 5.9 24 47 26 15 133 24 43 133 6 133 6 133MTX po 15-20 Yes 6.5 24 37 18 7 133 24 49 133 6 133 5 133

Takeuchi(19)§ 2012 GO-MONO IR L/L/L/L/L/LGOL sc 100 No 9.4 14 60 33 12 102 14 2 102 1 102 2 102GOL sc 50 Yes 8.1 14 51 29 13 101 14 5 101 2 101 1 101PLA 9.2 14 20 6 1 105 14 13 105 3 105 2 105

Kremer(20)§ 2010 GO-LIVE IR L/L/L/L/L/LGOL iv 2 No 7.4 24 29 11 4 128 16 NR NR 8 128GOL iv 4 No 8.4 24 38 15 8 129 16 NR NR 2 129MTX po 15-25 Yes 7.4 24 32 12 4 129 16 NR NR 2 129

INF Maini(21)¶ 1998 IR L/L/L/L/L/L

INF iv 1 No 7.6 26 1 0 NR 15 26 7 15 2 15 0 15INF iv 3 No 7.8 26 2 2 NR 14 26 2 14 1 14 0 14INF iv 10 No 9.7 26 4 2 NR 15 26 3 15 1 15 0 15MTX po 7.5 No 7.6 26 2 0 NR 14 26 8 14 0 14 0 14

RIT Edwards(22)¶ 2004 IR L/L/L/L/L/L

RIT iv 1000 Yes 9.0 24 26 13 6 40 24 2 40 2 40 2 40

MTX po ≥10 Yes 11.0 24 15 5 2 40 24 3 40 1 40 3 40

TOC

Nishimoto(23)§ 2009 SATORI IR L/L/L/L/L/L TOC iv 8 Yes 8.5 24 49 32 20 61 24 7 61 2 61 4 61MTX po 8 No 8.7 24 16 10 7 64 24 31 64 3 64 3 64

Maini(24)¶ 2006 CHARISMA IR L/L/L/L/L/L

TOC iv 2 No 9.2 16 16 3 1 52 20 12 53 4 53 8 53TOC iv 4 No 9.8 16 33 15 3 54 20 11 54 5 54 5 54TOC iv 8 Yes 9.2 16 32 21 8 51 20 8 52 5 52 3 52MTX po 10-25 Yes 11.2 16 20 14 8 49 20 9 49 4 49 2 49

Jones(25)¶ 2010 AMBITION Naïve L/L/L/L/U/L TOC iv 8 Yes 6.4 24 200 126 80 286 24 25 288 11 288 11 288MTX po 20 Yes 6.2 24 149 95 43 284 24 33 284 15 284 8 284

Nishimoto(26)§ 2004 STREAM IR L/L/L/L/L/LTOC iv 4 No 7.3 12 31 14 11 54 12 2 54 0 54 1 54TOC iv 8 Yes 8.3 12 43 22 9 55 12 4 55 2 55 2 55PLA 8.4 12 6 1 0 53 12 25 53 4 53 2 53

Gabay(27)¶ 2013 ADACTA IR L/L/L/L/L/L ADA sc 40 Yes 6.3 24 80 45 29 162 24 38 163 10 162 16 162TOC iv 8 Yes 7.3 24 106 77 53 163 24 31 163 9 162 19 162

NCT01007435¤¶ 2013 FUNCTION Naïve L/L/L/L/L/L TOC iv 8 Yes NR 24 205 139 88 292 52 56 292 31 292 25 292MTX po 20 Yes NR 24 187 124 73 287 52 63 289 16 289 24 282

Adm. = administration form. F/Y = frequency of administrations per year. e = events. N = number of patients analysed. NR = not reported. DMARD = conventional synthetic disease-modifying antirheumatic drug; IR = inadequate responder; Rec. = recommended. WD = withdrawal. WDAE = WD due to adverse events. SAE = serious adverse events. ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate.* Risk of Bias: Random sequence generation (selection bias), Allocation concealment (selection bias), Blinding of participants and personnel (performance bias), Blinding of outcome assessment (detection bias), Incomplete outcome data, Selective reporting (reporting bias). L = Low risk of bias. U = unclear risk of bias. H = high risk of bias.# Only data from certolizumab pegol monotherapy and placebo without csDMARDs patients included.¤ Published after completion of systematic search (i.e. identified in clinicaltrials.gov search): Burmester GR, et al. Ann Rheum Dis. 2016 Jun;75(6):1081-91.§ ACR50 evaluated with last observation carried forward for discontinued patients.

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¶ ACR50 evaluated with non-responder imputation for discontinued patients.Reference List(1) Moreland LW, Alten R, van den BF, Appelboom T, Leon M, Emery P et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial

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(3) Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van VR et al. The 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 treatment. Arthritis Rheum 2006; 54(1):26-37.

(4) van de Putte LB, Atkins C, Malaise M, Sany J, Russell AS, van Riel PL et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 2004; 63(5):508-16.

(5) Miyasaka N. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheumatol 2008; 18(3):252-62.

(6) van de Putte LB, Rau R, Breedveld FC, Kalden JR, Malaise MG, van Riel PL et al. Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study. Ann Rheum Dis 2003; 62(12):1168-77.

(7) Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64(3):617-29.

(8) Taylor PC, Genovese MC, Greenwood M, Ho M, Nasonov E, Oemar B et al. OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy. Ann Rheum Dis 2014.

(9) Bresnihan B, varo-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998; 41(12):2196-204.

(10) Fleischmann R, Vencovsky J, Van Vollenhoven RF, Borenstein D, Box J, Coteur G et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis 2009; 68(6):805-11.

(11) Weinblatt ME, Fleischmann R, Huizinga TW, Emery P, Pope J, Massarotti EM et al. Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study. Rheumatology (Oxford) 2012; 51(12):2204-14.

(12) Klareskog L, Van Der HD, De Jager JP, Gough A, Kalden J, Malaise M et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363(9410):675-81.

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(14) Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999; 130(6):478-86.

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(15) Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997; 337(3):141-7.

(16) Takeuchi T, Miyasaka N, Zang C, Alvarez D, Fletcher T, Wajdula J et al. A phase 3 randomized, double-blind, multicenter comparative study evaluating the effect of etanercept versus methotrexate on radiographic outcomes, disease activity, and safety in Japanese subjects with active rheumatoid arthritis. Mod Rheumatol 2013; 23(4):623-33.

(17) Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 2009; 60(8):2272-83.

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(19) Takeuchi T, Harigai M, Tanaka Y, Yamanaka H, Ishiguro N, Yamamoto K et al. Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicentre, randomised, double-blind, placebo-controlled GO-MONO study through 24 weeks. Ann Rheum Dis 2013; 72(9):1488-95.

(20) Kremer J, Ritchlin C, Mendelsohn A, Baker D, Kim L, Xu Z et al. Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. Arthritis Rheum 2010; 62(4):917-28.

(21) 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.

(22) Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004; 350(25):2572-81.

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(24) Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006; 54(9):2817-29.

(25) Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010; 69(1):88-96.

(26) Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 50(6):1761-9.

(27) Gabay C, Emery P, van VR, Dikranian A, Alten R, Pavelka K et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013; 381(9877):1541-50.

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Supplement Table 4: Odds ratios for secondary benefit outcomesBenefit: ACR20 Benefit: ACR70

Drug1

Drug2 OR LCL UCL Favours OR LCL UCL Favours

ABA ADA 1.11 0.50 2.50 1.46 0.61 3.49

ABA ANA 2.09 0.64 6.83 8.30 1.81 37.93 ABA

ABA CER 1.09 0.40 3.00 2.32 0.70 7.70ABA ETA 0.62 0.27 1.42 0.87 0.36 2.13ABA GOL 1.19 0.50 2.81 1.30 0.52 3.27ABA INF 3.92 0.90 17.15 NEABA RIT 0.47 0.12 1.82 0.76 0.16 3.56ABA TOC 0.48 0.21 1.08 0.70 0.30 1.66ABA MTX 1.10 0.52 2.34 1.29 0.59 2.83

ABA PLA 4.80 2.22 10.40 ABA 14.02 4.96 39.59 ABA

ADA ANA 1.88 0.69 5.16 5.67 1.45 22.26 ADA

ADA CER 0.98 0.44 2.18 1.59 0.58 4.32ADA ETA 0.55 0.31 0.98 ETA 0.60 0.32 1.11ADA GOL 1.07 0.58 1.97 0.89 0.46 1.72ADA INF 3.53 0.92 13.53 NEADA RIT 0.42 0.12 1.42 0.52 0.13 2.11ADA TOC 0.43 0.25 0.73 TOC 0.48 0.28 0.82 TOCADA MTX 0.99 0.63 1.57 0.88 0.55 1.42

ADA PLA 4.32 2.75 6.78 ADA 9.59 4.49 20.50 ADA

ANA CER 0.52 0.16 1.68 0.28 0.06 1.37ANA ETA 0.29 0.10 0.83 ETA 0.11 0.03 0.42 ETAANA GOL 0.57 0.20 1.63 0.16 0.04 0.64 GOLANA INF 1.87 0.38 9.26 NEANA RIT 0.22 0.05 0.99 RIT 0.09 0.01 0.60 RITANA TOC 0.23 0.08 0.63 TOC 0.09 0.02 0.33 TOCANA MTX 0.53 0.20 1.41 0.16 0.04 0.60 MTXANA PLA 2.29 0.88 5.96 1.69 0.41 6.97CER ETA 0.56 0.25 1.29 0.38 0.13 1.06CER GOL 1.09 0.46 2.57 0.56 0.19 1.61CER INF 3.59 0.82 15.68 NECER RIT 0.43 0.11 1.66 0.33 0.07 1.67CER TOC 0.44 0.19 0.99 TOC 0.30 0.11 0.83 TOCCER MTX 1.01 0.47 2.17 0.55 0.21 1.46

CER PLA 4.40 2.10 9.21 CER 6.04 2.02 18.05 CER

ETA GOL 1.93 1.01 3.67 ETA 1.49 0.75 2.95ETA INF 6.37 1.64 24.81 ETA NE

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ETA RIT 0.76 0.22 2.60 0.87 0.21 3.58ETA TOC 0.77 0.43 1.39 0.81 0.44 1.46ETA MTX 1.79 1.12 2.89 ETA 1.47 0.92 2.36

ETA PLA 7.80 4.63 13.16 ETA 16.04 6.94 37.06 ETA

GOL INF 3.31 0.83 13.10 NEGOL RIT 0.39 0.11 1.38 0.59 0.14 2.46GOL TOC 0.40 0.22 0.75 TOC 0.54 0.28 1.03GOL MTX 0.93 0.55 1.57 0.99 0.57 1.71

GOL PLA 4.05 2.29 7.16 GOL 10.80 4.58 25.48 GOL

INF RIT 0.12 0.02 0.67 RIT NEINF TOC 0.12 0.03 0.47 TOC NEINF MTX 0.28 0.08 1.04 NEINF PLA 1.23 0.32 4.64 NERIT TOC 1.02 0.30 3.48 0.92 0.23 3.69RIT MTX 2.37 0.73 7.65 1.68 0.44 6.50

RIT PLA 10.30 3.09 34.36 RIT 18.35 4.04 83.23 RIT

TOC MTX 2.32 1.48 3.64 TOC 1.83 1.20 2.79 TOC

TOC PLA 10.09 6.05 16.82 TOC 19.93 8.96 44.30 TOC

MTX PLA 4.35 2.85 6.64 MTX 10.89 5.10 23.26 MTX

ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate. NE = not estimable. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. Odds ratios higher than 1 favour Drug 1. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold. Statistical significant estimates of primary efficacy outcome (ACR50) are highlighted in grey shading.

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Supplement Table 5: Odds ratios for secondary harm outcomesHarm: Withdrawals (total) Harm: Serious Adverse Events

Drug1 Drug2 OR LCL UCL Favours OR LCL UCL FavoursABA ADA 1.22 0.58 2.59 1.49 0.45 4.98ABA ANA 0.62 0.22 1.73 NEABA CER 2.18 0.74 6.46 0.51 0.08 3.39ABA ETA 1.82 0.86 3.85 1.74 0.62 4.84ABA GOL 1.67 0.70 3.95 1.72 0.56 5.32

ABA INF 2.55 0.61 10.74 1.70 <0.01 >999.99

ABA RIT 3.27 0.46 23.42 2.51 0.29 21.46

ABA TOC 2.21 1.03 4.72 TOC 1.31 0.47 3.67ABA MTX 1.32 0.66 2.63 1.63 0.65 4.11ABA PLA 0.41 0.20 0.84 ABA 1.41 0.41 4.89ADA ANA 0.51 0.22 1.16 NEADA CER 1.78 0.72 4.39 0.35 0.08 1.52ADA ETA 1.48 0.91 2.43 1.17 0.48 2.85ADA GOL 1.36 0.71 2.61 1.16 0.45 2.98ADA INF 2.08 0.55 7.84 1.14 <0.01 >999.99

ADA RIT 2.67 0.40 17.65 1.69 0.21 13.58

ADA TOC 1.80 1.13 2.89 TOC 0.88 0.45 1.71ADA MTX 1.08 0.71 1.63 1.10 0.50 2.38ADA PLA 0.34 0.23 0.49 ADA 0.95 0.62 1.45

ANA CER 3.51 1.15 10.76 CER NE

ANA ETA 2.92 1.24 6.91 NEANA GOL 2.69 1.03 7.03 GOL NE

ANA INF 4.11 0.91 18.55 NE

ANA RIT 5.27 0.70 39.72 NE

ANA TOC 3.56 1.48 8.52 TOC NEANA MTX 2.13 0.92 4.91 NEANA PLA 0.66 0.31 1.40 NECER ETA 0.83 0.33 2.11 3.38 0.61 18.62CER GOL 0.77 0.27 2.13 3.35 0.60 18.81CER INF 1.17 0.25 5.51 3.31 <0.01 >999.99

CER RIT 1.50 0.19 11.67 4.89 0.39 62.13

CER TOC 1.01 0.39 2.60 2.55 0.52 12.66CER MTX 0.61 0.24 1.51 3.18 0.61 16.49CER PLA 0.19 0.08 0.43 CER 2.74 0.66 11.36ETA GOL 0.92 0.48 1.75 0.99 0.45 2.18ETA INF 1.41 0.38 5.25 0.98 <0.01 >999.99

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ETA RIT 1.80 0.27 11.85 1.45 0.20 10.55

ETA TOC 1.22 0.74 2.00 0.76 0.40 1.43ETA MTX 0.73 0.50 1.05 0.94 0.60 1.47ETA PLA 0.23 0.15 0.35 ETA 0.81 0.32 2.09GOL INF 1.53 0.38 6.10 0.99 <0.01 >999.99

GOL RIT 1.96 0.29 13.49 1.46 0.19 11.25

GOL TOC 1.32 0.69 2.54 0.76 0.36 1.64GOL MTX 0.79 0.45 1.38 0.95 0.50 1.82GOL PLA 0.25 0.13 0.46 GOL 0.82 0.31 2.18

INF RIT 1.28 0.14 12.07 1.48 <0.01 >999.99

INF TOC 0.87 0.23 3.24 0.77 <0.01 >999.99INF MTX 0.52 0.14 1.86 0.96 <0.01 >999.99INF PLA 0.16 0.04 0.60 INF 0.83 <0.01 >999.99RIT TOC 0.68 0.10 4.44 0.52 0.07 3.81RIT MTX 0.40 0.06 2.58 0.65 0.09 4.50RIT PLA 0.13 0.02 0.83 RIT 0.56 0.07 4.61TOC MTX 0.60 0.41 0.87 TOC 1.24 0.79 1.95TOC PLA 0.19 0.12 0.30 TOC 1.07 0.51 2.25MTX PLA 0.31 0.21 0.46 MTX 0.86 0.38 1.99ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate. NE = not estimable. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. Odds ratios lower than 1 favour Drug 1. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold.

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Supplement Table 6: Odds ratios for primary benefit/harm outcomes - recommended dose (incl. MTX)

Benefit: ACR50 Harm: Withdrawals d/t AEsDrug1 Drug2 OR LCL UCL Favours OR LCL UCL FavoursABA ADA 1.75 0.94 3.26 1.25 0.34 4.62ABA CER 2.23 1.05 4.73 ABA 1.60 0.25 10.46ABA ETA 0.96 0.51 1.83 1.90 0.49 7.35ABA GOL 1.53 0.63 3.73 4.27 0.45 40.30ABA RIT 0.97 0.34 2.76 1.38 0.14 13.30ABA TOC 0.80 0.43 1.49 1.24 0.34 4.58ABA MTX 1.18 0.66 2.12 1.34 0.39 4.55ABA PLA 9.83 4.93 19.61 ABA 2.80 0.71 11.09ADA CER 1.28 0.75 2.17 1.29 0.29 5.77ADA ETA 0.55 0.38 0.81 ETA 1.52 0.68 3.41ADA GOL 0.88 0.43 1.79 3.42 0.49 23.87ADA RIT 0.56 0.23 1.37 1.10 0.15 8.03ADA TOC 0.46 0.34 0.63 TOC 0.99 0.51 1.95ADA MTX 0.68 0.51 0.90 MTX 1.07 0.59 1.95ADA PLA 5.63 3.71 8.54 ADA 2.24 1.07 4.72 PLACER ETA 0.43 0.25 0.76 ETA 1.18 0.25 5.68CER GOL 0.69 0.30 1.56 2.66 0.26 27.70CER RIT 0.44 0.16 1.17 0.86 0.08 9.39CER TOC 0.36 0.21 0.62 TOC 0.77 0.17 3.53CER MTX 0.53 0.32 0.89 MTX 0.83 0.19 3.68CER PLA 4.41 2.50 7.77 CER 1.75 0.40 7.63ETA GOL 1.59 0.76 3.35 2.25 0.31 16.55ETA RIT 1.01 0.40 2.53 0.73 0.10 5.48ETA TOC 0.84 0.57 1.22 0.65 0.29 1.45ETA MTX 1.23 0.90 1.68 0.70 0.37 1.34ETA PLA 10.22 6.34 16.46 ETA 1.48 0.60 3.63GOL RIT 0.64 0.21 1.91 0.32 0.02 4.76GOL TOC 0.53 0.26 1.08 0.29 0.04 2.06GOL MTX 0.77 0.38 1.56 0.31 0.05 2.16GOL PLA 6.42 3.08 13.37 GOL 0.66 0.10 4.46RIT TOC 0.83 0.34 2.04 0.90 0.12 6.55RIT MTX 1.22 0.50 2.94 0.97 0.14 6.77RIT PLA 10.11 3.92 26.07 RIT 2.03 0.27 15.38TOC MTX 1.47 1.14 1.90 TOC 1.08 0.61 1.88TOC PLA 12.23 7.86 19.04 TOC 2.26 1.00 5.09 PLAMTX PLA 8.32 5.46 12.66 MTX 2.10 0.98 4.48ABA = abatacept. ADA = adalimumab. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. For ACR50 odds ratios higher than 1 favour Drug 1; for withdrawal due to adverse events odds ratios higher than 1 favour drug 2. To obtain odds ratios for comparisons in

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the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold. Statistical significant estimates of primary model are highlighted in grey shading.

Supplement Table 7: Odds ratios for primary benefit/harm outcomes – DMARD-IR patients

Benefit: ACR50 Harm: Withdrawals d/t AEsDrug1

Drug2 OR LCL UCL Favour

s OR LCL UCL Favours

ABA ADA 0.46 0.13 1.61 1.02 0.22 4.67ABA ANA 0.83 0.18 3.80 0.83 0.15 4.45ABA CER 0.50 0.13 2.00 0.97 0.14 6.82ABA ETA 0.25 0.07 0.91 ETA 0.72 0.15 3.50ABA GOL 0.54 0.15 2.02 1.84 0.33 10.37ABA INF 1.21 0.18 8.12 0.49 0.06 3.87ABA RIT 0.27 0.05 1.43 0.93 0.09 9.97ABA TOC 0.23 0.06 0.83 TOC 1.11 0.23 5.33ABA MTX 0.68 0.19 2.41 1.24 0.26 5.98ABA PLA 2.17 0.63 7.47 1.63 0.35 7.53ADA ANA 1.81 0.62 5.26 0.81 0.30 2.17ADA CER 1.10 0.46 2.58 0.96 0.24 3.83ADA ETA 0.54 0.26 1.11 0.71 0.32 1.58ADA GOL 1.19 0.57 2.48 1.82 0.63 5.23ADA INF 2.64 0.55 12.66 0.48 0.10 2.29ADA RIT 0.59 0.17 2.10 0.91 0.13 6.39ADA TOC 0.50 0.26 0.96 TOC 1.09 0.53 2.25ADA MTX 1.49 0.79 2.82 1.22 0.56 2.67ADA PLA 4.75 2.68 8.42 ADA 1.60 0.83 3.10ANA CER 0.61 0.18 2.03 1.18 0.25 5.58ANA ETA 0.30 0.10 0.91 ETA 0.87 0.30 2.56ANA GOL 0.66 0.21 2.03 2.23 0.62 8.00ANA INF 1.46 0.25 8.71 0.59 0.11 3.30ANA RIT 0.33 0.07 1.51 1.12 0.14 8.95ANA TOC 0.28 0.09 0.83 TOC 1.34 0.47 3.87ANA MTX 0.82 0.28 2.40 1.50 0.52 4.36ANA PLA 2.62 0.95 7.24 1.97 0.78 5.00CER ETA 0.49 0.20 1.24 0.74 0.17 3.16CER GOL 1.09 0.43 2.77 1.89 0.38 9.43CER INF 2.41 0.45 12.82 0.50 0.07 3.61CER RIT 0.54 0.13 2.17 0.95 0.10 9.42CER TOC 0.46 0.19 1.12 1.14 0.27 4.79CER MTX 1.36 0.58 3.23 1.27 0.30 5.39CER PLA 4.34 1.94 9.72 CER 1.67 0.43 6.52ETA GOL 2.21 0.99 4.94 2.57 0.84 7.85ETA INF 4.91 0.99 24.36 0.68 0.14 3.41

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ETA RIT 1.09 0.30 4.07 1.29 0.18 9.36ETA TOC 0.93 0.44 1.99 1.55 0.65 3.68ETA MTX 2.77 1.40 5.49 ETA 1.73 0.84 3.57ETA PLA 8.83 4.48 17.42 ETA 2.27 0.99 5.18GOL INF 2.22 0.45 11.07 0.26 0.05 1.53GOL RIT 0.50 0.13 1.85 0.50 0.06 4.11GOL TOC 0.42 0.20 0.91 TOC 0.60 0.20 1.83GOL MTX 1.25 0.64 2.48 0.67 0.24 1.93GOL PLA 3.99 1.99 8.02 GOL 0.88 0.31 2.55INF RIT 0.22 0.03 1.51 1.90 0.17 20.89INF TOC 0.19 0.04 0.92 TOC 2.28 0.46 11.29INF MTX 0.56 0.12 2.67 2.55 0.52 12.52INF PLA 1.80 0.38 8.53 3.34 0.69 16.29RIT TOC 0.85 0.24 3.10 1.20 0.17 8.62RIT MTX 2.53 0.73 8.74 1.34 0.19 9.42RIT PLA 8.07 2.29 28.45 RIT 1.76 0.25 12.50TOC MTX 2.97 1.56 5.65 TOC 1.12 0.50 2.51TOC PLA 9.47 4.96 18.07 TOC 1.47 0.66 3.25MTX PLA 3.19 1.73 5.87 MTX 1.31 0.58 2.97DMARD-IR = conventional synthetic disease-modifying antirheumatic drug inadequate responder. ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. For ACR50 odds ratios higher than 1 favour Drug 1; for withdrawal due to adverse events odds ratios higher than 1 favour drug 2. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold. Statistical significant estimates of primary model are highlighted in grey shading.

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Supplement Table 8: Odds ratios for primary benefit/harm outcomes – DMARD-IR patients (excluding the ADACTA study)

Benefit: ACR50 Harm: Withdrawals d/t AEsDrug1 Drug2 OR LCL UCL Favours OR LCL UCL FavoursABA ADA 0.47 0.12 1.78 1.08 0.20 5.68ABA ANA 0.82 0.17 4.06 0.86 0.14 5.30ABA CER 0.50 0.12 2.12 0.98 0.12 7.84ABA ETA 0.24 0.06 0.96 ETA 0.76 0.14 4.17ABA GOL 0.55 0.14 2.16 1.90 0.30 12.07ABA INF 1.22 0.17 8.74 0.49 0.05 4.56ABA RIT 0.27 0.05 1.55 0.94 0.08 11.76ABA TOC 0.26 0.07 1.02 1.26 0.22 7.27ABA MTX 0.69 0.19 2.58 1.32 0.25 7.16ABA PLA 2.18 0.60 7.89 1.68 0.33 8.63ADA ANA 1.76 0.56 5.55 0.80 0.27 2.42ADA CER 1.07 0.42 2.71 0.91 0.20 4.09ADA ETA 0.52 0.24 1.16 0.70 0.28 1.78ADA GOL 1.17 0.52 2.64 1.77 0.55 5.68ADA INF 2.60 0.51 13.34 0.46 0.08 2.53ADA RIT 0.58 0.15 2.23 0.88 0.11 7.03ADA TOC 0.55 0.24 1.26 1.18 0.43 3.22ADA MTX 1.48 0.72 3.03 1.23 0.50 3.03ADA PLA 4.65 2.46 8.82 ADA 1.56 0.75 3.23ANA CER 0.61 0.17 2.17 1.13 0.21 5.99ANA ETA 0.30 0.09 0.97 ETA 0.88 0.27 2.85ANA GOL 0.67 0.20 2.19 2.21 0.56 8.69ANA INF 1.48 0.23 9.42 0.57 0.09 3.66ANA RIT 0.33 0.07 1.64 1.09 0.12 9.92ANA TOC 0.31 0.09 1.04 1.46 0.42 5.08ANA MTX 0.84 0.27 2.59 1.53 0.48 4.88ANA PLA 2.65 0.91 7.73 1.94 0.72 5.25CER ETA 0.49 0.19 1.29 0.78 0.16 3.68CER GOL 1.10 0.41 2.93 1.95 0.35 10.76CER INF 2.44 0.43 13.69 0.50 0.06 4.19CER RIT 0.54 0.13 2.33 0.97 0.09 10.95CER TOC 0.52 0.19 1.39 1.29 0.26 6.45CER MTX 1.39 0.56 3.42 1.35 0.29 6.32CER PLA 4.37 1.87 10.17 CER 1.71 0.41 7.25ETA GOL 2.24 0.96 5.24 2.51 0.77 8.25ETA INF 4.97 0.95 26.01 0.65 0.12 3.69ETA RIT 1.11 0.28 4.35 1.25 0.15 10.13ETA TOC 1.05 0.45 2.49 1.67 0.59 4.70ETA MTX 2.83 1.37 5.83 ETA 1.75 0.81 3.75

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ETA PLA 8.91 4.36 18.18 ETA 2.21 0.91 5.38GOL INF 2.22 0.42 11.65 0.26 0.04 1.70GOL RIT 0.49 0.13 1.95 0.50 0.05 4.56GOL TOC 0.47 0.20 1.12 0.66 0.19 2.36GOL MTX 1.26 0.61 2.59 0.70 0.23 2.10GOL PLA 3.97 1.91 8.25 GOL 0.88 0.29 2.70INF RIT 0.22 0.03 1.61 1.92 0.15 24.40INF TOC 0.21 0.04 1.12 2.56 0.43 15.23INF MTX 0.57 0.11 2.83 2.69 0.49 14.81INF PLA 1.79 0.36 8.92 3.40 0.62 18.61RIT TOC 0.95 0.24 3.80 1.34 0.16 11.33RIT MTX 2.56 0.70 9.31 1.40 0.18 10.95RIT PLA 8.05 2.17 29.85 RIT 1.77 0.22 14.10TOC MTX 2.69 1.28 5.63 TOC 1.05 0.41 2.70TOC PLA 8.45 3.98 17.96 TOC 1.33 0.50 3.53MTX PLA 3.15 1.67 5.95 MTX 1.27 0.53 3.02DMARD-IR = conventional synthetic disease-modifying antirheumatic drug inadequate responder. ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. For ACR50 odds ratios higher than 1 favour Drug 1; for withdrawal due to adverse events odds ratios higher than 1 favour drug 2. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold. Statistical significant estimates of primary model are highlighted in grey shading.

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Supplement Table 9: Odds ratios for primary benefit outcome – imputation method for discontinued patients

Benefit: ACR50 (LOCF method) Benefit: ACR50 (NRI method)

Drug1 Drug2 OR LCL UCL Favours OR LCL UCL Favours

ABA ADA NA 1.02 0.48 2.16ABA ANA NA NAABA CER NA 1.18 0.44 3.15ABA ETA NA 0.71 0.27 1.88ABA GOL NA 0.74 0.31 1.78ABA INF NA 1.92 0.39 9.44ABA RIT NA 0.43 0.12 1.53ABA TOC NA 0.59 0.28 1.27ABA MTX NA 0.88 0.44 1.75ABA PLA NA 4.79 2.15 10.64 ABAADA ANA NA NAADA CER NA 1.16 0.54 2.51ADA ETA NA 0.70 0.32 1.50ADA GOL NA 0.72 0.36 1.45ADA INF NA 1.89 0.43 8.36ADA RIT NA 0.42 0.13 1.32ADA TOC NA 0.58 0.36 0.95 TOCADA MTX NA 0.86 0.56 1.34ADA PLA NA 4.70 2.91 7.58 ADAANA CER NA NAANA ETA 0.26 0.09 0.79 ETA NAANA GOL 0.46 0.15 1.37 NAANA INF NA NAANA RIT NA NAANA TOC 0.14 0.04 0.44 TOC NAANA MTX 0.43 0.15 1.25 NAANA PLA 2.66 1.04 6.77 ANA NACER ETA NA 0.60 0.23 1.58CER GOL NA 0.63 0.24 1.61CER INF NA 1.63 0.33 8.18CER RIT NA 0.36 0.10 1.34CER TOC NA 0.50 0.22 1.15CER MTX NA 0.75 0.34 1.65CER PLA NA 4.05 1.95 8.43 CERETA GOL 1.75 0.79 3.86 1.04 0.41 2.67ETA INF NA 2.71 0.54 13.58ETA RIT NA 0.60 0.16 2.23ETA TOC 0.52 0.23 1.21 0.83 0.37 1.90

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ETA MTX 1.64 1.07 2.51 ETA 1.24 0.57 2.73ETA PLA 10.13 3.93 26.10 ETA 6.75 3.23 14.15 ETAGOL INF NA 2.61 0.55 12.42GOL RIT NA 0.58 0.17 1.98GOL TOC 0.30 0.12 0.77 TOC 0.80 0.40 1.59GOL MTX 0.94 0.46 1.92 1.19 0.67 2.13GOL PLA 5.79 2.43 13.79 GOL 6.49 3.03 13.91 GOLINF RIT NA 0.22 0.04 1.36INF TOC NA 0.31 0.07 1.37INF MTX NA 0.46 0.11 1.98INF PLA NA 2.49 0.55 11.33RIT TOC NA 1.38 0.44 4.37RIT MTX NA 2.06 0.68 6.20RIT PLA NA 11.21 3.42 36.76 RITTOC MTX 3.13 1.44 6.81 TOC 1.49 0.99 2.24TOC PLA 19.36 7.05 53.11 TOC 8.11 4.44 14.82 TOCMTX PLA 6.18 2.51 15.21 MTX 5.44 3.12 9.49 MTXLOFC = last observation carried forward for discontinued patients. NRI = non-responder imputation for discontinued patients. ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. PLA = placebo. MTX = methotrexate. NE = not estimable. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. Odds ratios higher than 1 favour Drug 1. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold. Statistical significant estimates of primary efficacy outcome (ACR50) are highlighted in grey shading.

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Supplement Table 10: Odds ratios for primary benefit/harm outcomes – inclusion of tofacitinib

Benefit: ACR50 Harm: Withdrawals d/t AEsDrug1 Drug2 OR LCL UCL Favours OR LCL UCL FavoursABA ADA 0.89 0.40 1.97 1.15 0.40 3.33

ABA ANA 1.78 0.56 5.70 1.07 0.26 4.47

ABA CER 1.08 0.40 2.93 1.23 0.23 6.59

ABA ETA 0.55 0.24 1.23 1.21 0.41 3.57

ABA GOL 0.87 0.38 2.03 2.50 0.70 8.93

ABA INF 2.20 0.45 10.88 0.62 0.10 3.80

ABA RIT 0.48 0.13 1.79 1.14 0.14 9.10

ABA TOC 0.47 0.21 1.04 1.22 0.42 3.52

ABA TOF 0.46 0.20 1.07 1.65 0.55 4.92

ABA MTX 0.88 0.42 1.83 1.22 0.46 3.26

ABA PLA 4.19 1.92 9.16 ABA 1.91 0.66 5.49

ADA ANA 2.00 0.75 5.35 0.93 0.29 2.99

ADA CER 1.21 0.55 2.66 1.07 0.25 4.62

ADA ETA 0.62 0.36 1.06 1.06 0.52 2.15

ADA GOL 0.98 0.55 1.77 2.17 0.82 5.79

ADA INF 2.47 0.57 10.84 0.54 0.11 2.73

ADA RIT 0.53 0.16 1.74 1.00 0.15 6.71

ADA TOC 0.53 0.32 0.86 TOC 1.06 0.55 2.04

ADA TOF 0.52 0.30 0.90 TOF 1.43 0.71 2.92

ADA MTX 0.99 0.65 1.52 1.06 0.61 1.87

ADA PLA 4.71 2.99 7.42 ADA 1.66 0.88 3.13

ANA CER 0.60 0.19 1.91 1.15 0.20 6.54

ANA ETA 0.31 0.11 0.84 ETA 1.14 0.34 3.76

ANA GOL 0.49 0.18 1.38 2.34 0.60 9.18

ANA INF 1.24 0.23 6.80 0.58 0.09 3.81

ANA RIT 0.27 0.06 1.14 1.07 0.13 9.06

ANA TOC 0.26 0.10 0.71 TOC 1.14 0.35 3.70

ANA TOF 0.26 0.09 0.72 TOF 1.54 0.47 5.10

ANA MTX 0.49 0.19 1.29 1.15 0.37 3.53

ANA PLA 2.35 0.92 6.01 1.79 0.60 5.35

CER ETA 0.51 0.23 1.15 0.99 0.22 4.40

CER GOL 0.81 0.35 1.90 2.04 0.40 10.41

CER INF 2.05 0.41 10.13 0.50 0.06 4.05

CER RIT 0.44 0.12 1.67 0.93 0.09 9.42

CER TOC 0.44 0.20 0.97 TOC 0.99 0.23 4.34

CER TOF 0.43 0.19 0.99 TOF 1.35 0.30 5.97

CER MTX 0.82 0.39 1.74 1.00 0.24 4.18

CER PLA 3.90 1.86 8.19 CER 1.56 0.38 6.46

ETA GOL 1.59 0.87 2.92 2.06 0.76 5.58

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ETA INF 4.02 0.91 17.75 0.51 0.10 2.61

ETA RIT 0.86 0.26 2.84 0.94 0.14 6.41

ETA TOC 0.85 0.50 1.47 1.00 0.49 2.02

ETA TOF 0.84 0.47 1.53 1.36 0.64 2.88

ETA MTX 1.60 1.04 2.46 ETA 1.01 0.59 1.73

ETA PLA 7.64 4.57 12.78 ETA 1.57 0.78 3.18

GOL INF 2.52 0.56 11.35 0.25 0.04 1.45

GOL RIT 0.54 0.16 1.83 0.46 0.06 3.50

GOL TOC 0.54 0.30 0.97 TOC 0.49 0.18 1.30

GOL TOF 0.53 0.28 1.00 0.66 0.24 1.82

GOL MTX 1.01 0.62 1.64 0.49 0.20 1.19

GOL PLA 4.80 2.73 8.44 GOL 0.76 0.29 2.00

INF RIT 0.22 0.04 1.33 1.85 0.17 20.61

INF TOC 0.21 0.05 0.93 TOC 1.97 0.39 10.00

INF TOF 0.21 0.05 0.94 TOF 2.67 0.52 13.83

INF MTX 0.40 0.09 1.70 1.98 0.41 9.62

INF PLA 1.90 0.44 8.31 3.09 0.61 15.70

RIT TOC 0.99 0.30 3.21 1.06 0.16 7.16

RIT TOF 0.98 0.29 3.27 1.44 0.21 9.89

RIT MTX 1.86 0.60 5.77 1.07 0.17 6.90

RIT PLA 8.84 2.72 28.67 RIT 1.67 0.25 11.27

TOC TOF 0.99 0.56 1.76 1.36 0.65 2.81

TOC MTX 1.88 1.25 2.83 TOC 1.01 0.59 1.71

TOC PLA 8.97 5.42 14.84 TOC 1.57 0.80 3.10

TOF MTX 1.90 1.16 3.11 TOF 0.74 0.40 1.36

TOF PLA 9.05 5.42 15.09 TOF 1.16 0.59 2.28

MTX PLA 4.76 3.12 7.28 MTX 1.56 0.87 2.79ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. TOF = tofacitinib. PLA = placebo. MTX = methotrexate. OR = odds ratio. LCL = lower limit of 95% confidence interval. UCL = upper limit of 95% confidence interval. For ACR50 odds ratios higher than 1 favour Drug 1; for withdrawal due to adverse events odds ratios higher than 1 favour drug 2. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. Statistically significant (P<0.05) results are in bold. Statistical significant estimates of primary model are highlighted in grey shading.

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Supplement Figure 1: Direct pairwise meta-analysis for ACR50 - compared with placebo

ABA = abatacept. ADA = adalimumab. ANA = anakinra. CER = certolizumab pegol. ETA = etanercept. GOL = golimumab. INF = infliximab. RIT = rituximab. TOC = tocilizumab. MTX = methotrexate. CI = confidence interval.

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Supplement Figure 2: Direct pairwise meta-analysis for ACR50 - compared with methotrexate


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Supplement Figure 3: Direct pairwise meta-analysis for withdrawal due to adverse events - compared with placebo


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Supplement Figure 4: Direct pairwise meta-analysis for withdrawal due to adverse events - compared with methotrexate


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Supplement Figure 5: Direct pairwise meta-analysis for ACR50 – tofacitinib compared with placebo

Supplement Figure 6: Direct pairwise meta-analysis for ACR50 – tofacitinib compared with methotrexate

Supplement Figure 7: Direct pairwise meta-analysis for ACR50 – tofacitinib compared with adalimumab

Supplement Figure 8: Direct pairwise meta-analysis for withdrawal due to adverse events – tofacitinib compared with placebo

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Supplement Figure 9: Direct pairwise meta-analysis for withdrawal due to adverse events – tofacitinib compared with methotrexate

Supplement Figure 10: Direct pairwise meta-analysis for withdrawal due to adverse events – tofacitinib compared with adalimumab

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