European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib

Figures & data

Table 1 Methods and outcomes reported in randomized controlled trials for tofacitinib in RA therapy

References	Study groups	Inclusion criteriaa	Concomitant therapy	ACR20b	ACR50b
Tofacitinib vs placebo
Burmester et al^Citation28	Placebo followed by tofacitinib 5 mg BID (n=66) Placebo followed by tofacitinib 10 mg BID (n=66) Tofacitinib 5 mg BID (n=133) Tofacitinib 10 mg BID (n=134)	Inadequate response to TNF inhibitors MTX administration	Antimalarials Corticosteroids	(Month 3) 1. Tofacitinib 5 mg vs placebo: 41.7 vs 24.4% (P=0.0024) 2. Tofacitinib 10 mg vs placebo: 48.1 vs 24.4% (P<0.0001)	(Month 3) 1. Tofacitinib 5 mg vs placebo: 26.5 vs 8.4% (P<0.0001) 2. Tofacitinib 10 mg vs placebo: 27.8 vs 8.4% (P<0.0001)
Fleischmann et al^Citation30	Placebo followed by tofacitinib 5 mg BID (n=61) Placebo followed by tofacitinib 10 mg BID (n=61) Tofacitinib 5 mg BID (n=243) Tofacitinib 10 mg BID (n=245)	Inadequate response to at least one nonbiologic or biologic DMARD	Antimalarials Corticosteroids	(Month 3) 1. Tofacitinib 5 mg vs placebo: 59.8 vs 26.7% (P<0.001) 2. Tofacitinib 10 mg vs placebo: 65.7 vs 26.7% (P<0.001)	(Month 3) 1. Tofacitinib 5 mg vs placebo: 31.1 vs 12.5% (P<0.001) 2. Tofacitinib 10 mg vs placebo: 36.8 vs 12.5% (P<0.001)
van der Heijde et al^Citation24	Placebo followed by tofacitinib 5 mg BID (n=81) Placebo followed by tofacitinib 10 mg BID (n=79) Tofacitinib 5 mg BID (n=321) Tofacitinib 10 mg BID (n=316)	1. Three distinct joint erosions on posteroanterior hand and wrist 2. Stable doses of MTX were required 3. Stable doses of low-dose corticosteroids and NSAIDs were allowed		(Month 6) 1. Tofacitinib 5 mg vs placebo: 51.5 vs 25.3% (P<0.0001) 2. Tofacitinib 10 mg vs placebo: 61.8 vs 25.3% (P<0.0001)	(Month 6) 1. Tofacitinib 5 mg vs placebo: 32.4 vs 8.4% (P<0.0001) 2. Tofacitinib 10 mg vs placebo: 43.7 vs 8.4% (P<0.0001)
Kremer et al^Citation32	Placebo followed by tofacitinib 5 mg BID (n=79) Placebo followed by tofacitinib 10 mg BID (n=80) Tofacitinib 5 mg BID (n=315) Tofacitinib 10 mg BID (n=318)	1. Inadequate response to treatment with ≥1 stably dosed nonbiologic or biologic DMARDs before baseline; continue treatment with one or more background nonbiologic DMARDs at stable doses throughout the study 2. MTX administration; background, low-dose, oral corticosteroid therapy with stable dosing (prednisone ≤10 mg daily or equivalent) was permitted	Background DMARDs MTX Oral corticosteroids	(Month 6) 1. Tofacitinib 5 mg vs placebo: 52.1 vs 30.8% (P<0.001) 2. Tofacitinib 10 mg vs placebo: 56.6 vs 30.8% (P<0.001) Tofacitinib vs placebo; difference percentage points: (month 6) 5 mg 28.7%; P<0.001 10 mg 30.3%; P<0.001	(Month 6) Tofacitinib vs placebo; difference in percentage points: 5 mg 22.1%; P<0.001 10 mg 24.8%; P<0.001
Kremer et al^Citation33	Placebo (n=65) Tofacitinib 5 mg BID (n=61) Tofacitinib 15 mg BID (n=69) Tofacitinib 30 mg BID (n=69)	1. All patients met the ACR 1991 revised criteria for global functional status in RA of class I, II, or III 2. Inadequate response to, or discontinued therapy due to unacceptable toxicity from, MTX, etanercept, infliximab, or adalimumab 3. Patients who discontinue all previous DMARD required suitable washout	Corticosteroids	(Week 6) Tofacitinib 5 mg vs placebo: 70.5 vs 29.2% (P<0.001)	(Week 6) Tofacitinib 5 mg increased response rates relative to placebo (P<0.001)
Kremer et al^Citation34	Placebo (n=69) Tofacitinib 1 mg BID (n=71)c Tofacitinib 3 mg BID (n=68) Tofacitinib 5 mg BID (n=71) Tofacitinib 10 mg BID (n=75)c Tofacitinib 15 mg BID (n=75) Tofacitinib 20 mg/day (n=80)	1. Patients must have been receiving oral or parenteral MTX continuously for ≥4 months 2. All other biologic or nonbiologic DMARDs and immunosuppressive therapy were discontinued ≥4 weeks prior to the study	Corticosteroids	(Week 12) 1. Tofacitinib 5 mg vs placebo: 50.7 vs 33.3% (P≤0.05) 2. Tofacitinib 10 mg vs placebo: 58.1 vs 33.3% (P≤0.05) (Week 24) 1. Tofacitinib 5 mg (29.0%) was higher vs placebo (P>0.05) 2. Tofacitinib 10 mg (22.6%) was significantly higher vs placebo (P≤0.05)	(Week 12) Tofacitinib 5 mg increased response rates relative to placebo (P≤0.05)
Tanaka et al^Citation36	Placebo (n=28) Tofacitinib 1 mg BID (n=28)c Tofacitinib 3 mg BID (n=27)c Tofacitinib 5 mg BID (n=27)c Tofacitinib 10 mg BID (n=26)c	1. Inadequate clinical response to MTX; all patients were required to remain on stable background MTX 6 mg/week 2. All other traditional and biologic DMARDs and immunosuppressive therapy were discontinued at least 4 weeks prior to the study	Low-dose corticosteroids	(Week 12) 1. Tofacitinib 5 mg vs placebo: 96.3 vs 14.3% (P<0.0001) 2. Tofacitinib 10 mg vs placebo: 80.8 vs 14.3% (P<0.0001)	(Week 12) Tofacitinib treatment had significantly greater effect vs placebo: 5 mg (P<0.0001), 10 mg (P<0.001)
Tofacitinib vs MTX
Lee et al^Citation35	Tofacitinib 5 mg BID (n=373) Tofacitinib 10 mg BID (n=397) MTX (n=186)	≥3 distinct joint erosions detected on hand and wrist or foot radiographs or a positive test for IgM rheumatoid factor or antibodies to cyclic citrullinated peptide		(Month 24) Tofacitinib 5 mg: 64.2% Tofacitinib 10 mg: 64.2% MTX: 42.4% Tofacitinib 5 and 10 mg for the comparison with MTX (P<0.001)	(Month 24) Tofacitinib 5 mg: 49.3% Tofacitinib 10 mg: 49.2% MTX: 28.3% Tofacitinib 5 and 10 mg for the comparison with MTX (P<0.001)
Tofacitinib or adalimumab vs placebo
Fleischmann et al^Citation29	Placebo (n=59) Tofacitinib 1 mg BID (n=54) Tofacitinib 3 mg BID (n=51) Tofacitinib 5 mg BID (n= 49) Tofacitinib 10 mg BID (n=61) Tofacitinib 15 mg BID (n=57) Adalimumab 40 mg qow (n=53)	Failure of at least one DMARD due to lack of efficacy or toxicity and washout of all DMARDs except antimalarial agents at stable doses	Antimalarials Corticosteroids	(Week 24) 1. Tofacitinib 5 mg vs placebo: 51.0 vs 25.4% (P≤0.05) 2. Tofacitinib 10 mg vs placebo: 65.6 vs 25.4% (P<0.0001)	(Week 24) 1. Tofacitinib 5 mg vs placebo: 34.7 vs 10.2% (P≤0.05) 2. Tofacitinib 10 mg vs placebo: 44.3 vs 10.2% (P<0.0001)
van Vollenhoven et al^Citation27	Placebo followed by tofacitinib 5 mg BID (n=56) Placebo followed by tofacitinib 10 mg BID (n=52) Tofacitinib 5 mg BID (n=204) Tofacitinib 10 mg BID (n=201) Adalimumab 40 mg q2w (n=204)	Patients were receiving 7.5–25 mg of MTX weekly and had an incomplete response	Corticosteroids	(Month 6) 1. Tofacitinib 5 mg vs placebo: 51.5 vs 28.3% (P<0.0001) 2. Tofacitinib 10 mg vs placebo: 52.6 vs 28.3% (P<0.001)	(Month 6) Significantly greater responses were seen with the active treatments than with placebo (P≤0.05)
Tofacitinib monotherapy vs tofacitinib and MTX vs adalimumab and MTX
Fleischmann et al^Citation31	Tofacitinib 5 mg BID monotherapy (n=384) Tofacitinib 5 mg BID and MTX (n=376) Adalimumab 40 mg qow and MTX (n=386)	1. Classes I–III functional capacity as classified by the ACR 1991 revised criteria for RA 2. Inadequate responders to MTX treatment 3. Patients were required to discontinue all conventional synthetic DMARDs other than MTX but could continue to receive stable nonsteroidal anti-inflammatory drugs, analgesics, or oral corticosteroids or a combination	Corticosteroid use at baseline		(Month 12) 1. Tofacitinib monotherapy: 39% 2. Tofacitinib and MTX: 48% 3. Adalimumab and MTX: 46%

Notes: ACR20 indicates that symptoms have improved 20% from baseline. ACR50 indicates that symptoms have improved 50% from baseline.

a Inclusion criteria in all studies were as follows: at least 18 years old and active moderate-to-severe RA based on the ACR 1987 revised criteria.

b The results were presented only for registered doses of tofacitinib (5 mg and 10 mg BID).

c Randomized and treated patients.

Abbreviations: ACR, American College of Rheumatology; BID, twice a day; DMARDs, disease-modifying antirheumatic drugs; MTX, methotrexate; NSAIDs, nonsteroidal anti-inflammatory drugs; q2w, every 2 weeks; qow, once every other week; RA, rheumatoid arthritis; TNF, tumor necrosis factor.

Table 2 Opportunistic infections reported in randomized controlled trials for tofacitinib in RA, regarding follow-up periods

References	Follow-up period	Opportunistic infection/tuberculosis/herpes zoster (% or number of cases)
Kremer et al^Citation33	6 weeks	No opportunistic infections
Tanaka et al^Citation36	3 months	No opportunistic infections
Fleischmann et al^Citation30	6 months	One case (0.4%)a of serious tuberculous pleural effusion (tofacitinib 10 mg BID)
Kremer et al^Citation34	6 months	1.4% of patients with herpes zoster infection (tofacitinib 1, 3, 5, 10, and 15 mg BID)
Burmester et al^Citation28	6 months	No opportunistic infections
Fleischmann et al^Citation29
Kremer et al^Citation32	0–6 months	Four cases (0.5%)a of opportunistic infections (tofacitinib 5 and 10 mg BID) related to treatment: disseminated herpes zoster, cryptococcal pneumonia, and two cases of pulmonary tuberculosis
	6–12 months	Two cases (0.5%)a of pulmonary tuberculosis, one case of peritonitis and cryptococcal pneumonia (tofacitinib 10 mg BID)
van der Heijde et al^Citation24	12 months	Seven cases (1%)a of opportunistic infections: three serious (pneumonia and cytomegalovirus infections) and four nonserious (lymph node tuberculosis or candidiasis) (tofacitinib 5 and 10 mg BID)
van Vollenhoven et al^Citation27	12 months	Two cases (1%)a of pulmonary tuberculosis (tofacitinib 10 mg BID); cases of herpes zosterb (tofacitinib 5 and 10 mg BID)
Fleischmann et al^Citation31	12 months	1% of patients with opportunistic infections (tofacitinib 5 mg BID) and 2% of patients with opportunistic infections (tofacitinib 5 mg BID + MTX)
		Documented herpes zoster: 1% of patients in the tofacitinib 5 mg BID and 2% of patients in tofacitinib 5 mg BID + MTX
		1% of patients with mild cases of herpes zoster after vaccination; one case (0.3%)a of serious varicella zoster event (tofacitinib 5 mg BID); one case (0.3%)a of serious herpes zoster (tofacitinib 5 mg BID + MTX)
		One case (0.3%)a of tuberculosis in tofacitinib 5 mg BID and one case (0.3%)a in tofacitinib 5 mg BID + MTX
Lee et al^Citation35	24 months	3.5% of patients with herpes zoster infection in tofacitinib 5 mg BID and 4.5% in patients in tofacitinib 10 mg BID
		One case (0.3%)a of serious herpes zoster infection (tofacitinib 5 mg BID), two cases (0.5%)a of serious herpes zoster infection (herpes zoster and disseminated herpes zoster), and one case (0.3%)a of serious bone tuberculosis (tofacitinib 10 mg BID)

Notes:

a Percentage was calculated according to the information provided in the reference publication.

b No precise information on the number of cases or percentage of affected patients in the reference publication.

Abbreviations: BID, twice a day; MTX, methotrexate; RA, rheumatoid arthritis.

Table 3 Clinical laboratory results during tofacitinib treatment in RA

Parameter	Observation period
	0–3 months	3–24 months	>24 months (LTE studies)
Neutrophil count	Decrease^Citation53	Slow decrease^Citation53	Stabilization^Citation53
Lymphocyte count	Increase^Citation53	Slow decrease^Citation53	Stabilization^Citation53
Hemoglobin level	Increase^Citation53	Slow increase up to 12 months; then stabilization^Citation53	No clear tendency^Citation53
LDL level	Increase^Citation24,Citation30,Citation32,Citation33	Increase or stabilization^Citation24,Citation29,Citation30,Citation35	Stabilization^Citation38
HDL level	Increase^Citation32,Citation33	Increase or stabilization^Citation29,Citation35	No data available
Serum creatine level	Increase^Citation24,Citation32	Slow increase^Citation24,Citation34,Citation35	Stabilization^Citation38

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; LTE, long-term extension studies; RA, rheumatoid arthritis.

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