Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta‐analysis

Jasvinder A Singh; Alomgir Hossain; Elizabeth Tanjong Ghogomu; Amy S Mudano; Lara J Maxwell; Rachelle Buchbinder; Maria Angeles Lopez‐Olivo; Maria E Suarez‐Almazor; Peter Tugwell<sup>a</sup>; George A Wells<sup>a</sup>

doi:10.1002/14651858.CD012591

Table 1. Characteristics of included studies

Study name

Biologic(s)

Biologic dose(s)

Number of study arms

Non‐biologic comparator

Concomitant use of MTX/DMARD

Trial duration

RA duration

Biologic‐naive

Which biologic failed?

Reason(s) for previous biologic‐failure

DMARD‐naïve

Mono‐biologic

Total number of participants

Bingham 2015

Tocilizumab

HD

2

MTX

Yes

5 months

Late

Yes

≥ 1 TNF‐biologic

Inefficacy or intolerance

No

Yes

91

Burmester 2013

Tofacitinib

SD, HD

3

MTX + PL

Yes

3 months

Late

No

TNF‐biologic

Inadequate response

No

Yes

399

Cohen 2006 (REFLEX)

Rituximab

SD

2

MTX + PL

Yes

24 months

Late

No

≥ 1 TNF‐biologic

Inadequate response

No

Yes

520

Emery 2008a (RADIATE)

Tocilizumab

SD, HD

3

MTX + PL

Yes

6 months

Late

No

≥ 1 TNF‐biologic

Inefficacy or intolerance

No

Yes

498

Furst 2007

Etanercept/infliximab

SD

2

None

Yes

7 months

Established

No

Etanercept

Partial response

No

27

Genovese 2005

Abatacept

SD

2

PL

No

6 months

Late

No

≥ 1 TNF‐biologic

Inadequate response

No

Yes

389

Keystone 2008 (REFLEX)

Rituximab

SD

2

MTX + PL

Yes

24 months

Late

No

≥ 1 TNF‐biologic

Inadequate response

No

Yes

499

Moreland 2002

Abatacept

SD, LD, HD

4

PL

No

3 months

Established

No

Etanercept

Inadequate response

No

Yes

122

Schiff 2014b

Certolizumab

SD

2

PL

No

3 months

Late

No

TNF‐biologic except certolizumab

Secondary Inadequate response or intolerance

No

Yes

37

Smolen 2009

(GO‐AFTER)

Golilumab

SD, HD

3

DMARD + PL

Yes

6 months

Established

No

TNF‐biologic‐ etanercept, infliximab or adalimumab

Inadequate response (58%) or intolerance (53%)

No

Yes

461

Weinblatt 2007a

Abatacept/etanercept

SD, LD

2

None

No

12 months

Late

No

Etanercept

Inadequate response

No

121

Weinblatt 2008

Etanercept

SD, HD

2

None

No

3 months

Late

No

Etanercept 50 mg weekly

Inadequate response

No

Yes

200

DMARD: disease‐modifying anti‐rheumatic drug
HD: high dose
LD: low dose
MTX: methotrexate
PL: placebo
RA duration: established = mean/median duration 2 to 10 years; late = mean/median duration > 10 years
SD: standard dose

Table 1. Characteristics of included studies

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Table 2. Characteristics of excluded studies

Study	Reason for exclusion
Abe 2006	Wrong drug exposure
Axelsen 2015	Duplicate of Hørslev‐Petersen 2014
Bae 2013	Wrong drug exposure
Bathon 2000	Duplicate of Genovese 2002
Bejarano 2008	Wrong drug exposure
Bonafede 2015	Not a RCT
Boyle 2015	Wrong exposure
Breedveld 2006	Wrong drug exposure
Bresnihan 1998	Wrong drug exposure
Burmester 2014	Wrong drug exposure
Burmester 2015	Wrong drug exposure
Chen 2009	Wrong drug exposure
Cheng 2014	Conference abstract
Choy 2012	Wrong drug exposure
Cohen 2002	Wrong drug exposure
Cohen 2003	Wrong drug exposure
Cohen 2004	Wrong drug exposure
Combe 2006	Wrong drug exposure
Combe 2009	Wrong drug exposure
Conaghan 2013	Wrong drug exposure
Conaghan 2014	Sub‐study of Huizinga 2015
Coombs 2010	Wrong drug exposure
Detert 2013	Wrong drug exposure
Dougados 2013	Wrong drug exposure
Dougados 2014	Duplicate of Huizinga 2015
Doyle 2013	Wrong drug exposure
Durez 2004	Wrong drug exposure
Durez 2007	Wrong drug exposure
Edwards 2004	Wrong drug exposure
Emery 2006	Wrong drug exposure
Emery 2008a	Wrong drug exposure
Emery 2010	Wrong drug exposure
Emery 2014a	Duplicate
Emery 2014b	Conference abstract
Eriksson 2015	Follow‐up at two years of Van Vollenhoven 2012a NCT00764725
Fleischmann 2003	Wrong drug exposure
Fleischmann 2009	Wrong drug exposure
Fleischmann 2012a	Wrong drug exposure
Fleischmann 2012b	Wrong drug exposure
Fleischmann 2013	Conference abstract
Furst 2003	Wrong drug exposure
Furst 2015	Open label study
Gabay 2013	Wrong drug exposure
Gashi 2014	Comparing two doses of a biologic
Genovese 2002	Wrong drug exposure
Genovese 2004	Wrong drug exposure
Genovese 2008	Wrong drug exposure
Genovese 2011	Wrong drug exposure
Genovese 2015	Wrong drug exposure
Gherge 2014	Conference abstract
Goekoop‐Ruiterman 2007	Wrong drug exposure
Haraoui 2014	Duplicate of Pope 2014
Heimans 2014	Wrong drug exposure
Hobbs 2015	Wrong drug exposure
Hørslev‐Petersen 2014	Open label study
Huizinga 2015	Discontinuation study
Iannone 2014	Open label study
Jobanputra 2012	Wrong drug exposure
Johnsen 2006	Wrong drug exposure
Jones 2010	Wrong drug exposure
Kaine 2011	Wrong drug exposure
Kameda 2010	Wrong drug exposure
Kameda 2011	Wrong drug exposure
Kavanaugh 2013	Wrong drug exposure
Kavanaugh 2014	Conference abstract
Kay 2008	Wrong drug exposure
Kennedy 2014	Wrong drug exposure
Keystone 2004a	Wrong drug exposure
Keystone 2004b	Wrong drug exposure
Keystone 2009	Wrong drug exposure
Keystone 2014	Conference abstract
Kim 2007	Wrong drug exposure
Kim 2012	Wrong drug exposure
Kim 2013	Wrong drug exposure
Kivitz 2014	Vaccine response study
Koroleva 2014a	Conference abstract
Koroleva 2014b	Conference abstract
Kremer 2003	Wrong drug exposure
Kremer 2005	Wrong drug exposure
Kremer 2006	Wrong drug exposure
Kremer 2009	Wrong drug exposure
Kremer 2010	Wrong drug exposure
Kremer 2011	Wrong drug exposure
Kremer 2012	Wrong drug exposure
Kremer 2013	Wrong drug exposure
Kremer 2015	Cross over study design
Lan 2004	Wrong drug exposure
Landewé 2015	Conference abstract
Lipsky 2000	Wrong drug exposure
Lisbona 2008	Wrong drug exposure
Lisbona 2010	Wrong drug exposure
Machado 2014	Wrong drug exposure
Maini 1999	Wrong drug exposure
Maini 2006	Wrong drug exposure
Manders 2015	Trial participants switched therapy within one year/before completion of study period
Mathias 2000	Wrong drug exposure
McInnes 2015	Compared lipid levels in those randomized to CZP or PL, in MTX‐IR participants
Miyasaka 2008	Wrong drug exposure
Moreland 1999	Wrong drug exposure
Nam 2014a	Wrong drug exposure
Nam 2014b	Wrong drug exposure
Navarro 2014	Conference abstract
Nishimoto 2004	Wrong drug exposure
Nishimoto 2007	Wrong drug exposure
Nishimoto 2009	Wrong drug exposure
O'Dell 2013	Wrong drug exposure
Oakley 2014	Conference abstract
Pavelka 2013	Sub‐group analysis of Smolen 2013 NCT00565409
Pope 2014	Wrong drug exposure
Quinn 2005	Wrong drug exposure
Rantalaiho 2014	Wrong drug exposure
Rau 2004	Wrong drug exposure
Rigby 2011	Duplicate of Tak 2011
Rubbert‐Roth 2010	Wrong drug exposure
Schiff 2008	Wrong drug exposure
Schiff 2013	Wrong drug exposure
Smolen 2008	Wrong drug exposure
Smolen 2013	Wrong drug exposure
Smolen 2014b	Participants in the control group also received the intervention
Smolen 2015	Wrong drug exposure
Sonomoto 2014	Open label study
Soubrier 2009	Wrong drug exposure
St Clair 2004	Wrong drug exposure
Strand 2006	Wrong drug exposure
Strand 2012	Wrong drug exposure
Tada 2012	Wrong drug exposure
Tak 2011	Wrong drug exposure
Tak 2012	Wrong drug exposure
Takeuchi 2013a	Wrong drug exposure
Takeuchi 2013b	Wrong drug exposure
Takeuchi 2013c	Wrong drug exposure
Takeuchi 2014	Wrong drug exposure
Tam 2012	Wrong drug exposure
Tanaka 2011	Wrong drug exposure
Tanaka 2012	Wrong drug exposure
Taylor 2004	Wrong drug exposure
Taylor 2006	Wrong drug exposure
Van de Putte 2003	Wrong drug exposure
Van de Putte 2004	Wrong drug exposure
Van der Heidje 2006	Wrong drug exposure
Van der Heidje 2007	Wrong drug exposure
Van Der Heijde 2013	Wrong drug exposure
Van der Kooij 2009	Wrong drug exposure
Van Riel 2006	Wrong drug exposure
Van Vollenhoven 2009	Wrong drug exposure
Van Vollenhoven 2012a	Duplicate of Van Vollenhoven 2009
Van Vollenhoven 2012b	Wrong drug exposure
Vital 2015	B cell depletion study
Weinblatt 1999	Wrong drug exposure
Weinblatt 2003	Wrong drug exposure
Weinblatt 2006	Wrong drug exposure
Weinblatt 2012	Wrong drug exposure
Weinblatt 2013a	Wrong drug exposure
Weinblatt 2013b	Wrong drug exposure
Weinblatt 2014	Results at 1 year of Weinblatt 2013b GO‐FURTHER trial, NCT00973479
Weisman 2003	Wrong drug exposure
Weisman 2007	Wrong drug exposure
Westhovens 2006	Wrong drug exposure
Westhovens 2009	Wrong drug exposure
Westhovens 2014	Conference abstract
Yamamoto 2014a	Wrong drug exposure
Yamamoto 2014b	Wrong drug exposure
Yamanaka 2014	Post hoc analysis of Takeuchi 2014
Yazici 2012	Wrong drug exposure
Zhang 2006	Wrong drug exposure
Østergaard 2015	Wrong drug exposure
CZP: certolizumab pegol MTX‐IR: methotrexate incomplete responders PL: placebo

Table 2. Characteristics of excluded studies

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Table 3. 'Summary of findings' table for biologics vs. comparator in people previously unsuccessfully treated with biologics (all participants: 1 or more TNF‐biologic failed)

Comparison		No. of participants (studies)	Direct evidence			Network meta‐analysis
				Absolute risk difference, NNTB	Quality of evidence		Absolute risk difference, NNTB	Quality of evidence
Outcome: ACR50			RR (95% CI)			RR (95% Crl)
All biologics	vs. placebo	548 (3 studies)	4.10 (1.97 to 8.55)	14% (6% to 21%), NNTB = 8 (4 to 23)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	n/a
All biologics + MTX	vs. MTX/DMARD	1479 (3 studies)	4.07 (2.76 to 5.99)	16% (10% to 21%), NNTB = 7 (5 to 11)	⊕⊕⊕⊕ high^b	n/a
TNF biologic + MTX	vs. MTX/DMARD	461 (1 study)	2.84 (1.49 to 5.40)	12% (6% to 18%), NNTB = 9 (5 to 25)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	2.97 (1.38 to 6.41)	10% (2% to 25%), NNTB = 10 (4 to 48)	⊕⊕⊕⊖ moderate (downgraded for indirectness)^c
Non‐TNF biologic + MTX	vs. MTX/DMARD	1018 (2 studies)	4.99 (3.07 to 8.11)	18% (10% to 25%), NNTB = 6 (4 to 10)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	5.07 (3.21 to 8.14)	21% (13% to 30%), NNTB = 5 (3 to 9)	⊕⊕⊕⊖ moderate (downgraded for indirectness)^c
Tofacitinib + MTX	vs. MTX/DMARD	399 (1 study)	3.24 (1.78 to 5.89)	19% (12% to 26%), NNTB = 6 (3 to 14)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	3.61 (1.74 to 7.24)	13% (4% to 29%), NNTB = 8 (4 to 25)	⊕⊕⊕⊖ moderate (downgraded for indirectness)^c
Outcome: Health Assessment Questionnaire (HAQ) score, 0‐3 (higher = worse; A "negative sign" indicates improvement): A measure of function			MD (95% CI)
All biologics	vs. placebo	n/a
All biologics + MTX	vs. MTX/DMARD	959 (2 studies)	‐0.29 (‐0.36 to ‐0.21)	‐9.7% (‐12% to ‐7.0%), NNTB = 5 (4 to 7)	⊕⊕⊕⊕ high^b	n/a
TNF biologic + MTX	vs. MTX/DMARD	461 (1 study)	‐0.25 (‐0.40 to ‐0.10)	‐8.3% (‐13% to ‐3%), NNTB = 5 (7 to 16)	⊕⊕⊕⊕ high^b	‐0.37 (‐6.67 to 5.89)	‐12.3% (‐222.3% to 196.3%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Non‐TNF biologic + MTX	vs. MTX/DMARD	498 (1 study)	‐0.37 (‐0.46 to ‐0.28)	‐12.3% (‐15% to ‐9%), NNTB = 4 (3 to 5)	⊕⊕⊕⊕ high^b	‐0.25 (‐6.54 to 5.99)	‐8.3% (‐218% to 199.7%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Tofacitinib + MTX	vs. MTX/DMARD	399 (1 study)	‐0.27 (‐0.39 to ‐0.14)	‐9% (‐13% to ‐4.7%), NNTB = 5 (4 to 10)	⊕⊕⊕⊕ high^b	‐0.26 (‐6.57 to 5.95)	‐8.7% (‐219% to 198.3%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Outcome: Remission (defined as DAS <1.6 or DAS28 <2.6)			RR (95% CI)			RR (95% CI)
All biologics	vs. placebo	389 (1 study)	13.51 (1.85 to 98.45)	9% (5% to 13%), NNTB = 11 (3 to 136)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	n/a
All biologics + MTX	vs. MTX/DMARD	959 (2 studies)	20.73 (4.13 to 104.16)	10% (8% to 13%), NNTB = 17 (4 to 96)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	n/a
TNF biologic + MTX	vs. MTX/DMARD	461 (1 study)	16.21 (2.24 to 117.51)	10% (6% to 13%), NNTB = 11 (3 to 110)	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	22.27 (3.60 to 400.70)	8% (1% to 52%), NNTB = 9 (2 to 61)	⊕⊕⊕⊖ moderate (downgraded for indirectness)^c
Non‐TNF biologic + MTX	vs. MTX/DMARD	498 (1 study)	33.72 (2.08 to 546.23)	10% (7% to 14%), NNTB = n/a^e	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	31.20 (6.70 to 456.30)	11% (3% to 32%), NNTB = 18 (3 to 93)	⊕⊕⊕⊖ moderate (downgraded for indirectness)^c
Tofacitinib + MTX	vs. MTX/DMARD	398 (1 study)	15.44 (0.93 to 256.10)	6% (3% to 9%), NNTB = n/a^e	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	n/a
Outcome: Radiographic progression	No studies reported this outcome.
Outcome: Withdrawals due to adverse events			RR (95% CI)			RR (95% CI)
All biologics	vs. placebo	428 (2 studies)	0.62 (0.13 to 2.93)	‐1% (‐4% to 3%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,e	n/a
All biologics + MTX	vs. MTX/DMARD	611 (2 studies)	3.32 (0.86 to 12.85)	5% (‐3% to 13%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,e	n/a
TNF biologic + MTX	vs. MTX/DMARD	n/a
Non‐TNF biologic + MTX	vs. MTX/DMARD	611 (2 studies)	3.32 (0.86 to 12.85)	5% (‐4% to 13%), NNTB = n/a	⊕⊖⊖⊖ very low (downgraded for serious imprecision/inconsistency)^a,d,f	1.99 (0.80 to 5.98)	3% (‐1% to 8%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Tofacitinib + MTX	vs. MTX/DMARD	399 (1 study)	0.99 (0.41 to 2.39)	0% (‐5% to 5%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d	1.02 (0.29 to 3.65)	0% (‐2% to 6%), NNTB = n/a	⊕⊕⊖c low (downgraded for imprecision and indirectness)^c,d
Outcome: Serious adverse events			RR (95% CI)			RR (95% CI)
All biologics	vs. placebo	428 (2 studies)	0.93 (0.51 to 1.68)	‐1% (‐7% to 5%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d	n/a
All biologics + MTX	vs. MTX/DMARD	1072 (3 studies)	0.69 (0.44 to 1.09)	‐2% (‐5% to 1%), NNTB = n/a	⊕⊕⊕⊖ moderate (downgraded for imprecision)^a	n/a
TNF biologic + MTX	vs. MTX/DMARD	461 (1 study)	0.55 (0.25 to 1.22)	‐3% (‐8% to 1%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d	0.56 (0.20 to 1.51)	‐3% (‐6% to 3%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Non‐TNF biologic + MTX	vs. MTX/DMARD	611 (2 studies)	0.77 (0.45 to 1.33)	‐1% (‐6% to 3%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d	0.85 (0.49 to 1.53)	‐1% (‐4% to 3%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Tofacitinib + MTX	vs. MTX/DMARD	399 (1 study)	0.33 (0.09 to 1.15)	‐3% (‐7% to 1%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d	0.32 (0.07 to 1.27)	‐4% (‐8% to 2%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for imprecision and indirectness)^c,d
Outcome: Cancer (note: Peto OR used but can interpret as RR due to low event rate)			RR (95% CI)			RR (95% CI)
All biologics	vs. placebo	n/a
All biologics + MTX	vs. MTX/DMARD	550 (2 studies)	4.54 (0.24 to 85.36)	1% (‐1% to 2%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d	n/a
TNF biologic + MTX	vs. MTX/DMARD	459 (1 study)	4.54 (0.24 to 85.36)	1% (‐1% to 2%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d
Non‐TNF biologic + MTX	vs. MTX/DMARD	91 (1 study)	Not estimable	0% (‐5% to 5%), NNTB = n/a	⊕⊕⊖⊖ low (downgraded for serious imprecision)^a,d
Tofacitinib + MTX	vs. MTX/DMARD	n/a
Note ‐ no studies reported radiographic progression for either biologic or tofacitinib. High quality (⊕⊕⊕⊕): we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality (⊕⊕⊕⊖): we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality (⊕⊕⊖⊖): our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality (⊕⊖⊖⊖): we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. CI: confidence interval; CrI: credible interval; DAS: Disease Activity Score; DMARD: disease‐modifying anti‐rheumatic drug; MD: mean difference; MTX: methotrexate; n/a: not available; NNTB: number needed to treat for an additional beneficial outcome; RR: risk ration; TNF: tumor necrosis factor Comparator = placebo and/or MTX and/or DMARD ^aDowngraded for imprecision ‐ few events (< 300). ^bNo evidence of imprecision or inconsistency. Number of events > 300. ^cDowngraded for indirectness/intransitivity due to differing participant characteristics (established vs. late RA; types of failures); differing biologic doses and co‐interventions; and differing comparators. ^dDowngraded for imprecision ‐ 95% CI estimate includes both null effect and appreciable benefit or harm. ^eCould not be calculated, control event % = 0. ^f I² = 73% ‐ downgraded for inconsistency

Table 3. 'Summary of findings' table for biologics vs. comparator in people previously unsuccessfully treated with biologics (all participants: 1 or more TNF‐biologic failed)

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Table 4. ACR50 analysis for the type of medication (MTX/DMARD active comparator): odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
(MTX or DMARD) + non‐TNF	Comparator	6.48 (3.76 to 11.66)	5.07 (3.21 to 8.14)	0.21 (0.13 to 0.30)
(MTX or DMARD) + monoclonal antibodies against TNF		3.32 (1.41 to 8.65)	2.97 (1.38 to 6.41)	0.10 (0.02 to 0.25)
TOFA		4.20 (1.82 to 10.30)	3.61 (1.74 to 7.24)	0.13 (0.04 to 0.29)
(MTX or DMARD) + monoclonal antibodies against TNF	(MTX or DMARD) + non‐TNF	0.51 (0.18 to 1.54)	0.59 (0.24 to 1.38)	‐0.11 (‐0.24 to 0.08)
TOFA		0.65 (0.23 to 1.86)	0.71 (0.31 to 1.58)	‐0.07 (‐0.22 to 0.12)
TOFA	(MTX or DMARD) + monoclonal antibodies against TNF	1.26 (0.36 to 4.40)	1.21 (0.43 to 3.36)	0.03 (‐0.15 to 0.22)

Random‐effects model	Residual deviance	8.529 vs. 10 data point
	Deviance information criteria	65.147
Fixed‐effect model	Residual deviance	8.129 vs. 10 data point
	Deviance information criteria	64.307
Note:

Total participants	2267
Total studies	5
2‐arm	5
DMARD: disease‐modifying anti‐rheumatic drug MTX: methotrexate TOFA: tofacitinib TNF: tumor necrosis factor

Table 4. ACR50 analysis for the type of medication (MTX/DMARD active comparator): odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

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Table 5. ACR50 analysis by dose (MTX/DMARD active comparator): odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
MTX SD biologic	Comparator: MTX or DMARD	4.82 (2.94 to 8.08)	4.10 (2.64 to 6.51)	0.14 (0.09 to 0.20)
MTX HD biologic		7.12 (3.73 to 13.28)	5.55 (3.24 to 9.23)	0.21 (0.12 to 0.31)
MTX HD biologic	MTX SD biologic	1.47 (0.84 to 2.54)	1.35 (0.87 to 2.03)	0.07 (‐0.03 to 0.17)

Random‐effects model	Residual deviance	10.34 vs. 10 data points
	Deviance information criteria	64.487
Fixed‐effect model	Residual deviance	11.64 vs. 10 data points
	Deviance information criteria	64.41


Total participants	1868
Total studies	4
2‐arm	2
3‐arm	2
DMARD: disease‐modifying anti‐rheumatic drug HD: high dose MTX: methotrexate SD: standard dose

Table 5. ACR50 analysis by dose (MTX/DMARD active comparator): odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

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Table 6. ACR50 analysis by dose (placebo comparator): odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
SD	Comparator	3.88 (0.99 to 23.62)	3.41 (0.99 to 14.41)	0.11 (0.00 to 0.39)
HD		4.91 (1.10 to 33.03)	4.14 (1.09 to 17.12)	0.15 (0.01 to 0.47)
HD	SD biologic	1.24 (0.49 to 3.32)	1.19 (0.55 to 2.57)	0.03 (‐0.10 to 0.21)


Total participants	359
Total studies	3
HD: high dose SD: standard dose

Table 6. ACR50 analysis by dose (placebo comparator): odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

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Table 7. HAQ analysis (MTX/other DMARD active comparator) for the type of medication: mean difference (MD) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	MD (95% CrI)
(MTX or DMARD) + non‐TNF	Comparator: PL, MTX or DMARD
(MTX or DMARD) + medications targeting TNF		‐0.37 (‐6.67 to 5.89)
TOFA		‐0.26 (‐6.57 to 5.95)
(MTX or DMARD) + medications targeting TNF	(MTX or DMARD) + non‐TNF	‐0.12 (‐8.96 to 8.75)
TOFA		‐0.02 (‐8.82 to 8.80)
TOFA	(MTX or DMARD) + medications targeting TNF	0.11 (‐8.83 to 8.97)

Random‐effects model	Residual deviance	5.996 vs. 6 data points
	Deviance information criteria	‐13.527
Fixed‐effect model	Residual deviance	6.009 vs. 6 data points
	Deviance information criteria	‐13.496
Note: A Negative sign indicates improvement in function

Total participants	1358
Total studies	3
2‐arm	3
DMARD: disease‐modifying anti‐rheumatic drug MTX: methotrexate PL: placebo TOFA: tofacitinib TNF: tumor necrosis factor

Table 7. HAQ analysis (MTX/other DMARD active comparator) for the type of medication: mean difference (MD) for all treatment comparisons ‐ random‐effects model

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Table 8. Remission analysis (MTX/DMARD active comparator) for the type of medication: odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
MTX + non‐TNF	Comparator	30.61 (6.46 to 346.20)	27.18 (6.13 to 262.70)	0.11 (0.03 to 0.28)
MTX + TNF		23.11 (3.60 to 548.90)	21.04 (3.53 to 287.20)	0.08 (0.01 to 0.52)
MTX + TNF	MTX + non‐TNF	0.75 (0.04 to 26.40)	0.77 (0.05 to 13.49)	‐0.03 (‐0.26 to 0.47)

Random‐effects model	Residual deviance	5.167 vs. 6 data points
	Deviance information criteria	30.949
Fixed‐effect model	Residual deviance	5.271 vs. 6 data points
	Deviance information criteria	31.163
Note:

Total participants	1348
Total studies	3
2‐arm	2
3‐arm	1
MTX: methotrexate TNF: tumor necrosis factor

Table 8. Remission analysis (MTX/DMARD active comparator) for the type of medication: odds ratios (OR), risk ratios (RR) and risk difference (RD) for all treatment comparisons ‐ random‐effects model

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Table 9. Remission: analysis (MTX/other DMARD active comparator trials) by dose: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
MTX SD	Comparator	14.92 (3.49 to 96.81)	14.03 (3.40 to 87.45)	0.06 (0.02 to 0.13)
MTX HD		54.62 (11.77 to 402.30)	43.97 (10.54 to 272.50)	0.18 (0.07 to 0.40)
MTX HD	MTX SD	3.62 (1.19 to 12.87)	3.10 (1.16 to 8.95)	0.13 (0.01 to 0.33)

Random‐effects model	Residual deviance	8.496 vs. 8 data points
	Deviance information criteria	42.391
Fixed‐effect model	Residual deviance	14.72 vs. 8 data points
	Deviance information criteria	46.982
Note:

Total participants	1348
Total studies	3
2‐arm	1
3‐arm	2
HD: high dose MTX: methotrexate SD: standard dose

Table 9. Remission: analysis (MTX/other DMARD active comparator trials) by dose: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

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Table 10. Withdrawals due to adverse events: analysis (MTX/other DMARD active comparator trials) for the type of medication: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
MTX or DMARD + non‐TNF	Comparator	2.04 (0.80 to 6.49)	1.99 (0.80 to 5.98)	0.03 (‐0.01 to 0.08)
TOFA + MTX		1.02 (0.29 to 3.90)	1.02 (0.29 to 3.65)	0.00 (‐0.02 to 0.06)
TOFA + MTX	MTX or DMARD + non‐TNF	0.50 (0.09 to 2.55)	0.51 (0.10 to 2.42)	‐0.03 (‐0.09 to 0.05)

Random‐effects model	Residual deviance	9.006 vs. 8 data points
	Deviance information criteria	42.328
Fixed‐effect model	Residual deviance	9.557 vs. 8 data points
	Deviance information criteria	42.474
Note:

Total participants	1401
Total studies	4
2‐arm	4
DMARD: disease‐modifying anti‐rheumatic drug MTX: methotrexate TOFA: tofacitinib TNF: tumor necrosis factor

Table 10. Withdrawals due to adverse events: analysis (MTX/other DMARD active comparator trials) for the type of medication: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

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Table 11. Serious adverse events: analysis (MTX/other DMARD active comparator trials) for the type of medication: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
(MTX or DMARD) + non‐TNF	Comparator	0.84 (0.47 to 1.58)	0.85 (0.49 to 1.53)	‐0.01 (‐0.04 to 0.03)
(MTX or DMARD) + medications		0.54 (0.19 to 1.56)	0.56 (0.20 to 1.51)	‐0.03 (‐0.06 to 0.03)
TOFA + MTX		0.31 (0.07 to 1.29)	0.32 (0.07 to 1.27)	‐0.04 (‐0.08 to 0.02)
(MTX or DMARD) + medications	(MTX or DMARD) + non‐TNF	0.64 (0.19 to 2.13)	0.66 (0.20 to 2.02)	‐0.02 (‐0.07 to 0.05)
TOFA + MTX		0.36 (0.07 to 1.70)	0.38 (0.07 to 1.65)	‐0.03 (‐0.08 to 0.03)
TOFA + MTX	(MTX or DMARD) + medications	0.56 (0.09 to 3.37)	0.57 (0.09 to 3.21)	‐0.01 (‐0.08 to 0.05)

Random‐effects model	Residual deviance	8.969 vs. 10 data points
	Deviance information criteria	56.677
Fixed‐effect model	Residual deviance	8.795 vs. 10 data points
	Deviance information criteria	56.133
Note:

Total participants	1862
Total studies	5
2‐arm	5
DMARD: disease‐modifying anti‐rheumatic drug MTX: methotrexate TOFA: tofacitinib TNF: tumor necrosis factor

Table 11. Serious adverse events: analysis (MTX/other DMARD active comparator trials) for the type of medication: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

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Table 12. Serious adverse events analysis (MTX/other DMARD active comparator trials) by dose: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

Treatment	Reference	OR (95% CrI)	RR (95% CrI)	RD (95% Crl)
MTX SD	Comparator	0.80 (0.48 to 1.36)	0.82 (0.51 to 1.32)	‐0.01 (‐0.05 to 0.02)
MTX HD		0.48 (0.17 to 1.30)	0.50 (0.18 to 1.27)	‐0.04 (‐0.08 to 0.02)
MTX HD	MTX SD	0.60 (0.20 to 1.65)	0.62 (0.21 to 1.59)	‐0.02 (‐0.07 to 0.03)

Random‐effects model	Residual deviance	8.024 vs. 9 data points
	Deviance information criteria	49.853
Fixed‐effect model	Residual deviance	7.837 vs. 9 data points
	Deviance information criteria	49.137
Note:

Total participants	1463
Total studies	4
2‐arm	3
3‐arm	1
HD: high dose MTX: methotrexate SD: standard dose

Table 12. Serious adverse events analysis (MTX/other DMARD active comparator trials) by dose: odds ratio (OR) for all treatment comparisons ‐ random‐effects model

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