Supplementary Material

Supplementary Table 1. Studies contributing to evidence base network for the csDMARD-IR combination therapy population

Study name	Treatment name	Treatment code
ATTEST¹	Abatacept 8-10 mg/kg IV every 4 weeks + methotrexate	Abatacept combination
	Infliximab 3 mg/kg IV every 8 weeks + methotrexate	Infliximab combination
	methotrexate	csDMARD
Takeuchi et al 2013²	Abatacept 10 mg/kg IV every 4 weeks + methotrexate	Abatacept combination
Takeuchi et al 2013²	methotrexate	csDMARD
ASSURE³	Abatacept 8-10 mg/kg IV every 4 weeks + csDMARD	Abatacept combination
ASSURE³	csDMARD	csDMARD
AMPLE^{4, 5}	Abatacept 125 mg SC every week + methotrexate	Abatacept combination
AMPLE^{4, 5}	Adalimumab 40 mg SC every 2 weeks + methotrexate	Adalimumab combination
AIM^{6, 7}	Abatacept 8-10 mg/kg IV every 4 weeks + methotrexate	Abatacept combination
AIM^{6, 7}	methotrexate	csDMARD
Emery 2006^7-9	Abatacept 10 mg/kg IV every 4 weeks + methotrexate	Abatacept combination
Emery 2006^7-9	methotrexate	csDMARD
Kim 2007¹⁰	Adalimumab 40 mg SC every 2 weeks + methotrexate	Adalimumab combination
Kim 2007¹⁰	methotrexate	csDMARD
DE019^11-13	Adalimumab 40 mg SC every 2 weeks + methotrexate	Adalimumab combination
DE019^11-13	methotrexate	csDMARD
Weinblatt 2015⁵	Adalimumab 40 mg SC every 2 weeks + methotrexate	Adalimumab combination
Weinblatt 2015⁵	methotrexate	csDMARD
ARMADA¹⁴	methotrexate	csDMARD
ARMADA¹⁴	Adalimumab 40 mg SC every 2 weeks + methotrexate	Adalimumab combination
Choy 2012¹⁵	Certolizumab 400 mg SC every 4 weeks + methotrexate	Certolizumab combination
Choy 2012¹⁵	methotrexate	csDMARD
J-RAPID¹⁶	Certolizumab 200 mg SC every 2 weeks + methotrexate	Certolizumab combination
J-RAPID¹⁶	methotrexate	csDMARD
RAPID 2¹⁷	methotrexate	csDMARD
RAPID 2¹⁷	Certolizumab 200 mg SC every 2 weeks + methotrexate	Certolizumab combination
RAPID^{18, 19}	Certolizumab 200 mg SC every 2 weeks + methotrexate	Certolizumab combination
RAPID^{18, 19}	methotrexate	csDMARD
The Etanercept Study 309^{20, 21}	Etanercept 25 mg SC bid every week + csDMARD	Etanercept combination
The Etanercept Study 309^{20, 21}	Sulfasalazine	csDMARD
GO-FORTH²²	Golimumab 50 mg SC every 4 weeks + methotrexate	Golimumab combination
GO-FORTH²²	methotrexate	csDMARD
Kay 2008²³	Golimumab 50 mg SC every 4 weeks + methotrexate	Golimumab combination
Kay 2008²³	methotrexate	csDMARD
Li 2015^{24, 25}	Golimumab 50 mg SC every 4 weeks + methotrexate	Golimumab combination
Li 2015^{24, 25}	methotrexate	csDMARD
GO-FURTHER^26-28	Golimumab 2 mg/kg IV every 8 weeks + methotrexate	Golimumab combination
GO-FURTHER^26-28	methotrexate	csDMARD
GO-FORWARD^29-34	methotrexate	csDMARD
GO-FORWARD^29-34	Golimumab 50 mg SC every 4 weeks + methotrexate	Golimumab combination
The START Study group³⁵	Infliximab 3 mg/kg IV every 8 weeks + methotrexate	Infliximab combination
	Infliximab 10 mg/kg IV every 8 weeks + methotrexate	Infliximab combination
	methotrexate	csDMARD
SWEFOT^36-40	Sulfasalazine + hydroxychloroquine +methotrexate	methotrexate + 2 csDMARD
SWEFOT^36-40	Infliximab 3 mg/kg IV every 8 weeks + methotrexate	Infliximab combination
ATTRACT^41-43	Infliximab 3 mg/kg IV every 8 weeks + methotrexate	Infliximab combination
	Infliximab 3 mg/kg IV every 4 weeks + methotrexate	Infliximab combination
	Infliximab 10 mg/kg IV every 8 weeks + methotrexate	Infliximab combination
	methotrexate	csDMARD
DANCER⁴⁴	Rituximab 1000 mg IV at days 1 and 15 + methotrexate	Rituximab combination
DANCER⁴⁴	methotrexate	csDMARD
SERENE⁴⁵	Rituximab 2x1000 mg IV at days 1 and 15 + methotrexate	Rituximab combination
SERENE⁴⁵	methotrexate	csDMARD
Strand 2006^{46, 47}	Rituximab 1000 mg SC at days 1 and 15 + methotrexate	Rituximab combination
Strand 2006^{46, 47}	methotrexate	csDMARD
MOBILITY – B^{48, 49}	Sarilumab 150 mg SC every 2 weeks + methotrexate	Sarilumab 150 combination
	Sarilumab 200 mg SC every 2 weeks + methotrexate	Sarilumab 200 combination
	methotrexate	csDMARD
MEASURE^{50, 51}	Tocilizumab 8 mg/kg IV every 4 weeks + methotrexate	Tocilizumab 8 mg/kg IV combination
MEASURE^{50, 51}	methotrexate	csDMARD
LITHE^{52, 53}	Tocilizumab 8 mg/kg IV every 4 weeks + methotrexate	Tocilizumab 8 mg/kg IV combination
	Tocilizumab 4 mg/kg IV every 4 weeks + methotrexate	Tocilizumab 4 mg/kg IV combination
	methotrexate	csDMARD
BREVACTA^{54, 55}	Tocilizumab 162 mg every 2 weeks + csDMARD	Tocilizumab SC 162 mg q2w combination
BREVACTA^{54, 55}	Traditional DMARD	csDMARD
TOWARD⁵⁶	Tocilizumab 8 mg/kg IV every 4 weeks + csDMARD	Tocilizumab 8 mg/kg IV combination
TOWARD⁵⁶	csDMARD	csDMARD
OPTION⁵⁷	Tocilizumab 4 mg/kg IV every 4 weeks + methotrexate	Tocilizumab 4 mg/kg IV combination
	Tocilizumab 8 mg/kg IV every 4 weeks + methotrexate	Tocilizumab 8 mg/kg IV combination
	methotrexate	csDMARD
Kremer 2011⁵⁸	Tofacitinib 5 mg oral bid + methotrexate	Tofacitinib combination
Kremer 2011⁵⁸	methotrexate	csDMARD
ORAL Scan⁵⁹	Tofacitinib 5 mg oral bid + methotrexate	Tofacitinib combination
ORAL Scan⁵⁹	methotrexate	csDMARD
ORAL Standard⁶⁰	Tofacitinib 5 mg oral bid + methotrexate	Tofacitinib combination
	Adalimumab 40 mg SC every 2 weeks + methotrexate	Adalimumab combination
	methotrexate	csDMARD
SUMMACTA^61-63	Tocilizumab 162 mg SC every week + csDMARD	Tocilizumab 162 SC mg q1w combination
SUMMACTA^61-63	Tocilizumab 8 mg/kg IV every 4 weeks + csDMARD	Tocilizumab 8 mg/kg IV combination
RA-SCORE⁶⁴	methotrexate	csDMARD
RA-SCORE⁶⁴	Rituximab 1000 mg IV + methotrexate	Rituximab combination
STAR⁶⁵	Adalimumab 40 mg SC + Standard Treatment	Adalimumab combination
STAR⁶⁵	Placebo + Standard Treatment	csDMARD
ENCOURAGE⁶⁶	Etanercept 25 mg SC + methotrexate	Etanercept combination
ENCOURAGE⁶⁶	methotrexate	csDMARD
ROSE⁶⁷	Tocilizumab 8 mg/kg IV + csDMARD	Tocilizumab 8 mg/kg IV combination
ROSE⁶⁷	csDMARD	csDMARD
RA-BUILD⁶⁸	Baricitinib 2 mg SC OD + csDMARD	Baricitinib 2 mg combination
	Baricitinib 4 mg SC OD + csDMARD	Baricitinib 4 mg combination
	csDMARD	csDMARD
Kremer 2013⁶⁹	csDMARD	csDMARD
Kremer 2013⁶⁹	Tofacitinib 5mg oral + csDMARD	Tofacitinib combination
CERTAIN⁷⁰	Certolizumab 400 mg SC + csDMARD	Certolizumab combination
CERTAIN⁷⁰	csDMARD	csDMARD
RA-BEAM⁷¹	Placebo	csDMARD
	Baricitinib 4 mg SC OD + methotrexate	Baricitinib 4 mg combination
	Adalimumab + methotrexate	Adalimumab combination
AMARA⁷²	Rituximab 2x1000 mg IV at days 1 and 15 + csDMARD	Rituximab combination
AMARA⁷²	csDMARD	csDMARD
JADA^73-76	Baricitinib 2 mg SC OD + methotrexate	Baricitinib 2 mg combination
	Baricitinib 4 mg SC OD + methotrexate	Baricitinib 4 mg combination
	Placebo + methotrexate	csDMARD

csDMARD, conventional disease-modifying antirheumatic drugs; IV, intravenous; q2w, every 2 weeks; q4w, every 4 weeks; SC, subcutaneous.

*SWEFOT is included only in scenario analysis not in base case

Supplementary Table 2. Studies contributing to evidence base network for the TNFi-IR population

Study name	Treatment name	Treatment code
ATTAIN^{77, 78}	Abatacept 8-10 mg/kg every 4 weeks + csDMARD	Abatacept combination
ATTAIN^{77, 78}	csDMARD	csDMARD or methotrexate
Manders 2015^{79, 80}	Abatacept, dosage not reported	Abatacept combination
Manders 2015^{79, 80}	Rituximab, dosage not reported	Rituximab combination
GO-AFTER⁸¹	Golimumab 50 mg every 4 weeks +/- csDMARD	Golimumab combination
GO-AFTER⁸¹	Placebo +/- csDMARD	csDMARD or methotrexate
REFLEX^82-84	methotrexate	csDMARD or methotrexate
REFLEX^82-84	Rituximab 2x1000 mg at days 1 and 15 + methotrexate	Rituximab combination
TARGET⁸⁵	Tocilizumab 8 mg/kg every 4 weeks + methotrexate	Tocilizumab 8mg combination
	Tocilizumab 4 mg/kg every 4 weeks + methotrexate	Tocilizumab 4mg combination
	methotrexate	csDMARD or methotrexate
RADIATE^{18, 86}	Placebo+ methotrexate	csDMARD or methotrexate
	Baricitinib 2 mg OD + methotrexate	Baricitinib 2mg combination
	Baricitinib 4 mg OD + methotrexate	Baricitinib 4mg combination

csDMARD, conventional disease-modifying antirheumatic drugs; IV, intravenous; q2w, every 2 weeks; q4w, every 4 weeks; SC, subcutaneous.

Supplementary Table 3. Summary of scenario analyses

	Scenario	Rationale	Result
csDMARD-IR	Exclusion of studies in Asian populations in csDMARD-IR NMA	Weight was identified as a potential effect modifier via a regression analysis and also based on clinical advice. Therefore, Asian population was applied as a proxy to populations with relatively lower weight than other populations.	Results were similar to the ACR20/50 base cases for sarilumab 200 mg against all comparators. However, sarilumab 200 mg was superior to tocilizumab IV 4 mg/kg combination for ACR70.
	Inclusion of the outlier ATTRACT and SWEFOT studies for mTSS at 52 weeks	ATTRACT was excluded in the base case due to high degree of radiographic progression at baseline that was an outlier compared with other studies; this resulted in exclusion of the SWEFOT study due to the resulting disconnection to the network.	Sarilumab 200 mg combination therapy was found to be statistically superior to csDMARD and sarilumab 150 mg combination, and inferior to infliximab combination in fixed effects model. In random effects model, sarilumab 200 mg combination was found to be comparable against all treatments.
	TNFi pooled together as a class for each of the ACR20/50/70 outcomes	To inform cost-effectiveness evaluations of sarilumab.	Sarilumab 200 mg combination therapy was found to be superior to csDMARD and comparable to all other combination therapies.
TNFi-IR	Exclusion of studies assessing mixed monotherapy and combination therapy: 1) GO-AFTER which reported ACR20/50/70 and DAS remission outcomes	Although included in the base case, the GO-AFTER and SIRROUND-T were considered to be outlier studies. In GO-AFTER, around 30% of patients were treated with golimumab monotherapy (despite licensed use as combination with a csDMARD). Only 58% of patients had failed TNFi for efficacy reasons; the remainder could have failed for reasons including accessibility as well as intolerance. While the GO-AFTER trial was considered relevant to include in the base case as the only major trial evaluating a TNFi in patients after an initial TNFi, the conclusions regarding the relative efficacy and safety of sarilumab (or other non-TNFis) versus TNFis in TNFi-IR patients should be interpreted with caution.	Excluding the GO-AFTER study in the TNFi-IR population obtained results consistent with the base case for sarilumab 200 mg against all the comparators where comparisons were possible.

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