Impact of tofacitinib on patient outcomes in rheumatoid arthritis – review of clinical studies

Figures & data

Table 1 Studies included in this review of patient outcomes associated with the use of tofacitinib in rheumatoid arthritis

Design	Tofacitinib dose (no of patients)	Comparator(s) (no of patients)	Duration and reference
Tofacitinib DMARD monotherapy studies
Phase II, double-blind	5 mg bid (61)	Placebo (65)	6 weeks^Citation25,Citation26
	15 mg bid (69)
	30 mg bid (69)
Phase II, double-blind	1 mg bid (54)	Placebo (59)	24 weeks^Citation26
	3 mg bid (51)	Adalimumab (53)
	5 mg bid (49)
	10 mg bid (61)
	15 mg bid (57)
Phase III, double-blind	5 mg bid (243)		6 months^Citation30
	10 mg bid (245)
	Placebo then 5 or 10 mg bid (120)a
Phase III, double-blind	5 mg bid (373)	Methotrexate (186)	24 months^Citation35
	10 mg bid (397)
Phase II, double-blind	1 mg bid (53)	Placebo (52)	12 weeks^Citation38
	3 mg bid (53)
	5 mg bid (52)
	10 mg bid (53)
	15 mg bid (54)
Tofacitinib plus methotrexate or other nonbiologic DMARD studies
Phase II, double-blind	Methotrexate plus:	Methotrexate plus:	12 weeks^Citation27
	1 mg bid (28)	Placebo (28)
	3 mg bid (28)
	5 mg bid (28)
	10 mg bid (28)
Phase II, double-blind	Methotrexate plus:	Methotrexate plus:	24 weeks^Citation29
	1 mg bid (71)	Placebo (69)
	3 mg bid (68)
	5 mg bid (71)
	10 mg bid (75)
	15 mg bid (75)
	20 mg od (80)
Phase III, double-blind	Methotrexate plus:	Methotrexate plus:	12 months^Citation31
	5 mg bid (204)	Placebo (69)
	10 mg bid (201)	Adalimumab (204)
	Placebo then 5 mg bid (56)a
	Placebo then 10 mg bid (52)a
Phase III, double-blind	Methotrexate plus:		12 months^Citation32
	5 mg bid (321)
	10 mg bid (316)
	Placebo then 5 mg bid (81)a
	Placebo then 10 mg bid (79)a
Double-blind	Nonbiologic DMARD plus:		1 year^Citation34
	5 mg bid (318)
	10 mg bid (318)
	Placebo then 5 mg bid (79)a
	Placebo then 10 mg bid (80)a
Phase III, double-blind	Methotrexate plus:		6 months^Citation33,Citation37
	5 mg bid (133)
	10 mg bid (134)
	Placebo then 5 mg bid (66)a
	Placebo then 10 mg bid (66)a
Tofacitinib monotherapy and combination DMARD study
Open-label, long-term extension	With/without nonbiologic DMARDs:		48 months^Citation36
	5–10 mg bid (4,102)

Note:

a On placebo for 3–6 months, then randomly assigned to tofacitinib at the dose indicated.

Abbreviations: bid, twice daily; DMARD, disease-modifying antirheumatic drug; QD, daily or once daily.

Table 2 HAQ-DI and other composite measures

Outcome	Improvement from baseline in units (%)						Duration and reference
	Tofacitinib				Placebo	Comparator DMARD
	1–3 mg bid	5 mg bid	10 mg bid or 20 mg od	15–30 mg bid
Tofacitinib DMARD monotherapy studies
HAQ-DI		0.6 (35%)		0.7 (44%)	0.3 (18%)		6 weeks^Citation25
HAQ-DI		0.6*		0.74* (30 mg bid)	0.2		6 weeks^Citation26
HAQ-DI	0.25–0.44 (16%–29%)	0.51 (36%)	0.66 (44%)	0.82 (51%)	0.25 (16%)	Adalimumab 0.35 (24%)	24 weeks^Citation28
HAQ-DI		0.50*	0.57*		0.19		6 months^Citation30
HAQ-DI		0.9 (60%)*	1.0 (67%)*			Methotrexate 0.7 (47%)	24 months^Citation35
HAQ-DI responders#		(57%)*		(76%)*	(36%)		6 weeks^Citation26
HAQ-DI responders#		(53%)*	(56%)		(32%)		6 months^Citation30
HAQ-DI responders#	(55%)*	(74%)*	(82%)*	(73%)*	(21%)		12 weeks^Citation38
FACIT-Fatigue		6.7*	8.0*		2.8		6 months^Citation30
FACIT-Fatigue	2.5–5.4*	7.5*	8.5*	8.0*	–1.4		12 weeks^Citation38
SF-36 PCS		8.3*		9.9*	2.7		6 weeks^Citation26
SF-36 MCS		5.3		9.81*	2.64		6 weeks^Citation26
SF-36 PCS responders$	(62%)*	(82%)*	(86%)*	(83%)*	(25%)		12 weeks^Citation38
SF-36 MCS responders$	(45%)	(74%)*	(66%)	(56%)	(27%)		12 weeks^Citation38
Tofacitinib plus methotrexate or other nonbiologic DMARD studies
HAQ-DI	0.38–0.41 (32%–35%)¶	0.49 (41%)*	0.57 (48%)*		0.05 (4%)		12 weeks^Citation27
HAQ-DI	0.34–0.48 (22%–35%)*	0.49 (34%)*	0.39–0.53	0.43 (30%)*	0.16 (13%)		24 weeks^Citation29
			(29%–36%)*
HAQ-DI		0.55 (37%)*	0.61 (44%)*		0.24 (16%)	Adalimumab 0.49 (33%)	12 months^Citation31
HAQ-DI		0.40 (28%)	0.54 (39%)*		0.15 (11%)		12 months^Citation32
HAQ-DI		0.44 (31%)*	0.53 (37%)*		0.16 (12%)		1 year^Citation34
HAQ-DI		0.43 (27%)*	0.46 (31%)*		0.18 (11%)		6 months^Citation33
HAQ-DI responders#	(54%–63%)*	(79%)*	(81%)*		(33%)		12 weeks^Citation27
FACIT-Fatigue		5.8^,*	6.8^,*		2.0^		1 year^Citation34
FACIT-Fatigue		6.3*	4.6^,*		1.1		6 months^Citation37
SF-36 PCS		5.7 (18%)*	6.6 (20%)*		2.0 (7%)		6 months^Citation37
SF-36 PCS responders$	(75%)¶	(79%)*	(76%)*		(25%)		12 weeks^Citation27
SF-36 PCS responders$		(68%)*	(66%)*		(49%)		6 months^Citation37
SF-36 MCS		3.5 (8%)*	4.0 (9%)*		0.4 (1%)		6 months^Citation37
SF-36 MCS responders$	(58%)¶	NR	NR		(29%)		12 weeks^Citation27
SF-36 MCS responders$		(54%)*	(50%)*		(37%)		6 months^Citation37
MOS-SS		6.8 (16%)	5.8 (14%)		3.8 (8%)		6 months^Citation37
Tofacitinib monotherapy and combination DMARD study
HAQ-DI		0.8 (57%)					60 months^Citation36

Notes:

* P<0.05 for tofacitinib at this dose versus placebo or comparator;

¶ P<0.05 for tofacitinib at this dose versus placebo or comparator for only one of the two groups;

# HAQ-DI responders = improvement of ≥0.22 or ≥0.30 units on HAQ-DI;

$ SF-36 MCS or PCS responders = improvement of ≥2.5 units from baseline on SF-36 MCS or PCS;

^ estimated from a graph presented in the published study.

Abbreviations: bid, twice daily; DMARD, disease-modifying antirheumatic drug; FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-fatigue instrument; HAQ-DI, Health Assessment Questionnaire-Disability Index; MOS-SS, Medical Outcomes Study Sleep Scale; SF-36, Short Form 36-item survey instrument; SF-36 MCS, SF-36 Mental Component Scale; SF-36 PCS, SF-36 Physical Component Scale.

Table 3 Patient-reported assessment of pain and global assessment of disease in tofacitinib studies

Outcome	Improvement from baseline in units (%)						Duration and reference
	Tofacitinib				Placebo	Comparator DMARD
	1–3 mg bid	5 mg bid	10 mg bid or 20 mg od	15–30 mg bid
Tofacitinib DMARD monotherapy studies
Paina		34 (50%)		40–44 (59%–66%)	10 (15%)		6 weeks^Citation25
Paina	14–18 (23%–29%)	31 (48%)	34 (54%)	36 (56%)	17 (27%)	Adalimumab 21 (32%)	24 weeks^Citation28
Paina		32 (54%)	35 (58%)			Methotrexate 28 (47%)	24 months^Citation35
Patient globala		35 (50%)		39–40 (61%–62%)	15 (23%)		6 weeks^Citation25
Patient globala	16–19 (26%–32%)	31 (46%)	33 (53%)	36 (57%)	16 (27%)	Adalimumab 19 (30%)	24 weeks^Citation28
Patient globala		32 (53%)	35 (58%)			Methotrexate 27 (47%)	24 months^Citation35
Tofacitinib plus methotrexate or other nonbiologic DMARD studies
Paina	23–33	31	38		6		12 weeks^Citation27
Paina	22–24 (37%–44%)*	27 (50%)*	22–26 (39%–43%)*	24 (43%)*	13 (25%)		24 weeks^Citation29
Paina		27*	25*		8		6 months^Citation33
Paina		26 (45%)*	30 (52%)*		16 (29%)		12 months^Citation32
Patient globala	27–38	38	38		7		12 weeks^Citation27
Patient globala	28–32 (44%–56%)*	34 (60%)*	30–34 (51%–56%)*	37 (61%)*	23 (39%)		24 weeks^Citation29
Patient globala		26 (44%)*	29 (51%)*		14 (25%)		12 months^Citation32

Notes:

* P<0.05 versus placebo or comparator;

a patient assessment of pain and global assessment of disease on a 0–100 mm visual analog scale.

Abbreviations: bid, twice daily; DMARD, disease-modifying antirheumatic drug.

Table 4 Withdrawals in general and withdrawals due to lack of efficacy in tofacitinib studies

Event	Number of events (% of group)						Duration and reference
	Tofacitinib				Placebo	Comparator DMARD
	1–3 mg bid	5 mg bid	10 mg bid or 20 mg od	15–30 mg bid
Tofacitinib DMARD monotherapy studies
Wd all		3 (5%)		26 (19%)	17 (26%)		6 weeks^Citation25
Wd all	22 (21%)	6 (12%)	6 (10%)	5 (9%)	16 (27%)	Adalimumab 16 (30%)	24 weeks^Citation28
Wd all	6 (6%)	2 (4%)	4 (8%)	2 (4%)	4 (8%)		12 weeks^Citation38
Wd inefficacy		1 (2%)		2 (1%)	8 (12%)		6 weeks^Citation25
Wd inefficacy	6 (6%)	1 (2%)	1 (2%)	0	4 (7%)	Adalimumab 5 (9%)	24 weeks^Citation28
Wd inefficacy	2 (2%)	0	0	0	2 (4%)		12 weeks^Citation38
Tofacitinib plus methotrexate or other nonbiologic DMARD studies
Wd all	7 (13%)	5 (18%)	7 (25%)		5 (18%)		12 weeks^Citation27
Wd all	20 (14%)	15 (21%)	22 (14%)	15 (20%)	15 (22%)		24 weeks^Citation29
Wd all		38 (19%)	44 (23%)		6 (5%)		6 months^Citation33
Wd all		71 (22%)	51 (16%)				12 months^Citation32
Wd all		53 (17%)	64 (20%)		13 (8%)		1 year^Citation34
Wd inefficacy	1 (2%)	0	0		1 (4%)		12 weeks^Citation27
Wd inefficacy	2 (1%)	1 (1%)	1 (1%)	0	5 (7%)		24 weeks^Citation29
Wd inefficacy		5 (3%)	11 (6%)		2 (2%)		6 months^Citation33
Wd inefficacy		7 (2%)	3 (1%)				12 months^Citation32
Wd inefficacy		16 (4%)	12 (4%)				1 year^Citation34
Tofacitinib monotherapy and combination DMARD study
Wd all		852 (21%)					60 months^Citation36

Abbreviations: bid, twice daily; DMARD, disease-modifying antirheumatic drug; Wd, withdrawal.

Table 5 Major safety events: serious adverse drug reactions, serious infections, cancers, deaths, and withdrawal due to lack of efficacy in tofacitinib studies

Event	Number of events (% of group)						Duration and reference
	Tofacitinib				Placebo	Comparator DMARD
	1–3 mg bid	5 mg bid	10 mg bid or 20 mg od	15–30 mg bid
Tofacitinib DMARD monotherapy studies
Wd ADR		1 (2%)		9 (7%)	1 (2%)		6 weeks^Citation25
Wd ADR	2 (2%)	1 (2%)	1 (2%)	2 (4%)	0	Adalimumab 3 (6%)	24 weeks^Citation28
Wd ADRs		3 (1%)	11 (4%)		5 (4%)		6 months^Citation30
Wd ADRs		40 (11%)	41 (10%)			Methotrexate 25 (13%)	24 months^Citation35
Wd ADRs	1 (1%)	2 (4%)	3 (6%)	0	2 (4%)		12 weeks^Citation38
Serious ADRs		0		2 (1%)	1 (2%)		6 weeks^Citation25
Serious ADRs	3 (3%)	0	1 (2%)	4 (7%)	2 (3%)	Adalimumab 1 (2%)	24 weeks^Citation28
Serious ADRs		6 (2%)	11 (4%)		0		6 months^Citation30
Serious ADRs		40 (11%)	43 (11%)			Methotrexate 22 (12%)	24 months^Citation35
Serious ADRs	3 (3%)	1 (2%)	1 (2%)	1 (2%)	0		12 weeks^Citation38
Serious infections		1 (<1%)	4 (1%)		2 (1%)		6 months^Citation30
Serious infections		11 (3%)	8 (2%)			Methotrexate 5 (3%)	24 months^Citation35
Serious infections	0	0	0	0	0		12 weeks^Citation38
Cancers		2 (1%)	3 (1%)			Methotrexate 1 (1%)	24 months^Citation35
Deaths		0		0	0		6 weeks^Citation25
Deaths	0	0	0	1 (2%)	0	Adalimumab 0	24 weeks^Citation28
Deaths		0	1 (<1%)		0		6 months^Citation30
Deaths		3 (1%)	1 (<1%)			Methotrexate 0	24 months^Citation35
Tofacitinib combination DMARD studies
Wd ADRs	2 (4%)	4 (14%)	4 (14%)		2 (7%)		12 weeks^Citation27
Wd ADRs	3 (4%)	5 (4%)	1 (1%)	11 (7%)	7 (9%)		24 weeks^Citation29
Wd ADRs		15 (8%)	15 (8%)		2 (2%)		6 months^Citation33
Wd ADRs		14 (7%)	10 (5%)		3 (3%)	Adalimumab 19 (5%)	12 months^Citation31
Wd ADRs		36 (11%)	26 (8%)				12 months^Citation32
Wd ADRs		14 (4%)	20 (6%)				12 months^Citation34
Serious ADRs	2 (4%)	1 (4%)	2 (8%)		0		12 weeks^Citation27
Serious ADRs		10 (5%)	10 (5%)		6 (5%)		6 months^Citation33
Serious ADRs		12 (6%)	10 (5%)		2 (2%)	Adalimumab 2 (3%)	12 months^Citation31
Serious infections	1 (1%)	1 (1%)	2 (3%)	1 (1%)	0		24 weeks^Citation29
Serious infections		3 (2%)	2 (1%)		0		6 months^Citation33
Serious infections		3 (1%)	4 (2%)		1 (1%)	Adalimumab 0	12 months^Citation31
Deaths	0	0	0		0		12 weeks^Citation27
Deaths	1 (1%)	0	0	0	0		24 weeks^Citation27
Deaths		0	1 (1%)		0		6 months^Citation33
Deaths		1 (<1%)	0		0	Adalimumab 1 (<1%)	12 months^Citation31
Deaths		1 (<1%)	1 (<1%)		0		12 months^Citation32
Deaths		4 (1%)	1 (<1%)		1 (1%)		12 months^Citation34
Tofacitinib monotherapy and combination DMARD study
Wd ADRs		437 (11%)					60 months^Citation36
Serious ADRs		630 (15%)					60 months^Citation36
Serious infections		184 (4%)					60 months^Citation36
Cancers		107 (2%)					>42 months^Citation40
Cancers		60 (1%)					60 months^Citation36
Deaths		31 (1%)					60 months^Citation36

Abbreviations: ADRs, adverse drug effects; bid, twice daily; DMARD, disease-modifying antirheumatic drug; Wd, withdrawal.

KremerJMBloomBJBreedveldFCThe safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placeboArthritis Rheum20096071895190519565475

 PubMed Web of Science ®Google Scholar

CoombsJHBloomBJBreedveldFCImproved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trialAnn Rheum Dis201069241341619587388

 PubMed Web of Science ®Google Scholar

FleischmannRKremerJCushJORAL Solo InvestigatorsPlacebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritisN Engl J Med2012367649550722873530

 PubMed Web of Science ®Google Scholar

LeeEBFleischmannRHallSORAL Start InvestigatorsTofacitinib versus methotrexate in rheumatoid arthritisN Engl J Med2014370252377238624941177

 PubMed Web of Science ®Google Scholar

TanakaYTakeuchiTYamanakaHNakamuraHToyoizumiSZwillichSEfficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 studyMod Rheumatol201525451452125496464

 PubMed Web of Science ®Google Scholar

TanakaYSuzukiMNakamuraHToyoizumiSZwillichSHTofacitinib Study InvestigatorsPhase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexateArthritis Care Res (Hoboken)20116381150115821584942

 PubMed Web of Science ®Google Scholar

KremerJMCohenSWilkinsonBEA phase IIb dose-ranging study of the ORAL JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate aloneArthritis Rheum201264497098122006202

 PubMed Web of Science ®Google Scholar

van VollenhovenRFFleischmannRCohenSORAL Standard InvestigatorsTofacitinib or adalimumab versus placebo in rheumatoid arthritisN Engl J Med2012367650851922873531

 PubMed Web of Science ®Google Scholar

Van der HeijdeDTanakaYFleischmannORAL Scan InvestigatorsTofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic studyArthritis Rheum201365355957023348607

 PubMed Web of Science ®Google Scholar

KremerJLiZGHallSTofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trialAnn Intern Med2013159425326124026258

 PubMed Web of Science ®Google Scholar

BurmesterGRBlancoRCharles-SchoemanCORAL Step InvestigatorsTofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomized phase 3 trialLancet2013381986545146023294500

 PubMed Web of Science ®Google Scholar

StrandVBurmesterGRZerbiniCAFTofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patient-reported outcomes from a phase III trialArthritis Care Res (Hoboken)201567447548325186034

 PubMed Web of Science ®Google Scholar

WollenhauptJSilverfieldJLeeEBSafety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, long-term extension studiesJ Rheumatol201441583785224692527

 PubMed Web of Science ®Google Scholar

FleischmannRCutoloMGenoveseMCA phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugsArthritis Rheum201264361762921952978

 PubMed Web of Science ®Google Scholar

CohenSRadominskiSCGomez-ReinoJJAnalysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritisArthritis Rheumatol201466112924293725047021

 PubMed Web of Science ®Google Scholar