Scolaris Content Display Scolaris Content Display

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram

Network diagram for ACR50 in people with RA who are biologic‐experienced
Figures and Tables -
Figure 2

Network diagram for ACR50 in people with RA who are biologic‐experienced

ACR50: biologic monotherapy vs. placebo
Figures and Tables -
Figure 3

ACR50: biologic monotherapy vs. placebo

ACR50: biologic with MTX vs. MTX/DMARD
Figures and Tables -
Figure 4

ACR50: biologic with MTX vs. MTX/DMARD

HAQ: biologic with MTX vs. MTX/DMARD
Figures and Tables -
Figure 5

HAQ: biologic with MTX vs. MTX/DMARD

RA remission: biologic with MTX vs. MTX/DMARD
Figures and Tables -
Figure 6

RA remission: biologic with MTX vs. MTX/DMARD

Withdrawals due to adverse events: biologic monotherapy vs. placebo
Figures and Tables -
Figure 7

Withdrawals due to adverse events: biologic monotherapy vs. placebo

Withdrawals due to adverse events: biologic with MTX vs. MTX/DMARD
Figures and Tables -
Figure 8

Withdrawals due to adverse events: biologic with MTX vs. MTX/DMARD

Serious adverse events: biologic with MTX vs. MTX/DMARD
Figures and Tables -
Figure 9

Serious adverse events: biologic with MTX vs. MTX/DMARD

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

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

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

Figures and Tables -
Table 1. Characteristics of included studies
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

Figures and Tables -
Table 2. Characteristics of excluded studies
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)

⊕⊕⊕⊕ highb

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)

⊕⊕⊕⊕ highb

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)

⊕⊕⊕⊕ highb

‐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)

⊕⊕⊕⊕ highb

‐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)

⊕⊕⊕⊕ highb

‐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/ae

⊕⊕⊕⊖ 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/ae

⊕⊕⊕⊖ 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

Figures and Tables -
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)
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

Figures and Tables -
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
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

Figures and Tables -
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
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

Figures and Tables -
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
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

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

Figures and Tables -
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
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

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

Figures and Tables -
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
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

Figures and Tables -
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
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

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