Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

Solipuram, Vinod; Mohan, Akhila; Patel, Roshniben; Ni, Ruoning

doi:10.1186/s13317-021-00153-5

Table 2 Characteristics of included trials

From: Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

Name of study	Type of study	Study phase	Population	Duration of enrollment	Intervention	Number of patients	Follow up duration	Countries	Number of centers	Treatment arms	Primary outcome	Secondary outcomes
Burmester [18]	Double-blind	Phase 3	RA with IR to TNF inhibitors	October, 2009 to March 2011	Tofacitinib and placebo	399	6 months	13 countries including North America, Latin America and Europe	82	Tofacitinib 5 mg, 10 mg BID vs. placebo along with MTX	ACR 20, HAQ-DI	DAS28-ESR
Fleischman [20]	Double-blind	Phase 3/long term	RA with IR to MTX	NA	Upadactinib, placebo, adalimumab	1629	48 weeks	41	286	Upadactinib 15 mg, adalimumab 40 mg, placebo	DAS28-CRP, ACR20, inhibition of radiographic progression	DAS28-CRP mean change of DAS28-CRP, HAQ DI, SF-36, PCS, FACIT-F, CDAI < 10
Fleischman [19], RA-BEGIN	Double-blind	Phase 3	RA with no or minimal csDMARDs and naive to bDMARDs	01/13–08/14	Barictinib, MTX or combination of Barictinib and MTX	588	52 weeks	18 counries	198	Baricitnib 4 mg, Baricitinib 4 mg + MTX	Noninferioritiy of baricitnib monotherapy to MTX monotherapy by ACR20 at 24 weeks	Superiority comparision by ACR 20, HAQ-DI, SDAI, DAS28-CRP, vdH-mTSS
Genovese [21]	Double-blind	Phase 2b	RA with IR to MTX	03/14–07/15	Upadacitinib, placebo	300	12 weeks	16	63	Upadactinib 3 mg bid, 6 mg bid, 12 mg bid, 18 mg bid, 24 mg q day, placebo bid	ACR20	ACR50, ACR70, DAS28-CRP, CDAI
Van der Hejide [25] ORAL SCAN	Double-blind	Phase 3	Active RA with IR to MTX	NA	Tofacitinib vs. placebo	797	24 months	NA	NA	Tofacitinib 5 mg, 10 mg BID vs. placebo	ACR20, ACR50, ACR70, mean changes in DAS28-ESR, CDAI, SDAI, HAQ-DI	NA
Kivitz [22]	Double blind	Phase 2b	Modearte to severe RA with IR to MTX	NA	Peficitinib	378	12 weeks	(8) Usa, poland, hungary, Czech republic, Mexico, Bulgaria, Belgium, Colombia	43	Peficitinib 25, 50, 100, 150 mg	ACR20 using CRP at 12 weeks	ACR50, ACR70, DAS28-CRP, CDAI
Kremer [23]	Double blind	Phase 2b	RA with IR to MTX	10/13–07/15	Upadactinib, placebo, adalimumab	276	12 weeks	10 (North america, Europe, Australia)	123	Upadacitnib 3 mg, 6 mg, 12 mg, 18 mg	ACR20	ACR50, ACR70, Low disease points/remission by DAS28-CRP, CDAI, Change in DAS28-CRP, ACR core set changes, MCID of HAQ DI
Li [24]	Double blind	Phase 3	RA with IR to MTX	NA	Baricitinib, placebo	290	52 weeks	3 (China, Brazil, Argentina)	30	Baricitinib 4 mg	ACR 20 at 12 weeks	HAQ-DI, DAS28-CRP, remission and LDA, SDAI, CDAI, ACR50, ACR70
Takeuchi [26] RAJ4	Double blind	Phase 3	RA pt with IR to MTX	July 2014-Nov 2017	Peficitinib	519	52 weeks	Japan	161	Peficitinib 100 mg, 150 mg	ACR20 at 12 weeks/ET, baseline change in mTSS at 28 weeks/ET	ACR20/50/70 response, DAS28-CRP, DAS28-ESR, CRP, ESR, PGA, TJC68, SJC66, CDAI, SDAI
Tanaka [27]	Double-blind	Phase 2b	pt with moderate to severe RA on MTX	11/11–12/13	Baricitinib, placebo	145	12 weeks	Japan	24	Baricitinib 1 mg, 2 mg, 4 mg, 8 mg	ACR20 at 12 weeks/ET, baseline change in mTSS at 28 weeks/ET	ACR50, ACR70, ACR core components, DAS28-ESR, DAS28-CRP, SDAI, EULAR28
Taylor [28]	Double-blind	Phase 3	pt with RA on MTX	11/12–09/14	Baricitinib 4 mg, adalimumab 40q2wk	1307	52 weeks	26	281	Baricitinib 4 mg, adalimumab 40q2wk	ACR20 at 12 weeks,	mTSS score at 24 weeks, HAQDI, DAS28-CRP, SDAI, PRO at week 12
Vollenhoven [29] ORAL standard study	Double blind	Phase 3	RA pt with IR to MTX	01/09–02/11	Tofacitinib, adalimumab, placebo	717	12 months	Worldwide	115	Tofacitinib 5 mg, 10 mg twice daily, 40 mg of adalimumab q2wks, placeebo	ACR20 reduction in tender and swollen joints at 6 months, 3/5ACR components, HAQ-DI at 3 months, DAS28-ESR	ACR20, ACR50, ACR70 with respect to tender and swollen joints and HAQ-DI
Westhovens [30] DARWIN 1	Double blind	Phase 2b	Active RA with insufficient response to MTX	July 2013 to May 2015	Filgotinib vs. placebo in combination with MTX	594	24 weeks	21 (North and South America, Europe, Asia, Australia)	106	Filgotinib 50 mg, 100 mg, 200 mg once or twice daily vs. placebo	ACR20 at 12 weeks	ACR20, ACR50, ACR70, ACR-N, DAS28-CRP, LDA/remission, EULAR response, EULAR remission, CADI, SDAI

ACR American college of rheumatology, CRP C-reactive protein, CDAI clinical disease activity index, DAS28 disease activity score 28, ESR erythrocyte sedimentation rate, EULAR European League Against Rheumatism, FACIT-F functional assessment of chronic illness therapy fatigue scale, HAQ-DI health assessment questionnaire disability index, IR inadequate response, LDA low disease activity, MCID minimum clinically important difference, MTX methotrexate, NA not available, PCS physical component score, PGA physician’s global assessment of disease activity, PRO patient reported outcomes, RA rheumatoid Arthritis, SF-36 short-form 36, SDAI simplified disease activity index, SJC swollen joint count, TNF-alpha tumor necrosis factor-alpha, TJC total joint count, vdH-mTSS van der Heijde-modified total sharp score

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