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1 Efficacy and safety of biological and targeted synthetic DMARDs: a systematic literature review informing the 21 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis Online supplementary material Table of Contents 1. LITERATURE SEARCH STRATEGY Search terms Review flow chart 7 2. SUMMARY OF PUBLICATIO 8. RANDOMIZED CONTROLLED TRIALS and LTE OF TNF INHIBITORS 1.1. Etanercept 1.2. Infliximab 15.. Adalimumab Golimumab Certolizumab pegol 25.. Axial inflammation Safety outcomes 4. OBSERVATIONAL STUDIES OF TNF INHIBITORS Malignancies Infections / serious infections Tuberculosis 5. TRIALS ON NEW TREATMENT TARGETS Description of included studies, baseline characteristics and risk of bias assessment Efficacy outcomes Safety outcomes 4. ACTIVE COMPARATOR TRIALS 4.1. Description of included studies, baseline characteristics and risk of bias assessment 4.2. Efficacy outcomes 48.. Safety outcomes STRATEGY AND COST-EFFECTIVENESS TRIALS LIST OF PUBLICATIO LIST OF ABBREVIATIO 4 Page 1

2 1. LITERATURE SEARCH STRATEGY 1.1 Search terms Medline 1. exp Spondylitis/ 2. (ankylos$ or spondyl$).tw.. SpA.tw. 4. (bekhterev$ or bechterew$).tw. 5. or/1-4. exp biological therapy/ 7. exp antibodies, monoclonal/ 8. exp monokines/ 9. exp receptors, interleukin-1/ 1. exp receptors, interleukin-/ 11. exp immunoglobulin g/ 12. exp immunoconjugates/ 1. exp polyethylene glycols/ 14. exp immunoglobulin fab fragments/ 15. exp t-lymphocytes/ 1. biologic$.tw. 17. infliximab.tw. 18. remicade.tw. 19. adalimumab.tw. 2. humira.tw. 21. trudexa.tw. 22. abatacept.tw. 2. orencia.tw.. anakinra.tw. 25. kineret.tw. 2

3 2. Certolizumab.tw. 27. cimzia.tw. 28. Etanercept.tw. 29. enbrel.tw.. Golimumab.tw. 1. simponi.tw. 2. rituximab.tw.. rituxan.tw. 4. mabthera.tw. 5. Tocilizumab.tw.. actemra.tw. 7. RoActemra.tw. 8. secukinumab.tw. 9. Cosentyx.tw. 4. ustekinumab.tw. 41. Stelara.tw. 42. brodalumab.tw. 4. ixekizumab.tw. 44. or/ and (animals not (humans and animals)).sh not limit 47 to yr="29 -Current" EMBASE 1. 'spondylitis'/exp 2. ankylos*:ab,ti OR spondyl*:ab,ti. spa:ab,ti 4. bekhterev*:ab,ti OR bechterew*:ab,ti

4 5. #1 OR #2 OR # OR #4. 'biological therapy'/exp 7. biologic*:ab,ti 9. 'monoclonal antibody'/exp 1. 'infliximab':ab,ti 11. remicade:ab,ti 12. adalimumab:ab,ti 1. humira:ab,ti 14. trudexa:ab,ti 15. abatacept:ab,ti 1. orencia:ab,ti 17. anakinra:ab,ti 18. kineret:ab,ti 19. certolizumab:ab,ti 2. cimzia:ab,ti 22. 'etanercept'/de 2. etanercept:ab,ti. enbrel:ab,ti 25. golimumab:ab,ti 27. simponi:ab,ti 28. rituximab:ab,ti 29. rituxan:ab,ti. mabthera:ab,ti 1. tocilizumab:ab,ti 2. actemra:ab,ti. roactemra:ab,ti 4. secukinumab:ab,ti 5. cosentyx:ab,ti. ustekinumab:ab,ti 4

5 7. stelara:ab,ti 8. brodalumab:ab,ti 9. ixekizumab:ab,ti 4. # OR #7 OR #9 OR #1 OR #11 OR #12 OR #1 OR #14 OR #15 OR #1 OR #17 OR #18 OR #19 OR #2 OR #22 OR #2 OR # OR #25 OR #27 OR #28 OR #29 OR # OR #1 OR #2 OR # OR #4 OR #5 OR # OR #7 OR #8 OR #9 41. #5 AND #4 42. #5 AND #4 AND [humans]/lim AND [embase]/lim 4. #4 AND (29:py OR 21:py OR 211:py OR 212:py OR 21:py OR 214:py OR 215:py) AND AND ('article'/it OR 'article in press'/it OR 'review'/it) Cochrane Central #1. MeSH descriptor: [Spondylitis] explode all trees #2. (ankylos* or spondyl*):ti,ab #. spa:ti,ab #4. (bekhterev* or bechterew*):ti,ab #5. #1 or #2 or # or #4 #. MeSH descriptor: [Biological Therapy] explode all trees #7. MeSH descriptor: [Antibodies, Monoclonal] explode all trees #8. MeSH descriptor: [Monokines] explode all trees #9. MeSH descriptor: [Receptors, Interleukin-1] explode all trees #1. MeSH descriptor: [Receptors, Interleukin-] explode all trees #11. MeSH descriptor: [Immunoglobulin G] explode all trees #12. MeSH descriptor: [Immunoconjugates] explode all trees #1. MeSH descriptor: [Polyethylene Glycols] explode all trees #14. MeSH descriptor: [Immunoglobulin Fab Fragments] explode all trees #15. MeSH descriptor: [T-Lymphocytes] explode all trees #1. biologic*:ti,ab #17. infliximab:ti,ab #18. remicade:ti,ab 5

6 #19. adalimumab:ti,ab #2. humira:ti,ab #21. trudexa:ti,ab #22. abatacept:ti,ab #2. orencia:ti,ab #. anakinra:ti,ab #25. kineret:ti,ab #2. Certolizumab:ti,ab #27. cimzia:ti,ab #28. Etanercept:ti,ab #29. enbrel:ti,ab #. Golimumab:ti,ab #1. simponi:ti,ab #2. rituximab:ti,ab #. rituxan:ti,ab #4. mabthera:ti,ab #5. Tocilizumab:ti,ab #. actemra:ti,ab #7. RoActemra:ti,ab #8. secukinumab:ti,ab #9. Cosentyx:ti,ab #4. ustekinumab:ti,ab #41. Stelara:ti,ab #42. brodalumab:ti,ab #4. ixekizumab:ti,ab #44. # or #7 or #8 or #9 or #1 or #11 or #12 or #1 or #14 or #15 or #1 or #17 or #18 or #19 or #2 or #21 or #22 or #2 or # or #25 or #2 or #27 or #28 or #29 or # or #1 or #2 or # or #4 or #5 or # or #7 or #8 or #9 or #4 or #41 or #42 or #4 #45. #5 and #44 Publication Year from 29 to 215

7 1.2 Review flow chart Medline Biological (n=2,5) Non-biological (n=4,852) Total (n=7,58) Cochrane Biological (n=1) Non-biological (n=7) Total (n=59) Embase Biological (n=1,951) Non-biological (n=4,449) Total (n=,4) ACR / EULAR meetings 428 abstracts After de-duplication n=11,49 Excluded by title/abstract n=11,2 For detailed review n=2 Biological (n=82) Non-biological (n=1) Excluded by detailed review n=47 Wrong population (5) Wrong study type (192) Wrong intervention (2) Wrong outcome (45) Wrong comparator (41) Duplicate (9) Wrong publication date (1) Wrong language (1) Included (biological/tsdmards) n=1 (7 papers; abstracts) Included (non-biological/non-pharmacological) n=47 (45 papers; 2 abstracts) Figure S1. Flowchart for the systematic literature. 7

8 2. SUMMARY OF PUBLICATIO Table S1. Number of publications from clinical trials according to the study population. r-axspa axspa nr-axspa* nr-axspa* SpA SpA Total Total Drug (mny) (ASAS) (ASAS) (other) (Amor) (ESSG) publications trials Etanercept Infliximab Adalimumab Golimumab Certolizumab pegol Secukinumab Ustekinumab Rituximab Abatacept Tocilizumab Sarilumab Apremilast Tofacitinib CT-P Total publications Both nr-axspa and r-axspa (mny) patients included in the same study; *excluding patients fulfilling the mny; plus one Cochrane review; CT-P1, infliximab biosimilar. 8

9 Table S1.1. Number of clinical trials according to the study population. Drug (range publication year) N trials r-axspa (mny) axspa (ASAS) nr-axspa* (ASAS) nr-axspa* (other) SpA (Amor) SpA (ESSG) Etanercept (29-215) Infliximab (29-214) Adalimumab (29-21) 2 1 Golimumab ( ) Certolizumab pegol (214; 215) 1 1 Secukinumab (21-215) 1 1 Ustekinumab (214) 1 1 Rituximab (21; 21) 1 1 Abatacept (211) 1 1 Tocilizumab (214) 1 1 Sarilumab (215) 1 1 Apremilast (21) 1 1 Tofacitinib (215) 1 1 CT-P1 (21; 21) 1 1 Total Both nr-axspa and r-axspa (mny) patients included in the same study; *excluding patients fulfilling the mny; CT-P1, infliximab biosimilar. Table S2. Observational cohort studies. Adverse event Prospective cohort (comparator) Prospective cohort (SIR* reported) Total studies Malignancies Infections / serious infections 2 2 Tuberculosis 2 2 Total 4 7 *SIR, Standardized Incidence Ratio (the ratio between observed and expected cases in the general population). 9

10 . RANDOMIZED CONTROLLED TRIALS AND LTE OF TNF INHIBITORS Different publications stemming from the same study are included provided additional data for at least one of the pre-defined outcomes is reported. However, not all outcomes included in the PICO for this SLR are shown here (eg. patient global assessment, quality of life according to SF-, work-participation), thus some studies do not have data for the selected (main) outcomes. If more than one publication from the same study is available different colours are used to identify each publication and the respective data. Given the time-span (29-21) of the SLR the main phase RCTs for etanercept, infliximab, adalimumab and golimumab in r-axspa were not included, but only their LTE or other (subsequent) trials in different populations..1 Etanercept Table S: and patients main characteristics (etanercept) Type of patients ETA 25 TW Dijkmans 29 Rheuma r-axspa N Age (years) Males HLA-B Disease duration (years) Martín-Mola 21 C&ER r-axspa ETA 25 TW ETA 25 TW Barkham 21 ARD r-axspa ETA 5 QW Dougados 21 ARD (HEEL) SpA Dougados 211 ARD (SPINE) Dougados 212 Rheuma (SPINE) r-axspa ETA 5 QW (9.7) 9.4 (1.1) 4.5 (12.4) 4 (1.4) Previous TNFi 12 month months TNFi-naive 2.5 (1.9). (.) Baraliakos 21 AR&T axspa ETA 25 TW 1 (7.5) (7.7) Dougados 214 A&R (EMBARK) Dougados 215 JR (EMBARK) Maksymowych 215 ARD (EMBARK) Dougados 215 ACR (EMBARK) Brown 215 ACR (EMBARK) nr-axspa ETA 5 QW (11) 48 (1) 1.9 (7.8) 2. (7.8) (1) 2 (11) 2.4 (1.9) 2.5 (1.8) TNFi-naive TNFi-naive TNFi-naive 1

11 ETA 5 + AIDs Dougados 214 AR&T (SPARSE) axspa + AIDs (12.) 8.9 (11.4) according to modified New York criteria; according to Amor criteria; according to ASAS criteria; Median (9.) 5.5 (7.4) TNFi-naive Table S4: Cochrane risk of bias assessment (etanercept) Selection Other Overall Intervention Performance bias Detection bias Attrition bias Reporting bias bias bias RoB Dijkmans 29 Rheuma L L L L L L L L Martín-Mola 21 C&ER L M H H M L H H Barkham 21 ARD L L L L L L L L Dougados 21 ARD (HEEL) L L L L L L L L Dougados 211 ARD (SPINE) Dougados 212 Rheuma (SPINE) L L L L L L L L Baraliakos 21 AR&T L M H H M L H H Dougados 214 A&R (EMBARK) Dougados 215 JR (EMBARK) Maksymowych 215 ARD (EMBARK) Dougados 215 ACR (EMBARK) Brown 215 ACR (EMBARK) L L L L L L L L Dougados 214 AR&T (SPARSE) L L L L L L L L H= high risk; L = low risk; U = unclear risk. 11

12 Table S5: ASAS response outcomes (etanercept) Dijkmans 29 Rheuma ETA 25 TW Time-point ASAS 2 2 ASAS 4 ASAS 5/ ASAS PR Martín-Mola 21 C&ER* ETA 25 TW Barkham 21 ARD Dougados 21 ARD (HEEL) Dougados 211 ARD (SPINE) Dougados 212 Rheuma (SPINE) ETA 25 TW ETA 5 QW ETA 5 QW ETA 5 QW /ETA Baraliakos 21 AR&T* ETA 25 TW Dougados 214 A&R (EMBARK) Dougados 215 JR (EMBARK) Maksymowych 215 ARD (EMBARK) Dougados 215 ACR (EMBARK) Brown 215 ACR (EMBARK) ETA 5 QW ETA / ETA /ETA < < Dougados 214 AR&T (SPARSE) ETA 5 + AIDs + AIDs ref ref ref *Completers analysis (observed data); ITT analysis (I) Table S: ASDAS outcomes (etanercept) Timepoint Mean ASDAS change (SD) ASDAS CII ASDAS MI ASDAS I Dijkmans 29 Rheuma ETA 25 TW Martín-Mola 21 C&ER ETA 25 TW 12

13 Barkham 21 ARD ETA 25 TW Dougados 21 ARD (HEEL) ETA 5 QW ETA 5 QW (.87) < < <.1 4. <.1 Dougados 211 ARD (SPINE) -.49 (.87) Dougados 212 Rheuma (SPINE) ETA (1.2) /ETA (1.1) Baraliakos 21 AR&T* ETA 25 TW Dougados 214 A&R (EMBARK) ETA 5 QW -1.1 (.1) <.1 4 <.1 Dougados 215 JR (EMBARK) -.5 (.1) 17.4 Maksymowych 215 ARD (EMBARK) Dougados 215 ACR (EMBARK) ETA / ETA -1. (.2) 48 2 /ETA -1.7 (.1) 59.1 Brown 215 ACR (EMBARK) Dougados 214 AR&T (SPARSE) ETA 5 + AIDs + AIDs *Completers analysis (observed data); ITT analysis (I) (.1).5 (.1) (.1).5 (.1) Table S7: Other disease-activity outcomes (etanercept) Timepoint Mean BASDAI BASDAI 5 Mean CRP Mean TJC change (SD) change (SD) (SD) ETA 25 TW Dijkmans 29 Rheuma Martín-Mola 21 C&ER ETA 25 TW Barkham 21 ARD Dougados 21 ARD (HEEL) Dougados 211 ARD (SPINE) Dougados 212 Rheuma (SPINE) ETA 25 TW ETA 5 QW ETA 5 QW ETA 5 /ETA 5-1,97 -, (2.8) -4.4 (2.8) -2 (2) -14 (2) -7. (22.4) -28. (.) (14) -1 (14) < (.) -9. (1) Baraliakos 21 AR&T ETA 25 TW 84 1

14 Dougados 214 A&R (EMBARK) Dougados 215 JR (EMBARK) Maksymowych 215 ARD (EMBARK) Dougados 215 ACR (EMBARK) Brown 215 ACR (EMBARK) Dougados 214 AR&T (SPARSE) ITT analysis (I) ETA 5 QW ETA / ETA /ETA ETA 5 + AIDs + AIDs 2 2-2, (,) -1, (,1) -.4 (.2) -.9 (.2) 2. (,) 1.1 (,) <.5.2 -, (1,1),1 (1,).4-1, (.4) -1, (.4).989 Table S8: Mobility, function and quality of life outcomes (etanercept) Dijkmans 29 Rheuma ETA 25 TW Time-point Mean BASFI change (SD) Mean BASMI change (SD) Mean ASQoL change Martín-Mola 21 C&ER ETA 25 TW Barkham 21 ARD Dougados 21 ARD (HEEL) Dougados 211 ARD (SPINE) Dougados 212 Rheuma (SPINE) ETA 25 TW ETA 5 QW ETA 5 QW ETA 5 /ETA (1.8) -1. (1.8) (2.8) (2.9) (.5) -.2 (.5) -.8 (.8) -.5 (.7) (1.2) -1.7 (1.1) Baraliakos 21 AR&T ETA 25 TW Dougados 214 A&R (EMBARK) Dougados 215 JR (EMBARK) Maksymowych 215 ARD (EMBARK) Dougados 215 ACR (EMBARK) Brown 215 ACR (EMBARK) Dougados 214 AR&T (SPARSE) ITT analysis (I) ETA 5 QW ETA / ETA /ETA ETA 5 + AIDs + AIDs (.2) -.8 (.2) -2.4 (.2) -2.4 (.2) 1.7 (.).8 (.).1. ref -. (.2) -. (.1).4 (.2).1 (.2) (.5) -1.4 (.5).29 14

15 .2 Infliximab Table S9: and patients main characteristics (infliximab) Barkham 29 A&R Type of patients N Age (years) Males HLA-B27+ Disease duration (years) nr-axspa* INF 5 mg/kg INF mg/kg Inman 21 JR r-axspa INF mg/kg Maksymowych 21 JR r-axspa (1.4) 9. (9.) 4. (11.8) 41.7 (9.) months 1.4 months 11.1 (1.) 11.7 (1.) 2. (11.8) 2.2 (11.5) Previous TNFi TNFi-naïve TNFi-naïve TNFi-naïve Baraliakos 211 Rheuma r-axspa IFN mg/kg 7.8 (8) TNFi-naive * nr-axspa defined by: IBP (Calin definition) within months to years AND MRI-SI positive AND HLA-B27 +; according to modified New York criteria; according to ASAS criteria. Table S1: Cochrane risk of bias assessment (infliximab) Intervention Selection bias Performance bias Detection bias Attrition bias Reporting bias Other bias Overall RoB Barkham 29 A&R L L L L L L L L Inman 21 JR L L L L L L L L Maksymowych 21 JR L L L L L L L L Baraliakos 211 Rheuma L M H H M L H H H= high risk; L = low risk; U = unclear risk. 15

16 Table S11: ASAS response outcomes (infliximab) Barkham 29 A&R INF 5 mg/kg Time-point ASAS 2 4 ASAS ASAS 5/ ASAS PR Inman 21 JR INF mg/kg <.1 51 <.1 Maksymowych 21 JR INF mg/kg Baraliakos 211 Rheuma* IFN mg/kg NA. NA. NA.2 NA *Completers analysis (observed data) Table S12: ASDAS outcomes (infliximab) Barkham 29 A&R Inman 21 JR Maksymowych 21 JR INF 5 mg/kg INF mg/kg INF mg/kg Time-point Mean ASDAS change (SD) ASDAS CIII ASDAS MI ASDAS I 4 12 Baraliakos 211 Rheuma IFN mg/kg 9 Table S1: Other disease-activity outcomes (infliximab) Barkham 29 A&R Inman 21 JR INF 5 mg/kg INF mg/kg Time-point Mean BASDAI change (SD) BASDAI 5 Mean CRP change (SD) Mean TJC (SD)

17 Maksymowych 21 JR INF mg/kg (1.9) -.8 (2.2) Baraliakos 211 Rheuma* IFN mg/kg 9. *Completers analysis (observed data) Table S14: Mobility, function and quality of life outcomes (infliximab) Barkham 29 A&R Inman 21 JR Maksymowych 21 JR INF 5 mg/kg INF mg/kg INF mg/kg Time-point 4 Mean BASFI change (SD) -2.7 (2.) -.47 (2.25) Mean BASMI change (SD) -.45 (1.). (.) Mean ASQoL change Baraliakos 211 Rheuma IFN mg/kg

18 . Adalimumab van der Heijde 29 ARD (ATLAS) van der Heijde 29 AR&T (ATLAS) Maksymowych 21 JR (ATLAS) Sieper 212 ARD (ATLAS) van der Heijde 215 Rheuma (ATLAS) Type of patients r-axspa Table S15: and patients main characteristics (adalimumab) N Age (years) Males HLA-B27+ ADA 4 Q2W ADA 4 Q2W Hu 212 IJRD r-axspa Sieper 21 ARD (ABILITY-1) van der Heijde 214 EULAR (ABILITY-1) nr-axspa ADA 4 Q2W ADA4 Q4W ADA 4 Q2W Huang 214 ARD r-axspa ADA 4 Q2W Pedersen 21 A&R SpA according to modified New York criteria; according to ASAS criteria; according to the ESSG criteria Disease duration (years) Previous TNFi 4.2 (11.) (9.5) TNFi-naïve 28. (.9) 27.4 (7.2) (8.7) 29.7 (7.5) 9. (12.4) 7.5 (9.4) (5.7) 7. (4.) 1.1 (9.) 1.1 (8.8) 8.1 (.) 7.7 (4.7) 1.9 (1.8) 8.2 (8.1) TNFi-naïve TNFi-naïve TNFi-naïve Table S1: Cochrane risk of bias assessment (adalimumab) Intervention Selection bias Performance bias Detection bias Attrition bias Reporting bias Other bias Overall RoB van der Heijde 29 ARD (ATLAS) van der Heijde 29 AR&T (ATLAS) Maksymowych21 JR (ATLAS) Sieper 212 ARD (ATLAS) van der Heijde 215 Rheuma (ATLAS) L L L L L L L L Hu 212 IJRD L L L L L U U L Sieper 21 ARD (ABILITY-1) L L L L L U L L 18

19 van der Heijde 214 EULAR (ABILITY-1) Huang 214 ARD L L L L L U U L Pedersen 21 A&R L L L L L L L L H= high risk; L = low risk; U = unclear risk. Table S17: ASAS response outcomes (adalimumab) van der Heijde 29 ARD (ATLAS) van der Heijde 29 AR&T (ATLAS) Maksymowych21 JR (ATLAS) Sieper 212 ARD (ATLAS)* van der Heijde 215 Rheuma (ATLAS) Hu 212 IJRD Sieper 21 ARD (ABILITY-1) van der Heijde 214 EULAR (ABILITY-1)* Huang 214 ARD Pedersen 21 A&R *Completers analysis (observed data) Timepoint ASAS 2 ASAS 4 ASAS 5/ ASAS PR ADA4 Q4W ADA 4 Q2W ADA 4 Q2W ADA4 Q4W ADA 4 Q2W ADA 4 Q2W < <.1 < <.1 < <.1 Table S18: ASDAS outcomes (adalimumab) Timepoint Mean ASDAS change (SD) ASDAS CII ASDAS MI ASDAS I 19

20 van der Heijde 29 ARD (ATLAS) van der Heijde 29 AR&T (ATLAS) Maksymowych21 JR (ATLAS) Sieper 212 ARD (ATLAS)* van der Heijde 215 Rheuma (ATLAS) Hu 212 IJRD ADA4 Q4W 5..5 ADA 4 Q2W Sieper 21 ARD (ABILITY-1) van der Heijde 214 EULAR (ABILITY-1)* ADA 4 Q2W ADA4 Q4W < < <.1 Huang 214 ARD ADA 4 Q2W -2. (1.1) -. (.8) < < < <.1 Pedersen 21 A&R ADA 4 Q2W -1.9 (1.7) -.5 (1.) *Completers analysis (observed data) Table S19: Other disease-activity outcomes (adalimumab) van der Heijde 29 ARD (ATLAS) van der Heijde 29 AR&T (ATLAS) Maksymowych21 JR (ATLAS) Sieper 212 ARD (ATLAS)* van der Heijde 215 Rheuma (ATLAS) Hu 212 IJRD Sieper 21 ARD (ABILITY-1) van der Heijde 214 EULAR (ABILITY-1)* Huang 214 ARD ADA 4 Q2W ADA4 Q4W ADA 4 Q2W ADA 4 Q2W ADA4 Q4W ADA 4 Q2W Timepoint Mean BASDAI change (SD) <.1 BASDAI <.1 Mean CRP change (SD) Mean TJC (SD) (1.9) -1.4 (1.9).4 < < (2.8) -4.2 (21.2) <.1 < (.) -.7 (1.8).4 2

21 Pedersen 21 A&R ADA 4 Q2W - () -11 (19) *Completers analysis (observed data) Table S2: Mobility, function and quality of life outcomes (adalimumab) van der Heijde 29 ARD (ATLAS) van der Heijde 29 AR&T (ATLAS) Maksymowych21 JR (ATLAS) Sieper 212 ARD (ATLAS) van der Heijde 215 Rheuma (ATLAS)* Hu 212 IJRD Sieper 21 ARD (ABILITY-1) van der Heijde 214 EULAR (ABILITY-1)* ADA 4 Q2W ADA4 Q4W ADA 4 Q2W ADA 4 Q2W ADA4 Q4W Huang 214 ARD ADA 4 Q2W Pedersen 21 A&R ADA 4 Q2W *Completers analysis (observed data) Time-point Mean BASFI change (SD) <.1 Mean BASMI change (SD) -. Mean ASQoL change (2.2) -4.7 (1.4).5 < (.) -.2 (.7) < <.1 21

22 .4 Golimumab Table S21: and patients main characteristics (golimumab) Type of patients N Age (years) GOL 5 Q4W Bao 214 Rheuma r-axspa GOL 5 Q4W Tam 214 Rheuma r-axspa (8.).5 (1.2) 5. (9.9) 4.2 (1) Males HLA-B Disease duration (years) 7.5 (.).8 (.4) Previous TNFi TNFi-naive 8 (-17) 11 (-17.5) Sieper 215 A&R (GO-AHEAD) van der Heijde 215 ACR (GO-AHEAD) nr-axspa GOL 5 Q4W (7.1) 1.7 (7.2) % 1Y 5% 1Y TNFi-naive Braun 212 ARD (GO-RAISE) van der Heijde 214 JR (GO-RAISE) van der Heijde 214 Rheuma (GO-RAISE) Braun 214 ARD(GO-RAISE) Deodhar 215 ARD (GO-RAISE) r-axspa GOL 5 Q4W GOL 1 Q4W (12.5) 8. (11.) 4. (12.7) According to modified New York criteria; according to ASAS criteria; median (interquartile range) (8.1) 8.1 (8.) 1.8 (1.) TNFi-naive Table S22: Cochrane risk of bias assessment (golimumab) Bao 214 Rheuma Tam 214 Rheuma Intervention Selection bias Performance bias Detection bias Attrition bias Reporting bias Other bias Overall RoB Sieper 215 A&R (GO-AHEAD) van der Heijde 215 ACR (GO-AHEAD) GOL 5 Q4W GOL 5 Q4W GOL 5 Q4W L L L L U L L L L L L U H U L L L L L L L 22

23 Braun 212 ARD (GO-RAISE) van der Heijde 214 JR (GO-RAISE) GOL 5 Q4W van der Heijde 214 Rheuma (GO-RAISE) GOL 1 Q4W Braun 214 ARD(GO-RAISE) Deodhar 215 ARD (GO-RAISE)) H= high risk; L = low risk; U = unclear risk. L L L L L L L Table S2: ASAS outcomes (golimumab) Bao 214 Rheuma Tam 214 Rheuma Sieper 215 A&R (GO-AHEAD) van der Heijde 215 ACR (GO-AHEAD) GOL 5 Q4W GOL 5 Q4W GOL 5 Q4W GOL 5/GOL 5 /GOL 5 Braun 212 ARD (GO-RAISE)* GOL 5 van der Heijde 214 JR (GO-RAISE) GOL 1 van der Heijde 214 Rheuma (GO-RAISE) /GOL 5 Braun 214 ARD (GO-RAISE) Deodhar 215 ARD (GO-RAISE) GOL5+GOL1 *Completers analysis (observed data); ITT analysis (I) Time-point ASAS <.1. <.1 ASAS 4 ASAS 5/ ASAS PR <.1 Table S: ASDAS outcomes (golimumab) Bao 214 Rheuma Tam 214 Rheuma GOL 5 Q4W GOL 5 Q4W Timepoint Mean ASDAS change (SD) ASDAS CII ASDAS MI ASDAS I -1.9 (1.) -.8 (.81) <.1 2

24 Sieper 215 A&R (GO-AHEAD) van der Heijde 215 ACR (GO-AHEAD) Braun 212 ARD (GO-RAISE) van der Heijde 214 JR (GO-RAISE) van der Heijde 214 Rheuma (GO-RAISE)* Braun 214 ARD(GO-RAISE) Deodhar 215 ARD (GO-RAISE) GOL 5 Q4W GOL 5/GOL 5 /GOL 5 GOL 5 Q4W GOL 1 Q4W GOL 5 GOL 1 /GOL 5 *Completers analysis (observed data); ITT analysis (I) (1.2) -1.7 (1.) -. (1) -2.1 (1.1) -2. (1.2) -2. (1.) <.1 < <.1 < <.1 <.1 Table S25: Other disease-activity outcomes (golimumab) Bao 214 Rheuma Tam 214 Rheuma Sieper 215 A&R (GO-AHEAD) van der Heijde 215 ACR (GO-AHEAD) Braun 212 ARD (GO-RAISE) van der Heijde 214 JR (GO-RAISE) van der Heijde 214 Rheuma (GO-RAISE)* Braun 214 ARD(GO-RAISE) Deodhar 215 ARD (GO-RAISE) *Completers analysis (observed data) GOL 5 Q4W GOL 5 Q4W GOL 5 Q4W GOL 5 GOL 1 /GOL 5 Timepoint Mean BASDAI change (SD) BASDAI 5 Mean CRP change (SD) Mean TJC (SD) (1.4) -. (1.) (1.1) 2. (1.2) 2. (1.) 57.7 < (21.2) -4.8 (18.).4

25 Table S2: Mobility, function and quality of life outcomes (golimumab) Bao 214 Rheuma Tam 214 Rheuma Sieper 215 A&R (GO-AHEAD) van der Heijde 215 ACR (GO-AHEAD) Braun 212 ARD (GO-RAISE)* van der Heijde 214 JR (GO-RAISE) van der Heijde 214 Rheuma (GO-RAISE) Braun 214 ARD(GO-RAISE) Deodhar 215 ARD (GO-RAISE) *Completers analysis (observed data) GOL 5 Q4W GOL 5 Q4W GOL 5 Q4W GOL 5 GOL 1 /GOL 5 Time-point Mean BASFI change (SD) -1.2 (2.57).11 (2.1) (2.49) 1.7 (7.2) vale <.1.85 Mean BASMI change (SD) -.42 (.91) -.19 (.72) Mean ASQoL change (2.7) 2.9 (2.21) -2. (2.2) -.8 (.79) -.8 (.9) -.8 (.95).5 Certolizumab Pegol Table S27: and patients main characteristics (certolizumab pegol) Type of patients -controlled period N Age (years) Males HLA-B27+ Disease duration (years) Previous TNFi 25

26 van der Heijde 212 EULAR (RAPID-axSpA) Landewé 21 ACR (RAPID-axSpA) van der Heijde 21 EULAR (RAPID-axSpA) van der Heijde 214 ACR (RAPID-axSpA) Landewé 214 ARD (RAPID-axSpA) Mease 214 EULAR (RAPID-axSpA) Rosenbaum 214 ACR (RAPID-axSpA) Rudwaleit 2914 EULAR (RAPID-axSpA) Sieper 215 AC&R (RAPID-axSpA) Sieper 215 A&R (RAPID-axSpA) Braun 215 ARD (RAPID-axSpA) axspa axspa axspa axspa r-axspa r-axspa r-axspa r-axspa nr-axspa nr-axspa nr-axspa nr-axspa CZP 2 CZP 4 CZP 2+4 CZP 2 CZP 4 CZP 2+4 CZP 2 CZP 4 CZP (11.9) 9.8 (11.) 9.5 (11.) 9.9 (12.4) 41. (1.8) 41.9 (11.5) 41.4 (11.1) 41. (12.8). (1.) 7.5 (1.8) 7.1 (11.8) 8. (11.8) (.; 4.2) 7.9 (.; 44.8) 7.8 (.; 44.8) 7.7 (.; 5.9) 8.8 (.; 2.7) 8.8 (.; 44.8) 8,8 (.; 44.8) 1.2 (.; 5.9) 4.8 (.; 4.2) 7. (.; 25.) 5.9 (.; 4.2) 4.5 (.5; 41.5) according to ASAS criteria; median (min; max). Intervention Selection bias Performance bias Detection bias Attrition bias Reporting bias Other bias Overall RoB van der Heijde 212 EULAR (RAPID-axSpA) Landewé 21 ACR (RAPID-axSpA) van der Heijde 21 EULAR (RAPID-axSpA) van der Heijde 214 ACR (RAPID-axSpA) Landewé 214 ARD (RAPID-axSpA) Mease 214 EULAR (RAPID-axSpA) L L L L L L L L Rosenbaum 214 ACR (RAPID-axSpA) Rudwaleit 2914 EULAR (RAPID-axSpA) Sieper 215 AC&R (RAPID-axSpA) Sieper 215 A&R (RAPID-axSpA) Braun 215 ARD (RAPID-axSpA) Table S28: Cochrane risk of bias assessment (certolizumab pegol) H= high risk; L = low risk; U = unclear risk. Table S29: ASAS outcomes (certolizumab pegol) Time-point ASAS 2 ASAS 4 ASAS 5/ ASAS PR 2

27 van der Heijde 212 EULAR (RAPID-axSpA) Landewé 21 ACR (RAPID-axSpA) van der Heijde 21 EULAR (RAPID-axSpA) van der Heijde 214 ACR (RAPID-axSpA) Landewé 214 ARD (RAPID-axSpA) Mease 214 EULAR (RAPID-axSpA) Rosenbaum 214 ACR (RAPID-axSpA) Rudwaleit 2914 EULAR (RAPID-axSpA) Sieper 215 AC&R (RAPID-axSpA) Sieper 215 A&R (RAPID-axSpA) Braun 215 ARD (RAPID-axSpA) axspa CZP 2 axspa CZP 4 axspa CZP 2+4 axspa r-axspa CZP 2 r-axspa CZP 4 r-axspa CZP 2+4 r-axspa nr-axspa CZP 2 nr-axspa CZP 4 nr-axspa CZP 2+4 nr-axspa < < < < < < < < < Table S: ASDAS outcomes (certolizumab pegol) van der Heijde 212 EULAR (RAPID-axSpA) Landewé 21 ACR (RAPID-axSpA) van der Heijde 21 EULAR (RAPID-axSpA) van der Heijde 214 ACR (RAPID-axSpA) Landewé 214 ARD (RAPID-axSpA) Mease 214 EULAR (RAPID-axSpA) Rosenbaum 214 ACR (RAPID-axSpA) Rudwaleit 2914 EULAR (RAPID-axSpA) Sieper 215 AC&R (RAPID-axSpA) Sieper 215 A&R (RAPID-axSpA) Braun 215 ARD (RAPID-axSpA) axspa CZP 2 axspa CZP 4 axspa CZP 2+4 axspa r-axspa CZP 2 r-axspa CZP 4 r-axspa CZP 2+4 r-axspa nr-axspa CZP 2 nr-axspa CZP 4 nr-axspa CZP 2+4 nr-axspa Timepoint Mean ASDAS change (SD) <.1 <.1 <.1 <.1 <.1 <.1 ASDAS CII ASDAS MI ASDAS I <.1 < <.1 <.1 Table S1: Other disease-activity outcomes (certolizumab pegol) Timepoint Mean BASDAI BASDAI 5 Mean CRP change (SD) Mean TJC (SD) 27

28 van der Heijde 212 EULAR (RAPID-axSpA) Landewé 21 ACR (RAPID-axSpA) van der Heijde 21 EULAR (RAPID-axSpA) van der Heijde 214 ACR (RAPID-axSpA) Landewé 214 ARD (RAPID-axSpA) Mease 214 EULAR (RAPID-axSpA) Rosenbaum 214 ACR (RAPID-axSpA) Rudwaleit 2914 EULAR (RAPID-axSpA) Sieper 215 AC&R (RAPID-axSpA) Sieper 215 A&R (RAPID-axSpA) Braun 215 ARD (RAPID-axSpA) axspa CZP 2 axspa CZP 4 axspa CZP 2+4 axspa r-axspa CZP 2 r-axspa CZP 4 r-axspa CZP 2+4 r-axspa nr-axspa CZP 2 nr-axspa CZP 4 nr-axspa CZP 2+4 nr-axspa change (SD) <.1 <.1 <.1 <.1 <.1 < <.1 < Time-point axspa CZP 2 van der Heijde 212 EULAR (RAPID-axSpA) axspa CZP 4 Landewé 21 ACR (RAPID-axSpA) axspa CZP 2+4 van der Heijde 21 EULAR (RAPID-axSpA) axspa van der Heijde 214 ACR (RAPID-axSpA) r-axspa CZP 2 Landewé 214 ARD (RAPID-axSpA) r-axspa CZP 4 Mease 214 EULAR (RAPID-axSpA) r-axspa CZP 2+4 Rosenbaum 214 ACR (RAPID-axSpA) r-axspa Rudwaleit 2914 EULAR (RAPID-axSpA) nr-axspa CZP 2 Sieper 215 AC&R (RAPID-axSpA) nr-axspa CZP 4 Sieper 215 A&R (RAPID-axSpA) nr-axspa CZP 2+4 Braun 215 ARD (RAPID-axSpA) nr-axspa Table S2: Mobility, function and quality of life outcomes (certolizumab pegol) Mean BASFI change (SD) vale <.1 <.1 <.1 <.1 <.1 <.1 Mean BASMI change (SD) <.1 <.1.5 <.1.5 Mean ASQoL change Table S: Proportion of completers from studies reporting the longest follow-up Intervention N baseline Completers 2 years Completers 5 years Completers 7 years Completers 8 years 28

29 Baraliakos 21 AR&T ETA 25 BiW 2 21 (8.8) 1 (1.5) NA Baraliakos 211 Rheuma INF 5mg/Kg QW 9 49 (71.) 8 (55.1) 8 (55.1) (47.8) van der Heijde 215 Rheuma ADA 4 Q2W (.1) NA NA Deodhar 215 ARD GOL 5 Q4W (79.) 95 (9.) NA NA Sieper 215 A&R CZP 2 Q2W (79.) NA NA NA.. Axial inflammation on MRI Table S4: Effect of TNFi on axial inflammation Improvement treatment * Improvemen t placebo * r-axspa (mny) SMD (95% CI) treatment vs Improvement treatment * nr-axspa (ASAS) Improvement placebo * SMD (95% CI) treatment vs MRI spine SPARCC ( baseline to 12W) Etanercept (5 QW); EMBARK (n=215) NA NA NA NA 2.1 (.5) 1.2 (.5) 1.8 (1.48; 2.12).41 Adalimumab (4QW); ABILITY-1 (n=185) NA NA NA NA n/e.1 MRI ASspiMRI-a ( baseline to W14) Golimumab 5 Q4W; GO-RAISE (n=21) 5.9 (7.1) 2.5 (8.9).44 (.15;.72).11 NA NA NA NA Certolizumab; RAPID-axSpA (n=218) <.1 <.1 MRI SII SPARCC ( baseline to W12) Etanercept (5 QW); EMBARK (n=215) NA NA NA NA.8 (.7).8 (.) 4.1 (4.9; 5.12) <.1 Adalimumab; ABILITY-1 (n=185) NA NA NA NA.2. n/e. Golimumab 5 Q4W; GO-AHEAD (n=11) NA NA NA NA n/e <.1 Certolizumab; RAPID-axSpA (n=218) <.1 *Mean (SD) improvement compared to baseline : SPARCC MRI spinal score (range: -18); SPARCC MRI-SI score (range: -72); ASspiMRI-a score (range: -18). 29

30 .7. Safety outcomes Details on the included studies are provided above. Only placebo-controlled data is shown. If only absolute s are reported, proportions were calculated. Table S5: Main safety outcomes (etanercept) Dougados 21 ARD ETA 5 Timepoint N Withdrawals AE 8. Serious AE 8. Any infection Serious infections 8. Tuberculosis Malignancies Dougados 211 ARD ETA Dougados 215 JR ETA Table S: Other safety outcomes (etanercept)

31 Dougados 21 ARD ETA 5 Timepoint N Any CVD event Any hematological abnormality Any GI event Injection reactions %) 25 Headache Elevated Liver enzymes Dougados 211 ARD ETA Dougados 215 JR ETA Table S7: Main safety outcomes (infliximab) Barkham 29 A&R IFN 5 mg/kg Timepoint N 2 2 Withdrawals AE 5 Serious AE Any infection Serious infections Tuberculosis Malignancies Inman 21 JR IFN mg/kg / INF Table S8: Other safety outcomes (infliximab) Barkham 29 A&R IFN 5 mg/kg Timepoint N 2 2 Any CVD event Any hematological abnormality Any GI event Injection reactions %) 5 Headache Elevated Liver enzymes Inman 21 JR IFN mg/kg / INF

32 Table S9: Main safety outcomes (adalimumab) Sieper 21 ARD ADA 4 Timepoint N Withdrawals AE Serious AE.2 1. Any infection Serious infections Tuberculosis Malignancies Huang 214 ARD ADA Table S4: Other safety outcomes (adalimumab) Sieper 21 ARD Huang 214 ARD ADA 4 ADA 4 Timepoint N Any CVD event Any hematological abnormality Any GI event Injection reactions %) Headache Elevated Liver enzymes Table S41: Main safety outcomes (golimumab) Bao 214 Rheuma GOL 5 Timepoint N Withdrawals AE.9 1. Serious AE 5. Any infection Serious infections.9 Tuberculosis.9 Malignancies.9 2

33 Sieper 215 A&R GOL Table S42: Other safety outcomes (golimumab) Bao 214 Rheuma GOL 5 Timepoint N Any CVD event Any hematological abnormality Any GI event Injection reactions %).2. Headache Elevated Liver enzymes Sieper 215 A&R GOL

34 Table S4: Main safety outcomes (certolizumab pegol) Landewé 214 ARD axspa CZP 2 axspa CZP 4 axspa Timepoint N Withdrawals AE Serious AE Any infection Serious infections Tuberculosis Malignancies Table S44: Other safety outcomes (certolizumab pegol) Landewé 214 ARD axspa CZP 2 axspa CZP 4 axspa Timepoint N Any CVD event..9. Any hematological abnormality.9.. Any GI event..9.9 Injection reactions %) Headache Elevated Liver enzymes 4

35 4. OBSERVATIONAL STUDIES OF TNF INHIBITORS 4.1. Malignancies Table S45: Outcome and exposure definition Carmona 211 SA&R Register / cohort Total patientyears BIOBADASER 2,288 Outcome definition Any new cancer (except skin) Validation outcome Treating physician Biologic causal attribution On-drug (+ after follow-up case by case) Notes on analysis SIR as compared to general population Censoring at event yes Dreyer 21 ARD DANBIO First cancer diagnosis On-drug (assumed) SIR as compared to general population yes Westhovens 214 C&ER BIOSPAR 1,194 Any malignancy On-drug SIR as compared to general population yes Table S4: and patients main characteristics Carmona 211 SA&R Dreyer 21 ARD Westhovens 214 C&ER Type of patients r-axspa (not further defined) r-axspa (not further defined) r-axspa (not further defined) and controls N Age (years) TNFi (IFN. ETA. ADA) General population TNFi (IFN. ETA. ADA) General population Treated (male) (4 TNF*i) General population (male) Treated (female) (4 TNFi*) General population (female) * Etanercept, infliximab, adalimumab and golimumab. 71 NA 81 NA 74 NA 157 NA Males HLA-B27+ Disease duration (years) Previous TNFi TNFi-naive TNFi-naive 48.5 (12.1) (overall) 8 (overall) TNFi-naïve (and 2 nd and rd ) Table S47: Effect size intervention and control and comparison Carmona 211 SA&R Dreyer 21 ARD Westhovens 214 C&ER and controls TNFi (IFN. ETA. ADA) General population TNFi (IFN. ETA. ADA) General population Treated (female) (4 TNF*i) General population (female) Treated (male) (4 TNFi*) General population (male) Incidence rate (95% CI) Adjusted IR (95% CI) Type of ratio (I vs C) uratio aratio Adjusted for SIR.92 (.44; 1.7)* Age and gender 77.1 /1, py /1, py 7.2 /1, py 28.4 /1, py SIR.82 (.41; 1.4) NA * Colon and rectum: 2.8 (.49;.9); Lung: 1. (.4; 4.85); Prostate: 1.1 (.;.1); Bladder:.9 (.2; 5.7); non-hodgkin lymphoma: 2.72 (.7; 15.1); leukemia:.97 (.1; 22.1). SIR 1.54 ref 1.1 ref NA 5

36 Table S48: Risk of bias assessment (Hayden tool) Participation Attrition Carmona 211 SA&R Prognostic factor measurement Outcome measurement Confounding Analysis Overall RoB M L L M H L M Dreyer 21 ARD M L L M H M M Westhovens M L L L H M M 214 C&ER H= high risk; L = low risk; M = moderate risk Infections / serious infections Table S49: Outcome and exposure definition Wallis 215 Rheuma Moura 215 EULAR Register / cohort Toronto Western Hospital AS clinic NA Total patientyears 1,712 Outcome definition Serious infection: infection requiring i.v. antibiotics or hospitalization Serious infection: first occurrence of an infection requiring hospitalization Validation outcome Hospital records Biologic causal attribution On drug (+ 1 year before inclusion and after study end) On-drug Notes on analysis Multivariable GEE Multivariable Cox regression Censoring at event yes yes Table S5: and patients main characteristics Wallis 215 Rheuma Moura 215 EULAR Type of patients axspa (ASAS) r-axspa (ICD- 9 and 1 code) and controls N Age (years) Any TNF*i (any infection) no-tnfi (any infection) Any TNFi* (serious infection) no-tnfi (serious infection TNFi* (+/ csdmards) Only csdmards None (all) 8. (12.8) (overall) 5. (14.1) (overall) Males 7.2 (overall) 5.7 (overall) HLA-B27+ Disease duration (years) 14.7 (1.7) (overall) Previous TNFi TNFi-naive TNFi-naive

37 Table S51: Effect size intervention and control and comparison and controls Incidence rate (95% CI) Adjusted IR (95% CI) Type of ratio (I vs C) uratio aratio Adjusted for Wallis 215 Rheuma Any TNF*i (any infection) no-tnfi (any infection) Any TNFi* (serious infection) no-tnfi (serious infection 19/1 py (1; 22) 14/1 py (11; 17) 1.5/1 py (.7; ) 1.8/1 py (1.;.) OR 1.14 (.8; 1.51)] (for any infection) 1.25 (.9; 1.7) (for any infection) age, disease duration, smoking, csdmards, oral steroids, BASDAI, BASFI, co-morbidity score, hospitalization Moura 215 EULAR TNFi* (+/ csdmards) Only csdmards None 2.44/1 py 4.12/1 py 2.25/1 py HR 1.5 (.45; 2.45) 1.77 (.78; 4.2) Baseline patient sociodemographics, comorbidity, prior health service use, and time dependent use of AIDs, and corticosteroids. Table S52: Risk of bias assessment (Hayden tool) Participation Attrition Prognostic factor measurement Outcome measurement Confounding Analysis Overall RoB Wallis 215 Rheuma L L M L L M L Moura 215 EULAR a a a a a a a H= high risk; L = low risk; M = moderate risk. 4.. Tuberculosis Table S5: Outcome and exposure definition Kim 211 JR Kim 214 ClinRheum Register / cohort Total patient -years NA 1,784 NA 1,1 Outcome definition TB defined as 1 of the following criteria: (1) typical symptoms and isolation of Mycobacterium tuberculosis; or (2) typical symptoms and radiological or histological findings of TB; or () clinical symptoms and/or radiological signs and/or histological findings are compatible with TB and improvement with anti-tb medications. TB infection was diagnosed according to the presence of symptoms in conjunction with evidence of infection by Mycobacterium tuberculosis (positive culture, a positive TB PCR result, the presence of caseating granulomas on biopsy, and/or a clinical improvement upon anti-tb treatment). Validation outcome Biologic causal attribution On-drug (assumed) On-drug (assumed) Notes on analysis Coxregression Coxregression Censoring at event yes yes 7

38 Table S54: and patients main characteristics Kim 211 JR Type of patients r-axspa (mny) and controls N Age (years) Infliximab Adalimumab Etanercept Controls (11.). (1.) 5.9 (1.2) 5.5 (1.5) Males HLA-B Disease duration (years) 11.5 (7.) 11. (9.) 1. (.9) 1.2 (8.7 Previous TNFi Kim 214 ClinRheum r-axspa (mny) TNFi (ETA, INF, ADA, GOL, CZP) Controls 98. (12.) months Table S55: Effect size intervention and control and comparison Kim 211 JR and controls Infliximab Adalimumab Etanercept Controls Incidence rate (95% CI) 54//1, py 8//1, py /1, py 8/1, py Adjusted IR (95% CI) Type of ratio (I vs C) HR uratio aratio Adjusted for.5 (.14: 1.91) 1.57 (.4; 7.18) 1. (.17; 1.44) NA NA Kim 214 ClinRheum TNFi (ETA, INF, ADA, GOL, CZP Controls.2/1, py 12.1/1, py HR 4.9 (1.5; 15.4) NA Participation Attrition Table S5: Risk of bias assessment (Hayden tool) H= high risk; L = low risk; M = moderate risk. Prognostic factor measurement Outcome measurement Confounding Analysis Overall RoB Kim 211 JR L L L L H M M Kim 214 ClinRheum L L L L H H M 8

39 5. TRIALS ON NEW TREATMENT TARGETS 5.1. Description of included studies, baseline characteristics and risk of bias assessment Table S57: and patients main characteristics (new treatment targets) Song 21 A&R Song 21 ARD Sieper 215 ARD (ALIGN) Sieper 214 ARD (BUILDER-1) Baeten 21 Lancet Baraliakos 21 ARD Baeten 215 NEJM (MEASURE-1 ) Baraliakos 215 ARD (MEASURE-1 ) Baeten 215 NEJM (MEASURE-2 ) Sieper 21 ARD (MEASURE-2 ) Poddubnyy 214 ARD (TOPAS) Song 211 ARD Pathan 21 ARD van der Heijde 215 ACR design POC noncontrolled open-label RCT phase 2 double-blind RCT phase 2 double-blind RCT phase 2 double-blind RCT phase double-blind RCT phase double-blind POC noncontrolled open-label POC noncontrolled open-label RCT phase 2 double-blind RCT phase 2 double-blind Type of patients r-axspa r-axspa r-axspa r-axspa N Age (years) Males RTX TNFi-naive RTX TNFi-failure SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW TOC 8 mg/kg SEC 1 mg/kg SEC 15 r-axspa SEC 75 r-axspa SEC 15 SEC 75 SEC 15 TNFi-naive SEC 75 TNFi-naive TNFi-naïve SEC 15 TNFi- failure SEC 75 TNFi- failure TNFi- failure (1.5) 42.2 (1.) 42.4 (1.8) 4 (11.) 4.4 (11.5) 7.2 (1.4) 41.1 (11.1) 4. (11.7) 41. (11.2) 42.7 (12.) (11.) 42. (1.2) 4.1 (12.4) (12.9) 4.9 (14.1) 4.5 (1.) 9. (11.) 45.2 (11.) 4.8 (1.2) (12.5) 44.4 (1.1) 4. (1.2) 2 (59.1) 1 (8.9) 5 (77.8) 2 (71.4) 2 (71.4) 21 (72.4) HLA- B Disease duration (years) 1 (8.9) 2.5 (8.9) 5.4 (.1) 7.5 (8.1) (.9) 7.9 (9.7) 8. (8.9) (8.).7 (5.7).9 (.2) 8.5 (7.) 7.7 (9.) 1.2 (11.) r-axspa UST (1.8) (1.5) 5 r-axspa ABA TNFi-naive ABA TNFi-failure APR r-axspa r-axspa TOFA 2 bid TOFA 5 bid TOFA 1 bid (7.2) 45. (9.8) (11.1) (1.) 2.5 (1.8) 2.88 (12.2) 18.9 (1.17) According to modified New York criteria; not defined; Loading dose in MEASURE-1: 1 mg/kg IV weeks and MEASURE- 2: 15/75 mg SC weeks. Previous TNFi 1 TNFinaive TNFinaive (8.2) 5. (7.4).4 (8.9) TNFinaive

40 Table S58: Cochrane risk of bias assessment (new treatment targets) Song 21 A&R Sieper 215 ARD (ALIGN) Sieper 214 ARD (BUILDER-1) Baeten 21 Lancet Baeten 215 NEJM (MEASURE-1) Baeten 215 NEJM (MEASURE-2) Sieper 21 ARD (MEASURE-2) Poddubnyy 214 ARD (TOPAS) Song 211 ARD Pathan 21 ARD design POC noncontrolled open-label RCT phase 2 double-blind RCT phase 2 double-blind RCT phase 2 double-blind RCT phase double-blind RCT phase double-blind POC noncontrolled open-label POC noncontrolled open-label RCT phase 2 double-blind RCT phase 2 double-blind Selection bias van der Heijde 215 ACR H= high risk; L = low risk; U = unclear risk. Performance bias Detection bias Attrition bias Reporting bias Other bias H L H L L L H L L L L L L L L L L L L L L L L L L U L L L L L L L L L L L L L L L L H L H L H L H H L H L H L H L L L L L L L a a a a a a a Overall RoB 5.2. Efficacy outcomes ASAS response outcomes Table S59: ASAS outcomes (new treatment targets) Timepoint ASAS 2 ASAS 4 ASAS 5/ ASAS PR Song 21 A&R RTX TNFi-naive RTX TNFi-failure Sieper 215 ARD (ALIGN) SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW <

41 Sieper 214 ARD (BUILDER-1) Baeten 21 Lancet Baeten 215 NEJM (MEASURE-1) Baeten 215 NEJM (MEASURE-2) Sieper 21 ARD (MEASURE-2) Poddubnyy 214 ARD (TOPAS) Song 211 ARD Pathan 21 ARD van der Heijde 215 ACR TOC 8 mg/kg SEC 1 mg/kg SEC 15 SEC 75 SEC 15 SEC 75 SEC 15 TNFi-naive SEC 75 TNFi-naive TNFi-naïve SEC 15 TNFi- failure SEC 75 TNFi- failure TNFi- failure <.1 <.1 <.1 <.1 < <.1 <.1 <.1 <.5 <.1 < <.1 <.1 <.1 <.1 <.1 <.1 < <.1 <.1 UST ABA TNFi-naive ABA TNFi-failure APR TOFA 2 bid TOFA 5 bid TOFA 1 bid < <.5 <.1 < ASDAS outcomes Table S: ASDAS outcomes (new treatment targets) Song 21 A&R Sieper 215 ARD (ALIGN) Sieper 214 ARD (BUILDER-1) Baeten 21 Lancet Baeten 215 NEJM (MEASURE-1) Baeten 215 NEJM (MEASURE-2) Sieper 21 ARD (MEASURE-2) RTX TNFi-naive RTX TNFi-failure SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW TOC 8 mg/kg SEC 1 mg/kg SEC 15 SEC 75 SEC 15 SEC 75 SEC 15 TNFi-naive SEC 75 TNFi-naive Timepoint Mean ASDAS change (SD) vale ASDAS CII ASDAS MI ASDAS I -.5 (.9) -.8 (1.2) -1.1 (.8) -1.2 (.9) -1. (.9) -.4 (.7)

42 TNFi-naïve SEC 15 TNFi- failure SEC 75 TNFi- failure TNFi- failure Poddubnyy 214 ARD (TOPAS) UST Song 211 ARD ABA TNFi-naive ABA TNFi-failure Pathan 21 APR -.4 (.).5 ARD -.15 (.71) TOFA 2 bid -1.2 (.1)* <.1 van der Heijde TOFA 5 bid -1.4 (.1)* < ACR TOFA 1 bid -1.4 (.1)* < (.1)* * Least squares (standard error) Other disease-activity outcomes Table S1: Other disease-activity outcomes (new treatment targets) Song 21 A&R Sieper 215 ARD (ALIGN) Sieper 214 ARD (BUILDER-1) Baeten 21 Lancet Baeten 215 NEJM (MEASURE-1) Baeten 215 NEJM (MEASURE-2) Sieper 21 ARD (MEASURE-2) Poddubnyy 214 ARD (TOPAS) Song 211 ARD RTX TNFi-naive RTX TNFi-failure SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW TOC 8 mg/kg SEC 1 mg/kg SEC 15 SEC 75 SEC 15 SEC 75 SEC 15 TNFi-naive SEC 75 TNFi-naive TNFi-naïve SEC 15 TNFi- failure SEC 75 TNFi- failure TNFi- failure Timepoint Mean BASDAI change (SD) -2. (2.2) -.9 (1.) -.8 (1.9) -1.1 (2) -.4 (1.4) -.9 (1.8) -1.2 (1.8) -.9 (1.7) vale BASDAI 5 5 Mean CRP change (SD) -5.5 (7.2) -1.4 (18.5) 7.2 (2.41) 5.5 (1.72) -1.2 (17.9) -5.8 (27.) -1.5 (2.) (17.5) -14. (15.) -.7 (19.1) Mean TJC (SD) <.1 <.1 < (.)* -2. (.)* -1.2 (.)* -1. (.4)* -1.4 (.4)* -. (.4)* <.1 <.5 UST 9 5 ABA TNFi-naive ABA TNFi-failure.7 42

43 Pathan 21 ARD van der Heijde 215 ACR APR TOFA bid TOFA 5 bid TOFA 1 bid * Least squares (standard error) (1.48) -.77 (1.47) <.1 <.1 < Mobility, function and quality of life outcomes Table S2: Mobility, function and quality of life outcomes (new treatment targets) Song 21 A&R Sieper 215 ARD (ALIGN) RTX TNFi-naive RTX TNFi-failure SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW TOC 8 mg/kg SEC 1 mg/kg SEC 15 SEC 75 SEC 15 SEC 75 SEC 15 TNFi-naive SEC 75 TNFi-naive TNFi-naïve SEC 15 TNFi- failure SEC 75 TNFi- failure TNFi- failure Time-point Mean BASFI change (SD) -1. (2.2) -.5 (1.) vale Mean BASMI change (SD) -.4 (.) -. (.7) -.2 (.9) -.2 (.8) -.4 (.9) -.1 (.8) -.2 (.7) -.2 (.8) -1. (2.2) -.5 (1.) Mean ASQoL change -. (.4) -.1 (5.2) Sieper 214 ARD (BUILDER-1) Baeten (4.8) 7 Lancet 9. (5.91) -.58 (.42) Baeten 215 NEJM (.42) (MEASURE-1) -1.4 (.44) -4. (.5) -. (.54) -1.7 (.5) Baeten 215 NEJM -5. (.7)* (MEASURE-2) 4-4. (.7)* Sieper 21 ARD -1.9 (.7)* (MEASURE-2) -2.4 (.8)* -2.5 (.9)* -.5 (.8)* Poddubnyy 214 ARD (TOPAS) UST 9 Song 211 ARD ABA TNFi-naive ABA TNFi-failure Pathan 21 ARD APR (1.91) (1.2) (1.1) -.21 (.7) TOFA 2 bid -1.9 (.)* -. (.1)* van der Heijde TOFA 5 bid -2.4 (.)* < (.1)* 215 ACR TOFA 1 bid -2.2 (.)* <.1 -. (.1)* < (.)* -.2 (.1)* * Least squares (standard error). <.1 <.5 4

44 5.. Safety outcomes Only studies reporting safety outcomes are shown. In case only absolute s were reported, these were used to calculate proportions. Table S: Main safety outcomes (secukinumab; 52 weeks) Treatment arm SAEs n (cases/1 py) Withdrawals n (cases/1 py) Any infection n (cases/1 py) Opportunistic infections n (cases/1 py) Tuberculosis n (cases/1 py) Malignancies n (cases/1 py) Crohn s disease n (cases/1 py) MEASURE-1 SEC ( ) 5 (8.) 15 (-) 187 (.1) * (.7) () 4 (-) (.7) MEASURE-2 SEC ( ) 17 (7.1) 9 (-) 111 (7.7) * (1.7) () 1(-) 2 (.8) MEASURE-1 and MEASURE-2 SEC ( ) 52 (7.9) (-) 298 (8.8) * (.9) () 5 (-) 5 (.7) *All Candida spp infections. 44

45 Table S4: Main safety outcomes (other new targets) Song 21 A&R Sieper 215 ARD Sieper 214 ARD Poddubnyy 214 ARD Timepoint N Withdrawals AE Serious AE Any infection Serious infections Tuberculosis Malignancies RTX 2 2 SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW TOC 8 mg/kg UST Song 211 ARD ABA TNFi-naive ABA TNFi-failure Pathan 21 ARD APR TOFA 2 bid 52 van der TOFA 5 bid Heijde 215 TOFA 1 bid ACR *Two treatment-related herpes zoster cases (1 each with TOFA 2 and 1 mg) * 45

46 Table S5: Other safety outcomes (other new targets) Song 21 A&R4 Sieper 215 ARD Sieper 214 ARD Poddubnyy 214 ARD Song 211 ARD RTX TNFi-naive RTXTNFi-failure SAR 1 Q2W SAR 15 Q2W SAR 1 QW SAR 2 Q2W SAR 15 QW TOC 8 mg/kg Timepoint N Any CVD event Any hematological abnormality Any GI event Injection reactions %) Headache Elevated Liver enzymes UST ABA TNFi-naive ABA TNFi-failure Pathan 21 ARD van der Heijde 215 ACR APR TOFA 2 bid TOFA 5 bid TOFA 1 bid mean (SD) CBL in ANC (TOFA 2: -. (1.), TOFA 5: -. (1.4), TOFA 1: -.9 (1.), : -. (1.2)); mean (SD) CBL in ALC (TOFA 2:.1 (.4), TOFA 5: -.1 (.4), TOFA 1:. (.4), :. (.4)); mean (SD) CBL in Hgb (TOFA 2:.1 (.), TOFA

47 . ACTIVE COMPARATOR TRIALS.1. Description of included studies, baseline characteristics and risk of bias assessment Table S: and patients main characteristics (active comparator trials) Type of design N Age (years) Males patients ETA 5 QW (.8) 8 Giardina 21 RheumaInt RCT open-label r-axspa INF 5m/Kg QW (9.2) 7 Non-inferiority r-axspa CT-P1 5 mg/kg (18; 9) 79.2 trial INF 5 mg/kg (18-) 82.4 Park 21 ARD (PLANETAS) Park 21 AR&T (PLANETAS) Braun 211 A&R (ASCEND) Moots 212 Rheuma (ASCEND) Braun 212 JR (ASCEND) Song 211 ARD (ESTHER) Song 21 ARD (ESTHER) Song 214 JR (ESTHER) Poddubnyy 215 EULAR (ESTHER) Song 21 SAR (ESTHER) Sieper 214 ARD (INFAST-1) Sieper 212 ACR (INFAST-1) Poddubnyy 214 ACR (INFAST-1) RCT doubleblind r-axspa ETA 5 QW SSZ g/day ETA 25 TW RCT open-label axspa SSZ 2- g/day RCT doubleblind INF 5 + NPX 1 axspa + NPX 1 GOL 5 Q4W Mok 215 SJR RCT open-label axspa PAM Q4W (11.7) 4.9 (12.2) 4.5 (8.) 2.8 (8.4) 1.7 (8.51).7 (7.4) 2. (1.7). (11.4) HLA-B Disease duration (years) Previous TNFi TNFi-naive TNFi-naive TNFi-naive (1.7) (1.8) 1.7 (.89) 1.91 (1.49) 4.2 (.) 5. (.7) TNFi-naive TNFi-naive INF 5 QW Viapiana 214 Rheuma CCT open-label r-axspa Neridronate (12.18) 49.4 (15.2) (17) months 142 (145) months INF 5 QW Mulleman 211 AR&T RCT open-label r-axspa INF 5 + MTX (27-59) (29-55) (-28) (1-19) 14 ETA 12.5 Huang 211 C&ER CCT open-label r-axspa betamethasone According to modified New York criteria; according to ASAS criteria; median (interquartile range)

48 Table S7: Cochrane risk of bias assessment (active comparator trials) Giardina 21 RheumaInt Park 21 ARD (PLANETAS) Park 21 AR&T (PLANETAS) design Intervention Braun 211 A&R (ASCEND) Moots 212 Rheuma (ASCEND) Braun 212 JR (ASCEND) Song 211 ARD (ESTHER) Song 21 ARD (ESTHER) Song 214 JR (ESTHER) Poddubnyy 215 EULAR (ESTHER) Song 21 SAR (ESTHER) Sieper 214 ARD (INFAST-1) Sieper 212 ACR (INFAST-1) Poddubnyy 214 ACR (INFAST-1) RCT openlabel Noninferiority trial RCT doubleblind RCT openlabel RCT doubleblind Mok 215 SJR RCT openlabel Viapiana 214 Rheuma CCT openlabel Mulleman 211 AR&T RCT openlabel Huang 211 C&ER CCT openlabel H= high risk; L = low risk; U = unclear risk. ETA 5 QW INF 5m/Kg QW CT-P1 5 mg/kg INF 5 mg/kg ETA 5 QW SSZ g/day ETA 25 BiW SSZ 2- g/day IFN 5 + NPX 1 + NPX 1 GOL 5 Q4W PAM Q4W IFN 5 QW Neridronate 1 IFN 5 QW INF 5 + MTX 1 ETA 12.5 betamethasone Selection bias Performance bias Detection bias Attrition bias Reporting bias Other bias Overall RoB L L H L L L H L L L L L L L L L L L L L L L L H L L L U L L L L L L L L L H H L L U H L H L L L H L L H L H H H L H L L L H H 48