Drugs

DOI 10.1007/s40265-017-0835-9

ADIS DRUG EVALUATION

Tofacitinib: A Review in Rheumatoid Arthritis

Sohita Dhillon1

Ó Springer International Publishing AG 2017

Abstract Tofacitinib (XeljanzÒ) is a potent, selective JAK
inhibitor that preferentially inhibits Janus kinase (JAK) 1
and JAK3. In the EU, oral tofacitinib 5 mg twice daily is
indicated for the treatment of moderate to severe active
rheumatoid arthritis (RA) in adult patients who have
responded inadequately to, or who are intolerant of, one or
more DMARDs. Several clinical studies of B 24 months’
duration showed that tofacitinib monotherapy (as first- or
second-line treatment) and combination therapy with a
conventional synthetic DMARD (csDMARD; as second-
or third-line treatment) was effective in reducing signs and
symptoms of disease and improving health-related quality
of life (HR-QOL), with benefits sustained during long-term
therapy (B 96 months). Tofacitinib monotherapy inhibited
progression of structural damage in methotrexate-naı̈ve
patients during B 24 months’ treatment, with beneficial
effects also seen in patients receiving tofacitinib plus
methotrexate as second-line therapy for 12 months.
Tofacitinib was generally well tolerated during
B 114 months’ treatment, with most adverse events of mild
or moderate severity. The tolerability profile of tofacitinib
was generally similar to that of biological DMARDs
(bDMARDs), with infections and infestations the most
The manuscript was reviewed by: R. M. Fleischmann, Metroplex
Clinical Research Center, University of Texas Southwestern Medical
Center, Dallas, TX, USA; E. B. Lee, Division of Rheumatology,
Department of Internal Medicine, Seoul National University College
of Medicine, Seoul, Republic of Korea; D. L Scott, Department of
Clinical Rheumatology, Kings College London, Weston Education
Centre, London, UK.
& Sohita Dhillon
demail@springer.com
common adverse events (AEs) in tofacitinib recipients.
However, the incidence of herpes zoster (HZ) was higher
with tofacitinib than in the general RA population,
although infections were clinically manageable. When
added to background methotrexate, tofacitinib was nonin-
ferior to adalimumab in terms of efficacy, and both com-
bination therapies had generally similar tolerability
profiles. Although additional comparative studies are nee-
ded to more definitively position tofacitinib relative to
bDMARDs and other targeted synthetic DMARDs, current
evidence indicates that oral tofacitinib is a useful option for
the treatment of patients with RA.
Tofacitinib: clinical considerations in RA
Modulates immune and inflammatory responses by
inhibiting the JAK family of kinases, preferentially
JAK1 and JAK3
Effective in methotrexate-naı̈ve and DMARD-
experienced patients, including those with inadequate
response to TNF inhibitors
Reduces signs and symptoms of disease and
improves HR-QOL as monotherapy and in
combination with csDMARDs, with benefits
sustained during long-term therapy
Has beneficial effects on radiographic progression
Most common AEs are infections/infestations,
generally of mild or moderate severity; incidence of
HZ is higher than in the general RA population

1
Springer, Private Bag 65901, Mairangi Bay, Auckland 0754,
New Zealand

1 Introduction
Rheumatoid arthritis (RA) is a chronic, progressive,
autoimmune disease characterized by inflammatory syn-
ovitis and articular destruction. Conventional synthetic
disease-modifying antirheumatic drugs (csDMARDs; e.g.
methotrexate, sulfasalazine) and biological DMARDs
(bDMARDs; TNF inhibitors, IL-6 inhibitors) have been the
mainstay of disease management in patients with RA [1].
However, despite various treatment modalities and the
recommended treat-to-target approach for disease man-
agement, many patients still do not achieve therapeutic
targets, indicating an unmet need for additional therapies
[2, 3]. Recent advances in the understanding of interactions
between immune receptors and downstream signalling
pathways have led to the development of small-molecule
antirheumatic agents targeting key nodes in these pathways
[1]. The Janus kinase (JAK) family of tyrosine kinases are
critical for the signalling of cytokines that bind to type I
and II cytokine receptors, including cytokines responsible
for driving inflammatory processes implicated in the
pathogenesis of RA (e.g. type I interferons and several
interleukins) [1, 4]. JAKs were therefore considered logical
targets for pharmacological manipulation in inflammatory
diseases, leading to the development of JAK inhibitors.
Tofacitinib (XeljanzÒ) is one such JAK inhibitor approved
in several countries worldwide, and recently in the EU, for
the treatment of patients with RA. This narrative review is
written from the EU perspective [5], focusing on the
therapeutic efficacy and tolerability of tofacitinib in
patients with moderate to severe active RA and summa-
rizing relevant pharmacological data.
2 Pharmacodynamic Properties of Tofacitinib
The pharmacological properties of tofacitinib have been
reviewed in detail previously [4, 6]; therefore, a brief
overview is presented here. Tofacitinib is a potent, selec-
tive inhibitor of the JAK family of tyrosine kinases [7, 8],
comprising four non-receptor tyrosine kinases, JAK1,
JAK2, JAK3 and tyrosine kinase 2 (TYK2), with each
having specificity for a different set of cytokine receptors
[4]. Cytokine binding to its receptor activates receptor-as-
sociated JAKs, which act as docking sites for signal
transducers and activators of transcription (STATs) [4].
STATs, after being phosphorylated by the receptor-asso-
ciated JAKs, dissociate from the receptor units, dimerise
with each other and translocate to the cell nucleus where
they regulate gene transcription [4]. In in vitro enzymatic
assays, tofacitinib potently inhibited JAK1, JAK2 and
JAK3 [half maximal inhibitory concentrations (IC50)
1.6–3.2 nmol/L] and, to a lesser degree, TYK2 (IC50
S. Dhillon
34.0 nmol/L) [7]. Tofacitinib had limited selectivity for
other kinases in the human genome [8]. In cellular assays,
tofacitinib preferentially inhibited signalling by hetero-
dimeric cytokine receptors that associate with JAK3 and/or
JAK1 [5, 7]. Preclinical studies showed that tofacitinib
attenuated JAK1/JAK3-mediated signalling of IL-2, -4, -6,
-7, -15 and -21, as well as IFNa and IFNc, resulting in the
modulation of immune and inflammatory responses [7, 9].
For instance, in vitro and in vivo assays of samples from
RA patients showed that tofacitinib dose-dependently
inhibited IL-17 and IFNc production by, and proliferation
of, synovial and peripheral blood CD4? T cells, resulting
in the inhibition of IL-6 production in synovial fibroblasts,
inhibition of IL-8 production in CD14? monocytes and
decreased cartilage damage [9].
Tofacitinib rapidly reduced C-reactive protein (CRP)
levels in patients with RA, with these reductions main-
tained throughout therapy [5]. Treatment discontinuation
for 2 weeks did not completely reverse the change in CRP
levels, suggesting that tofacitinib has a longer duration of
pharmacodynamic activity than its half-life [5]. In RA
patients with inadequate response to methotrexate, tofaci-
tinib reduced the synovial expression of key genes impli-
cated in the pathogenesis of RA (e.g. matrix
metalloproteinases 1 and 3, and chemokines CCL2,
CXCL10 and CXCL13), and reduced synovial STAT1 and
STAT3 phosphorylation (which correlated with clinical
improvement), suggesting that IFN and IL-6 signalling
play a key role in the synovial response to tofacitinib-
mediated JAK blockade [10]. Tofacitinib (with or without
methotrexate) also reduced bone marrow oedema and
inhibited progression of structural damage in methotrexate-
naı̈ve RA patients (as assessed by MRI endpoints) [11]. In
addition, studies in patients with RA and in rodent models
of RA suggested that tofacitinib reduced structural damage
to the arthritic joints by suppressing osteoclast-mediated
bone resorption through decreased RANKL production
[12, 13].
During B 6 months’ therapy, tofacitinib dose-depen-
dently decreased NK cell counts (by median 35%) and
increased B cell counts (by median & 30%) from baseline
[14]. By contrast, during long-term therapy (median
exposure 5 years), NK cell counts increased (by med-
ian & 73%) from baseline, but there was no further
increase in B cell counts (median increase from base-
line & 3%) [14]. Changes in CD3?, CD4? and CD8? T
cells correlated with changes in absolute lymphocyte
counts (ALC; Sect. 5.2). Importantly, changes in lympho-
cyte subset counts were not related to the occurrence of
serious or opportunistic infections or herpes zoster (HZ)
[5], and were reversed following temporary treatment
discontinuation [14]. Tofacitinib was associated with dose-
dependent and moderate increases in lipid parameters (e.g.
Tofacitinib: A Review
15–20% increase in LDL-C and HDL-C) during
B 24 months’ therapy, with maximum effects seen within
6 weeks and levels remaining generally stable thereafter;
mean LDL-C/HDL-C and ApoB/ApoA1 ratios were gen-
erally unchanged [5]. Statins (e.g. atorvastatin) rapidly
(within 4–6 weeks) reduced tofacitinib-associated increa-
ses in total cholesterol, LDL-C, triglyceride and ApoB
levels [15]. Small, reversible increases in mean serum
creatinine levels have also been seen with tofacitinib
therapy, which plateaued early and did not appear to be
associated with progressive worsening of renal function or
acute renal failure [16].
Tofacitinib may diminish the immunogenicity of coad-
ministered vaccines (e.g. the 23-valent pneumococcal
polysaccharide vaccine, particularly when used in combi-
nation with methotrexate [17]); therefore, it is recom-
mended that patients be brought up to date with all
immunisations prior to initiating tofacitinib therapy and
live vaccines not be coadministered with tofacitinib [5].
3 Pharmacokinetic Properties of Tofacitinib
Tofacitinib is rapidly absorbed, with peak plasma con-
centrations reached within 0.5–1 h after administration;
steady-state is reached in 24–48 h and there is negligible
accumulation after twice daily dosing [5]. The oral
bioavailability of tofacitinib is 74% and its volume of
distribution after intravenous administration is 87 L.
Approximately 40% of tofacitinib is bound to plasma
proteins (largely albumin). Clearance of tofacitinib is via
hepatic metabolism (70%) and renal excretion (30%).
Tofacitinib is metabolised primarily by CYP3A4 and to a
minor extent by CYP2C19; 35% of a tofacitinib dose is
excreted as eight metabolites that are 10-fold less potent
than tofacitinib, and 65% of the dose is excreted as
unchanged drug. Tofacitinib is rapidly eliminated with a
half-life of & 3 h [5].
4 Therapeutic Efficacy of Tofacitinib
The therapeutic efficacy of oral tofacitinib as monotherapy
[18–20] or combination therapy [20–24] in patients with
RA was assessed in several 6- to 24-month, randomized,
double-blind, multicentre, phase 3 or 3b/4 ORAL studies.
Patients included were either naı̈ve to methotrexate therapy
[18] or had an inadequate response to C 1 cs/bDMARD
[19–23] or C 1 TNF-inhibitor [24]. They had to be
C 18 years old and have active RA according to the
American College of Rheumatology (ACR) 1987 revised
criteria (C 6 tender or painful joints, C 6 swollen joints and
either an ESR of [28 mm/h or CRP of [7 mg/L)
[18, 19, 21–24] or 2010 revised criteria (C 4 tender or
painful joints, C 4 swollen joints, CRP of C 3 mg/L and
class I–III functional capacity) [20]. Two studies assessed
radiographic outcomes and required that patients addi-
tionally have C 3 distinct joint erosions on hand and wrist
or foot radiographs, or a positive test for IgM rheumatoid
factor (RF) or antibodies to citrullinated peptide (anti-CCP)
[18, 21]. Patients included had a mean age of approxi-
mately 50–55 years and were largely female (79–87%).
This section focuses on results relevant to the approved
dosage of tofacitinib 5 mg twice daily. With the exception
of one study [20], all studies included a tofacitinib 10 mg
twice daily study arm, results for which are presented in the
table for completeness, but not discussed further. Copri-
mary endpoints were assessed sequentially, using a step-
down approach to assign significance.
4.1 As Combination Therapy After Inadequate
Response to cs/bDMARDs
The efficacy of tofacitinib compared with placebo and/or
adalimumab (as combination therapy with DMARDs) was
assessed in the ORAL Scan, ORAL Standard, ORAL Sync,
ORAL Step and ORAL Strategy in patients with RA who
had an inadequate response to methotrexate [20–22], C 1
cs/bDMARD [23] or C 1 TNF inhibitor [24] (Table 1). The
mean disease duration ranged between 5 and 13 years.
4.1.1 Compared with Placebo
4.1.1.1 Clinical Responses The addition of tofacitinib
5 mg twice daily to a stable dose of methotrexate or C 1
csDMARD was more effective in improving signs and
symptoms of disease than the addition of placebo to
background therapy (Table 1) [21–24]. At month 3 in the
ORAL Step study and at month 6 in the ORAL Scan,
ORAL Standard and ORAL Sync studies, significantly
more patients in the tofacitinib than placebo groups
achieved ACR20 (coprimary endpoint) ACR50 or ACR70
responses (Table 1) [21–24]. Tofacitinib had a rapid onset
of action, as indicated by significantly higher ACR20,
ACR50 and ACR70 response rates within 2–4 weeks of
therapy (p\0.05 vs. placebo [22, 24] or baseline [21, 23]).
Moreover, in a post hoc analysis of the ORAL Scan study,
ACR20, ACR50 and ACR70 response rates at month 6
were significantly (p\0.05) higher in the tofacitinib group
than in the placebo group regardless of the background
dose of methotrexate [low (B 12.5 mg/week), moderate
([12.5 to \17.5 mg/week) or high (C 17.5 mg/week)]
[25].
In the ORAL Scan study, owing to the step-down
assessment of coprimary endpoints, and as no statistically
significant between-group difference was seen for
 S. Dhillon

Table 1 Efficacy of oral tofacitinib 5 or 10 mg twice daily in rheumatoid arthritis patients with inadequate response to cs/bDMARDs in
6-[19, 24], 12-[20, 22, 23] or 24- [21] month, randomized, double-blind, multicentre, phase 3 [19, 21–24] or 3b/4 [20] studies
Study (prior therapy) Timept Treatment (no. of ptsc) Response ratesa (% pts) Remissiona,b LDAa,b Change from BL
(months)
ACR20 ACR50 ACR70 (% pts) (% pts) HAQ-DI [BL]d

ORAL Scan [21] 6 TOF 5 ? MTXe (321) 51.5***f 32.4*** 14.6*** 7.2f,g 14.3*** - 0.40f,g,h [1.4]
(MTX-IR) TOF 10 ? MTX (316) e
61.8*** f
43.7*** 22.3*** 16.0*** f
28.4*** – 0.54***f,h [1.4]
PL ? MTXi,e (160) 25.3f 8.4 1.3 1.6f 3.1 - 0.15f,h [1.3]
ORAL Standard [22] 6 TOF 5 ? MTXe (204) 51.5***f 37*j 20*j 6.2*f - 0.55***f,h [1.5]
(MTX-IR) TOF 10 ? MTX (201) e
52.6*** f
35* j
22* j
12.5*** f
– 0.61***f,h [1.5]
e f j j f
ADA ? MTX (204) 47.2*** 29* 10* 6.7* - 0.49***f,h [1.5]
i,e j j
PL ? MTX (108) 28.3 12 2.5 1.1 - 0.24f,h [1.5]
ORAL Sync [5, 23] 6 TOF 5 ? csDMARDe (315) 52.1***f 34*** 13*** 8.5**f - 0.44***f,h [1.4]
(cs/bDMARD-IR) TOF 10 ? csDMARDe (318) 56.6***f 36*** 16*** 12.5***f – 0.53***f,h [1.4]
PL ? csDMARDi,e (159) 30.8f 12.5 3.1 2.6f - 0.16f,h [1.5]
ORAL Step [24] 3 TOF 5 ? MTXe (133) 41.7**f 26.5*** 13.6*** 6.7*f 14.3* - 0.43***f [1.6]
(TNFi-IR) TOF 10 ? MTX (134) e
48.1*** f
27.8*** 10.5** 8.8* f
20.8*** – 0.46***f [1.5]
i,e f f
PL ? MTX (132) 24.4 8.4 1.5 1.7 5.0 - 0.18f [1.6]
ORAL Strategy 6 TOF 5 (384) 65 38f 18 10 21 - 0.52j [1.6]
[20] (MTX-IR) TOF 5 ? MTXe (376) 73 46f,k 25 12 27 - 0.58j [1.6]
e f,k
ADA ? MTX (386) 71 44 21 12 27 - 0.54j [1.6]
12 TOF 5 62 39 21 11 23 - 0.57j
e
TOF 5 ? MTX 70 48 29 15 27 - 0.62j
ADA ? MTXe 68 46 16 17 33 - 0.63j
ORAL Solo [19] 3 TOF 5 (243) 59.8***f 31.1*** 15.4** 5.6f 12.5* - 0.5***f [1.5]
(cs/bDMARD-IR) TOF 10 (245) 65.7***f 36.8*** 20.3*** 8.7f 17.0*** – 0.57***f [1.5]
i f f
PL (122) 26.7 12.5 5.8 4.4 5.3 - 0.2f [1.5]

ACR ‘x’ C x% improvement in ACR criteria, ADA subcutaneous adalimumab 40 mg every two weeks, bid twice daily, BL baseline, DAS28-ESR Disease Activity Score
28-erythrocyte sedimentation rate, cs/bDMARD conventional synthetic/biological disease modifying anti-rheumatic drug(s), HAQ-DI Health Assessment Questionnaire-
Disability Index score (lower scores indicate less disability), IR inadequate response, LDA low disease activity, MTX methotrexate, PL placebo, pts patients, timept timepoint,
TNFi TNF-inhibitors, TOF tofacitinib
*p B 0.05, **p B 0.01, ***p\0.001
a
Missing values imputed using nonresponse imputation
b
Proportion of pts in remission (DAS28-ESR of \2.6) or with LDA (DAS28-ESR of B 3.2 [19, 21, 24] or \3.2 [20])
c
Full analysis set [20–24] or modified intent-to-treat population [19]
d
Least-squares mean changes from BL; all BL values are means
e
Stable doses of MTX 15–25 mg/week [20, 21] or 7.5–25 mg/week [22, 24], stable doses of DMARDs (e.g. B 25 mg/week of MTX) [23]
f
Primary [20] or coprimary [19, 21–24] endpoints; significance of coprimary endpoints was assessed using a step-down approach
g
Owing to the step-down assessment of coprimary endpoints, and as no significant between-group difference was seen for radiographic progression, significance was not
declared
h
Assessed at month 3
i
In ORAL Solo and Step, at 3 months, PL recipients were switched to TOF 5 or 10 mg bid [19, 24]. In ORAL Scan, Standard and Sync, PL recipients who did not have C 20%
improvement in swollen and tender joint counts at 3 months were switched to TOF 5 or 10 mg bid; the remaining PL recipients switched to TOF 5 or 10 mg bid at 6 months
[21–23]
j
Values estimated from graphs
k
TOF ? MTX was noninferior to ADA ? MTX

radiographic progression [as assessed by the modified total
Sharp score (mTSS); Sect. 4.1.1.2], significance was not
declared for the proportion of patients with DAS28-ESR
remission (score of \2.6) at month 6 (coprimary endpoint;
Table 1) [21]. However, the rate of DAS28-ESR low dis-
ease activity (score of B 3.2) was significantly higher ([4-
fold) in the tofacitinib group than in the placebo group
(Table 1) [21]. The DAS28-ESR remission rates at month
6 in the ORAL Standard and ORAL Sync studies, and the
DAS28-ESR remission and low disease activity rates at
month 3 in the ORAL Step study were significantly higher
in the tofacitinib groups than in the placebo groups
(Table 1) [22–24]. Patients in the tofacitinib group also had
significantly (p B 0.05 vs. placebo [21, 22, 24] or baseline
[23]) greater improvements in the DAS-ESR at month 3
[24] or 6 [21–23] in the four studies.
Where reported, ACR20, ACR50 and ACR70 response
rates [21–24], DAS28-ESR remission and low disease
Tofacitinib: A Review

Table 2 Radiographic outcomes with oral tofacitinib 5 or 10 mg twice daily in randomized, double-blind, multicentre, phase 3 studies in
patients with rheumatoid arthritis who had inadequate response to methotrexate [21] or who were methotrexate naı̈ve [18]

Study Treatment (no. of ITT pts) Timepoint LS mean change from BL in scores No radiographic
(months) progressiona (% pts)
mTSS (BL) Erosion (BL) JSN (BL)

ORAL Scan [21] TOF 5 ? MTX (321) 6 0.12b (31.1) 0.07c (13.8) 0.05c (17.3) 88.8**
b c
TOF 10 ? MTX (316) 0.06* (37.3) 0.02 (17.7) 0.02c (19.6) 86.9*
PL ? MTX (160) 0.47b (32.6) 0.17c (14.4) 0.32c (18.2) 77.7
TOF 5 ? MTX 12 0.29 0.18c 0.1*c 86.0**
TOF 10 ? MTX 0.05** 0.0c 0.03*c 86.4**
c
PL ? MTX 0.92 0.29 0.61c 74.1
ORAL Start [18] TOF 5 (373) 6 0.2***b (19.1) 0.1* (9.1) 0.1* (10.0) 87.1***
TOF 10 (397) \0.1***b (17.9) 0.1*** (9.1) 0.1* (8.8) 89.3***
MTX (186) 0.8b (16.1) 0.4 (8.4) 0.3 (7.7) 73.7
TOF 5 24 0.6*** 0.2*** 0.4* 79.9***
TOF 10 0.3*** 0.2*** 0.1*** 83.7***
MTX 2.1 1.0 1.1 64.9
MTX stable dose of 15–25 mg/week [21] or target-dose after titration of 20 mg/week [18]
BL baseline, JSN joint-space narrowing, LS least-squares, PL placebo, pts patients, mTSS van der Heijde modified total Sharp score, MTX
methotrexate, TOF tofacitinib
*p B 0.05, **p\0.01, ***p\0.001
a
Proportion of patients with a B 0.5 unit increase from BL in mTSS
b
Coprimary endpoints; significance assessed using a step-down approach
c
Values estimated from graphs

activity rates [21, 23, 24] and the change from baseline in
DAS28-ESR [21–24] were maintained or improved during
B 12 months’ treatment with tofacitinib plus background
DMARD.
4.1.1.2 Radiographic Responses At month 6 in ORAL
Scan, there was no significant difference in the least square
(LS) mean change from baseline in the mTSS between
patients receiving tofacitinib 5 mg twice daily and those
receiving placebo, in addition to background methotrexate
therapy (coprimary endpoint; Table 2) [21]. However,
when results were analysed using a trimmed analysis (to
assess the effect of outliers), a significant (p\0.05) benefit
of tofacitinib over placebo was seen both at months 6 and
12 (e.g. at 1% trimming the between-group differences in
mTSS at months 6 and 12 were - 0.37 and - 0.68,
respectively) [26]. The LS mean change from baseline in
the mTSS at month 12, the erosion score at months 6 and
12, and the joint-space narrowing score at month 6 did not
differ significantly between the tofacitinib and placebo
groups. However, at month 12, the LS mean change from
baseline in the joint-space narrowing score was signifi-
cantly smaller in patients receiving tofacitinib than in those
receiving placebo, indicating less structural damage
(Table 2). Significantly more patients in the tofacitinib
group than placebo group had no radiographic progression
in terms of the mTSS (B 0.5 unit increase from baseline) at
months 6 and 12 (Table 2) and no radiographic progression
in terms of the erosion score (B 0.5 unit increase from
baseline) at month 12 (92.0 vs. 83.5%; p B 0.05). More-
over, post hoc analyses in subgroups of patients with
prognostic factors predictive of greater progression of
structural joint damage (i.e. anti-CCP positive, DAS28-
ESR[5.1, anti-CCP and/or RF positive with erosion score
C 3, baseline mTSS greater than baseline median mTSS
value) showed greater benefits with tofacitinib than pla-
cebo at 6 and 12 months (95% CIs generally excluded ‘0’)
[21].
4.1.1.3 Health-Related Quality of Life In the ORAL
Standard, ORAL Sync and ORAL Step studies, the addi-
tion of tofacitinib 5 mg twice daily to background
DMARD significantly improved physical function, as
assessed by the LS mean change from baseline to month 3
in the HAQ-DI score (coprimary endpoint; Table 1)
[22–24]. In ORAL Scan, significance was not declared for
the HAQ-DI score (coprimary endpoint; Table 1) owing to
the step-down assessment of coprimary endpoints [21]. In
ORAL Scan, ORAL Standard and ORAL Sync, a signifi-
cant improvement in the LS mean change from baseline in
the HAQ-DI score with tofacitinib was evident within
1–2 weeks of treatment (p\0.05 vs. placebo [21, 27] or

baseline [23]), with the magnitude of response maintained
or improved during B 12 months’ therapy [21, 23, 27].
Fatigue (FACIT-F) scores and pain scores were also
improved from baseline to a significantly (p\0.01)
greater extent in the tofacitinib groups than in the placebo
groups at month 3 in ORAL Standard, ORAL Sync and
ORAL Step and at month 6 in ORAL Scan
[21, 24, 27, 28]. At month 3, other health-related quality
of life (HR-QOL) outcomes in ORAL Standard, ORAL
Sync and ORAL Step, including the patient’s global
assessment (PtGA) score, SF-36 physical component
summary (PCS) score, SF-36 mental component summary
(MCS) score (in ORAL Sync and ORAL Step), Medical
Outcomes Study (MOS) sleep score (in ORAL Standard
and ORAL Sync) and scores for most SF-36 domains
were improved from baseline to a significantly (p\0.05)
greater extent in tofacitinib than placebo recipients
[24, 27, 28]. Significant improvements with tofacitinib
relative to placebo in some measures were seen as early
as within 1 month of treatment, e.g. pain scores in ORAL
Standard, ORAL Sync and ORAL Step [27–29]. Signifi-
cantly (p\0.05) more patients receiving tofacitinib than
placebo in ORAL Standard, ORAL Sync and ORAL Step
had improvements of greater than or equal to the mini-
mum clinically important differences (MCIDs) in HR-
QOL outcomes, including HAQ-DI, pain, fatigue, PtGA,
SF-36 PCS, SF-36 MCS (in ORAL Sync and ORAL Step)
and several SF-36 domains [27–29]. MCID was defined
as a decrease from baseline of C 0.22 points in HAQ-DI
scores and C 10 points in PtGA and pain scores; and an
increase from baseline of C 4 points in FACIT-F scores,
C 2.5 points in SF-36 PCS and MCS scores and C 5-
points in SF-36 domain scores.
4.1.2 Compared with Adalimumab
In the ORAL Strategy study in patients with RA who had
inadequate response to methotrexate, tofacitinib 5 mg
twice daily plus methotrexate was noninferior to adali-
mumab plus methotrexate in terms of the ACR50 response
at month 6 (primary endpoint; Table 1). Tofacitinib
monotherapy did not achieve statistical noninferiority to
either tofacitinib plus methotrexate or adalimumab plus
methotrexate for the primary endpoint (Table 1). The
ACR50 response achieved in all three treatment groups
was maintained during 12 months’ therapy (Table 1) [20].
The ACR20 and ACR70 response rates and DAS28-ESR
remission and low disease activity rates at month 6 were
generally similar in patients receiving tofacitinib plus
methotrexate or adalimumab plus methotrexate, with the
rates in both combination therapy groups being numeri-
cally greater than the rates in the tofacitinib monotherapy
group (Table 1).
S. Dhillon
Physical function improved from baseline to a generally
similar extent in patients receiving tofacitinib plus
methotrexate, adalimumab plus methotrexate or tofacitinib
monotherapy, as assessed by the LS mean change from
baseline in the HAQ-DI score at months 6 and 12 (Table 1)
[20]. In addition, similar proportions of patients in the three
treatment groups had a MCID in the HAQ-DI score at
month 6 (70, 67 and 66% in the respective groups) and
month 12 (64, 64 and 63%) [20]. Other HR-QOL outcomes
at these timepoints, including pain, FACIT-F, PtGA, SF-36
PCS and MCS scores, improved from baseline to a gen-
erally similar extent with tofacitinib plus methotrexate and
adalimumab plus methotrexate, with improvements in the
tofacitinib combination therapy group numerically greater
than those in the tofacitinib monotherapy group [30].
The ORAL Standard study also included an adalimumab
plus methotrexate treatment arm (Table 1) and although
the efficacy of tofacitinib plus methotrexate was not
directly compared, the magnitude of efficacy responses in
the two treatment arms was similar [22]. Treatment with
tofacitinib or adalimumab resulted in significant (p\0.05)
improvements versus placebo in HR-QOL outcomes,
including HAQ-DI (Table 1), PtGA, FACIT-F and SF-36
PCS scores [27].
4.2 As Monotherapy After Inadequate Response
to Methotrexate
Tofacitinib 5 mg twice daily as monotherapy was effective in
reducing signs and symptoms of disease and improving
physical function in the 6-month, phase 3 ORAL Solo study in
patients with RA (mean disease duration & 8 years) who had
an inadequate response to C 1 cs/bDMARD (Table 1) [19]. At
month 3, ACR20 (coprimary endpoint), ACR50 and ACR70
response rates were significantly higher ([2-fold) in patients
receiving tofacitinib monotherapy than in those receiving
placebo (Table 1). Significant (p B 0.05) between-group dif-
ferences in ACR20, ACR50 and ACR70 response rates were
evident by 2–4 weeks of treatment and generally sustained
during 6 months’ treatment with tofacitinib (ACR20, ACR50
and ACR70 response rates at month 6 were 65, 42 and 22%,
respectively; values estimated from graphs). The DAS28-ESR
remission rate (coprimary endpoint) at month 3 did not differ
significantly between the tofacitinib and placebo groups
(Table 1); however, the DAS28-ESR low disease activity rate
(Table 1) and the LS mean change from baseline in DAS28-
ESR [- 2.0 vs. - 1.1 (baseline 6.7); p\0.001] was signifi-
cantly greater in tofacitinib than placebo recipients [19]. Fol-
lowing 6 months’ treatment with tofacitinib, 9.8% of patients
were in remission, 22.0% had low disease activity and the LS
mean change from baseline in DAS28-ESR was - 2.4 [19].
Physical function at month 3, as assessed by the LS
mean change from baseline in the HAQ-DI score
Tofacitinib: A Review

(coprimary endpoint), was significantly improved with
tofacitinib relative to placebo (Table 1) [19, 31]. Other
HR-QOL outcomes at month 3, including PtGA, pain,
FACIT-F, and SF-36 PCS and MCS scores, were also
significantly improved (p\0.05) with tofacitinib relative to
placebo. Moreover, the improvements from baseline in
HAQ-DI, PtGA, pain, and SF-36 PCS and MCS scores
with tofacitinib exceeded the MCIDs [31]. Tofacitinib had
a rapid onset of action, with significant (p\0.01 vs. pla-
cebo) benefits in HAQ-DI, PtGA and pain scores evident as
early as week 2 of treatment and the magnitude of response
with tofacitinib sustained during 6 months’ therapy
[19, 31].
At month 6, the ACR20, ACR50 and ACR70 response
rates and HAQ-DI scores in patients who switched from
placebo to tofacitinib at month 3 (see Table 1 for study
details) were generally similar to those in patients who had
received tofacitinib for 3 months [19].
Tofacitinib monotherapy in this clinical setting was also
assessed in the ORAL Strategy study. Results showed that
monotherapy did not achieve statistical noninferiority to
combination treatment with tofacitinib plus methotrexate
or adalimumab plus methotrexate, while the two combi-
nation therapies were noninferior to each other (Table 1;
see Sect. 4.1.2) [20].
4.3 As Monotherapy in Methotrexate-Naı̈ve
Patients
Tofacitinib 5 mg twice daily as monotherapy was more
effective than methotrexate monotherapy in reducing
signs and symptoms of disease and inhibiting progression
of structural joint damage in the 24-month, phase 3
ORAL Start study in methotrexate-naı̈ve patients with RA
[18]. For the majority (65.5%) of patients the interval
between diagnosis and enrolment was \2 years and for
40% of patients the duration was \6 months (median
0.7–0.8 years); the mean disease duration was & 3 years.
At month 6, ACR70 (coprimary endpoint), ACR20 and
ACR50 response rates were significantly higher in tofac-
itinib than methotrexate recipients (Table 3), with signif-
icant (p\0.001) improvements seen as early as month 1
of therapy and sustained over 24 months’ treatment.
DAS28-ESR remission and DAS28-ESR low disease
activity rates at month 6 were almost 2-fold higher with
tofacitinib than methotrexate (Table 3), with the magni-
tude of response generally sustained over 24 months’
therapy. In addition, the proportion of patients achieving a
‘good or moderate’ EULAR response was significantly
(p\0.001) higher in tofacitinib than methotrexate recip-
ients at month 6 (79 vs. 61%) [18].
Tofacitinib monotherapy was associated with signifi-
cantly less radiographic damage than methotrexate
monotherapy [18]. At month 6, the mTSS (coprimary
endpoint), erosion score and joint-space narrowing score
increased from baseline to a significantly smaller extent in
tofacitinib than methotrexate recipients, with benefits
maintained at month 24 (Table 2). The proportion of
patients with no radiographic progression (B 0.5 unit
increase in mTSS) at month 24 was also significantly
higher in the tofacitinib than the methotrexate group
(Table 2) [18].

Table 3 Efficacy of oral tofacitinib 5 or 10 mg twice daily in methotrexate-naı̈ve patients with rheumatoid arthritis in the 24-month, ran-
domized, double-blind, multicentre, phase 3 ORAL Start study [18]

Study Timepoint Treatment Response ratesa (% pts) Remissiona,b LDAa,b Change from
(months) (no. of FAS pts) BL HAQ-DI [BL]c
ACR20 ACR50 ACR70 (% pts) (% pts)

ORAL Start 6 TOF 5 (373) 71.3*** 46.6*** 25.5***d 14.6* 27.8*** - 0.8*** [1.5]
TOF 10 (397) 76.1*** 56.4*** 37.7***d 21.8*** 38.2*** – 0.9*** [1.5]
MTXe (186) 50.5 26.6 12.0d 7.6 14.0 - 0.6 [1.5]
24 TOF 5 64.2*** 49.3*** 34.4*** 20.8*** 34.8*** - 0.9***
TOF 10 64.2*** 49.2*** 37.6*** 22.3*** 36.0*** – 1.0***
MTXe 42.4 28.3 15.2 9.9 15.8 - 0.7
ACR ‘x’ C x% improvement in ACR criteria, BL baseline, DAS28-ESR Disease Activity Score 28-erythrocyte sedimentation rate, FAS full
analysis set, HAQ-DI Health Assessment Questionnaire – Disability Index score (lower scores indicate less disability), LDA low disease activity,
MTX methotrexate, pts patients, TOF tofacitinib
*p B 0.05, **p B 0.01, ***p\0.001
a
Missing values imputed using nonresponse imputation
b
Proportion of pts in remission (DAS28-ESR of \2.6) or with LDA (DAS28-ESR of B 3.2)
c
Least-squares mean changes from BL; all BL values are means
d
Coprimary endpoints; significance of coprimary endpoints was assessed using a step-down approach
e
MTX target-dose after titration of 20 mg/week

At month 6, physical function (assessed by the LS mean
change from baseline in the HAQ-DI score) had improved to
a significantly greater extent in tofacitinib than methotrexate
recipients (Table 3), with significant (p\0.05) between-
group differences seen from month 1 and sustained over
24 months’ therapy [18, 32]. Tofacitinib reduced fatigue
(FACIT-F scores) and arthritis pain to a significantly greater
extent than methotrexate at month 6, with significant
(p\0.05) between-group differences seen at month 1 and
generally maintained during 24 months’ therapy [18, 32].
Other HR-QOL outcomes, including PtGA, and SF-36 PCS
scores, were also significantly (p\0.05) improved with
tofacitinib relative to methotrexate at months 3, 6, 12 and
24; improvements in PtGA scores were seen from month 1
onwards [32]. In addition, significantly (p\0.05) more
tofacitinib than methotrexate recipients at month 6 had
MCIDs in PtGA scores and in three SF-36 domains (phys-
ical functioning, bodily pain and mental health) [32].
4.4 Long-Term Efficacy
Pooled data from two open-label long-term extension
(LTE) studies (a 72-month Japanese study A3921041 and
the ongoing ORAL Sequel study, data cut-off March 2017)
involving patients participating in phase 1–3 studies,
showed that the efficacy of tofacitinib (5 or 10 mg twice
daily with or without DMARDs) was sustained for at least
96 months [33, 34]. In 1421 patients receiving tofacitinib
5 mg twice daily (with or without background DMARDs),
ACR20 response rates at months 1 and 48 were 73.8 and
74.4%, respectively; ACR50 response rates were 49.8 and
49.6; ACR70 response rates were 28.8 and 34.1; DAS28-
ESR remission was achieved by 23.1 and 21.6% of patients;
DAS28-ESR low disease activity was achieved by 39.3 and
42.4% of patients; the mean DAS28-ESR was 3.69 and
3.56; and the mean HAQ-DI score was 0.78 and 0.81 [33].
The total tofacitinib exposure in this analysis was 3215
patient-years (PY) and the mean (maximum) duration of
therapy was 826 (1844) days [33]. Similar results were seen
at 96 months, with 77.9, 59.5 and 41.7% of patients who
received tofacitinib 5 or 10 mg twice daily maintaining
ACR20, ACR50 and ACR70 responses, respectively; the
mean DAS28-ESR was 3.34 and the mean HAQ-DI was
0.77. By month 96, 4967 patients had received tofacitinib 5
or 10 mg twice daily with or without background DMARDs
for a mean (maximum) duration of 3.5 (9.4) years [34].
Assessment of radiographic progression in a radio-
graphic substudy of ORAL Sequel (n = 1156) showed that
patients receiving tofacitinib 5 or 10 mg twice daily (with
or without DMARDs) had limited structural progression
during longer-term therapy (mean treatment duration after
LTE entry 1113 days; data cut off March 2017) [35]. At
months 12 and 36, a slight increase from baseline in mTSS
S. Dhillon
(mean change 0.25 and 1.17), erosion score (0.21 and 0.68)
and joint-space narrowing score (0.24 and 0.78) was seen
with tofacitinib; baseline was the last visit in the index
study prior to LTE entry. The proportion of patients with
no radiographic progression (change from baseline in
mTSS of B 0.5) decreased during this period from 84.5% at
month 12 to 72.2% at month 36, and the proportion of
patients with no new erosions (change from baseline in
erosion score of B 0.5) decreased from 92.3 to 85.3%. At
months 12 and 36, x-ray data were available from 1003
(86.8%) and 858 (76%) of patients, respectively [35].
4.5 Other Studies
Post hoc pooled data from five phase 3 ORAL studies
(Solo, Scan, Standard, Sync and Step) and four phase 2
studies showed that tofacitinib was effective in improving
the signs and symptoms of RA when used before or after
bDMARDs [36]. For instance, at month 3, ACR20
responses were achieved in 60.3% of tofacitinib 5 mg
twice daily recipients versus 26.5% of placebo recipients
(p\0.0001) in the bDMARD-naı̈ve group (n = 2812) and
in 43.4 versus 24.6% (p\0.0001) of patients in the
bDMARD-experienced group (n = 705) [36]. Another
post hoc pooled analysis of data from five phase 3 ORAL
studies (Solo, Scan, Standard, Sync and Step) suggested
that the treatment response may be greater if tofacitinib
5 mg twice daily is initiated earlier in the course of RA,
thereby potentially reducing the time patients experience
active disease [37].
Tofacitinib 5 mg twice daily (with or without DMARDs)
improved RA outcomes regardless of body mass index at
baseline (\25, 25 to \30, and C 30 kg/m2) [38] or prior
therapy (inadequate response/intolerance to methotrexate,
bDMARD or csDMARD other than methotrexate) [39] in
post hoc pooled analyses of six phase 3 [38] and 14 phase 2
or 3 trials [39]. In addition, the Japanese LTE study
(A3921041) [40], a post hoc subgroup analysis of the
ORAL Sync study [41] and post hoc pooled analyses of
phase 2, 3 and/or LTE studies [38, 42–44] suggested that the
efficacy of tofacitinib 5 mg twice daily (with or without
DMARDs) was generally consistent between Chinese [41],
Japanese [40] or Latin American [42] patients and the
overall tofacitinib population; between patients in the USA
and rest of the world [43]; and between younger
(\65 years) and older (aged C 65 years) patients [44].
5 Tolerability of Tofacitinib
The tolerability profile of oral tofacitinib in patients with
active RA is based on the pivotal studies discussed in Sect.
4, pooled data from two LTEs (study A3921041 and ORAL
Tofacitinib: A Review
Sequel study; Sect. 4.4) [5, 34, 45], and pooled data from
phase 1–3 studies (including ORAL Start, ORAL Solo,
ORAL Scan, ORAL Standard, ORAL Sync and ORAL
Step) and the LTE studies [5, 45]. The latter pooled anal-
ysis included data from a total of 6194 patients (referred to
as the long-term safety population hereafter) who had
received tofacitinib (all doses, with or without DMARDs)
for a mean duration of 3.13 years (median 3.4 years; data
cut-off of 31 March 2015; accumulated total exposure of
19406 PY, based on B 8.5 years of exposure) [5, 45, 46].
Tofacitinib was generally well tolerated in patients with
RA, with a tolerability profile generally similar to that of
bDMARDs. In the long-term safety population, the inci-
dence of treatment-emergent adverse events (AEs) with
tofacitinib (all doses) was 136.9 patients/100 PY, the rate
of discontinuation because of AEs was 7.5 patients/100 PY
and that of serious treatment-emergent AEs (SAEs) was 9.4
patients/100 PY [45]. During the first 3 months of treat-
ment in 6- to 24-month randomized, controlled studies
(n = 1849 tofacitinib and 1079 placebo recipients), treat-
ment-emergent AEs occurred in 51.4% of patients receiv-
ing tofacitinib 5 mg twice daily (vs. 51.8% of placebo
recipients), with headache (4.5 vs. 2.4%), upper respiratory
tract infections (URTI; 3.8 vs. 3.8%), nasopharyngitis (3.5
vs. 3.2%), diarrhoea (3.5 vs. 2.6%) and nausea (2.8 vs.
2.3%) reported most frequently (incidence [2.5%) [46].
SAEs occurred in approximately 2.7% of patients each in
the tofacitinib and placebo groups during this period, with
the most common SAEs being infections and infestations,
occurring in 0.8 and 0.4% of patients in the respective
groups [46]. The adverse event-related withdrawal rate was
3.8 and 3.4% in the tofacitinib and placebo groups,
respectively; the most common infections leading to
treatment withdrawal in tofacitinib recipients were HZ and
pneumonia [5, 46].
The tolerability profile of tofacitinib (5 or 10 mg twice
daily with or without DMARDs) in the pooled LTEs
[B 9.4 years’ (B 114 months) therapy] was generally con-
sistent with that seen during short-term treatment [34].
Infections and infestations occurred most commonly
(69.6% of patients) in tofacitinib recipients, with the most
frequently reported infections being nasopharyngitis
(19.1%), URTI (17.9%), bronchitis (12.6%) and urinary
tract infection (UTI; 12.5%). SAEs occurred in 29.4% of
tofacitinib recipients (9.13 patients/100 PY), with serious
infections reported in 8.9% of patients (2.46 patients/100
PY); 23.9% of tofacitinib recipients discontinued treatment
because of AEs [34].
An earlier pooled analysis of the two LTE studies (data
cut-off March 2015; n = 4867), showed that during a mean
(maximum) treatment duration of 3.0 (7.9) years, the
median overall drug survival of tofacitinib 5 or 10 mg
twice daily was 5.0 years (5.1 years as monotherapy and
4.9 years with background csDMARDs) [47]. AE-associ-
ated withdrawal rates with tofacitinib were higher than
rates associated with loss of efficacy (21.6 vs. 3.1%), with
the most common reasons for treatment discontinuation
being infections and infestations (8.8%), investigations
(4.2%) and benign, malignant or unspecified neoplasms
(3.2%). Drug survival and treatment discontinuation rates
for the two tofacitinib doses were generally similar [47].
5.1 Infections
During B 8.5 years’ treatment with tofacitinib 5 mg twice
daily in the long-term safety population, the incidence rate
of infections was 43.8 patients/100 PY (48.9 patients/100
PY with tofacitinib monotherapy and 41.0 patients/100 PY
with tofacitinib plus DMARDs) and the rate of serious
infections was 2.4 patients/100 PY, with the most com-
mon serious infections being pneumonia, HZ, UTI, cel-
lulitis, gastroenteritis and diverticulitis [5]. Significant
(p\0.05) risk factors for serious infections included use
of glucocorticoids at baseline, higher baseline HAQ-DI
score, prior confirmed post-baseline lymphopenia (\500
cells/mm3), line of therapy (third-line vs. second-line) and
geographical region (e.g. Asian patients vs. patients in the
USA/Canada) [45]. Age was also a significant (p\0.05)
risk factor for serious infections [45], with a two-fold
higher incidence in the elderly (aged C 65 years) than in
younger patients (aged \65 years) (4.8 vs. 2.4 patients/
100 PY) [5].
Viral reactivation and cases of herpes virus reactivation
(e.g. HZ), as well as opportunistic infections, such as
tuberculosis (TB) and other mycobacterial infections,
cryptococcus and histoplasmosis, have also been reported
with tofacitinib therapy [5]. In the long-term safety popu-
lation, HZ was reported in 703 patients (incidence 3.9
patients/100 PY), active TB in 36 patients (0.2 patients/100
PY; four patients had latent TB at screening with adequate
therapy) and opportunistic infections excluding TB in 61
patients (0.3 patients/100 PY) receiving tofacitinib (all
doses) [45]. The incidence of HZ appears to be higher in
several patient subgroups, including Asian patients (par-
ticularly Japanese and Korean patients) and patients with
long-standing RA who had prior treatment with C 2
bDMARDs; patients with an ALC of \1000 cells/mm3
may also be at increased risk of HZ [5]. There was no
notable increase in the incidence rate of serious infections
or HZ during long-term therapy [45]. Owing to a risk of HZ
with tofacitinib, consideration should be given to prophy-
lactic zoster vaccination, particularly in high risk patients
[5]; tofacitinib did not adversely affect humoral and cell-
mediated immune responses against, and the safety of, live
zoster virus vaccine in patients with RA who had pre-ex-
isting immunity to varicella zoster virus [48].

5.2 Cardiovascular Safety and Haematological
Changes
Tofacitinib was associated with a low incidence of car-
diovascular (CV) events [45]. In the long-term safety
population, 71 patients experienced Major Adverse Car-
diovascular Events (MACE; CV death and non-fatal CV
events) during B 8.5 years’ treatment with tofacitinib (all
doses); the incidence rate of MACE ranged between 0.2
and 0.7 patients/100 PY over this period [45].
Moderate increases in lipid levels seen with tofacitinib
(Sect. 2) appear to be non-atherogenic [46]. However, an
association between increased lipid levels and higher risk
of cardiovascular disease (CVD) cannot be excluded, par-
ticularly in the RA population which is at increased risk of
CVD [46]. A post hoc pooled analysis of six phase 3
ORAL studies (Start, Solo, Scan, Standard, Sync and Step)
assessed the impact of changes in lipids and high-sensi-
tivity (hs) CRP on CV risk by using the Framingham and
Reynolds risk scores to calculate the 10-year risk of
developing CVD [49]. Results showed that the Framing-
ham CV risk score was significantly higher with tofacitinib
(5 or 10 mg twice daily with or without DMARDs) than
with placebo in ORAL Sync (both doses) and ORAL Step
(10 mg dose), and significantly higher than with
methotrexate in ORAL Start (both doses) (all p\0.05).
The Reynolds risk score, which includes hsCRP as a
variable, was generally reduced with tofacitinib relative to
placebo in five studies (all p\0.05, except p = non-
significant for the 5 mg dose in ORAL Step) and did not
differ significantly from placebo in ORAL Start [49].
Clinically relevant decreases in haemoglobin levels of
B 7 g/dL were reported infrequently (\2% of patients)
with tofacitinib (5 or 10 mg twice daily with or without
DMARDs) during B 7 years’ (B 84 months) therapy [50].
There have also been reports of neutropenia and lym-
phopenia in tofacitinib recipients [5]. After an initial
transient increase in the mean ALC during the first
3 months of treatment with tofacitinib (5 or 10 mg twice
daily with or without DMARDs), lymphocyte counts
decreased gradually until month 48 and stabilized there-
after [50]. During B 8.5 years’ treatment in the long-term
safety population, a confirmed decrease in ALC of \500
cells/mm3 and 500–750 cells/mm3 was reported in 1.3%
and 8.4% of patients, respectively [5]. Most patients with
an ALC of \500 cells/mm3 achieved counts C 500 cells/
mm3 after & 3 weeks of treatment discontinuation
[14, 50]. Mean neutrophil counts decreased during the first
3 months of treatment with tofacitinib (5 or 10 mg twice
daily with or without DMARDs) and then remained rela-
tively stable during B 66 weeks’ therapy [50]. During
B 8.5 years’ treatment in the long-term safety population, a
confirmed decrease in absolute neutrophil count (ANC) of
S. Dhillon
\1000 cells/mm3 was reported in 0.08% of patients [5].
An ALC of \750 cells/mm3 was associated with an
increased incidence of serious infections, but no clear
relationship was seen between an ANC of \1000 cells/
mm3 and the occurrence of serious infections [5].
5.3 Malignancies and Other Adverse Events
During B 8.5 years’ treatment with tofacitinib (all doses) in
the long-term safety population, 173 patients (incidence 0.9
patients/100 PY) had malignancies [excluding non-me-
lanoma skin cancer (NMSC)], which included lung cancer
(0.2 patients/100 PY), breast cancer (0.2 patients/100 PY)
[45] and lymphomas (0.1 patients/100 PY) [51]. NMSC
occurred at an incidence of 0.6 patients/100 PY (118
patients) [45], which was no higher than that in the general
RA population [46]. No notable increase in the incidence rate
of malignancies was evident during long-term therapy [45].
Although the incidence of lymphoma was low in the tofac-
itinib clinical trials, the risk of developing lymphoma may be
higher in patients with RA than in the general population,
particularly in patients with highly active disease [5].
GI perforations were reported infrequently (n = 22
patients) with tofacitinib (all doses) in the long-term safety
population (incidence 0.11 patients/100 PY) [45]. All tofac-
itinib recipients with GI perforations were receiving con-
comitant NSAIDs or corticosteroids, 13 patients had a history
of diverticulitis or diverticulosis and two patients had a his-
tory of gastric ulcers [45]; treatment with NSAIDs and/or
corticosteroids and prior history of diverticulitis are known
risk factors for GI perforations in patients with RA [52].
Confirmed increases in liver enzymes (ALT or AST) of
greater than three times the upper limit of normal (ULN)
were uncommon in patients receiving tofacitinib (with or
without DMARDs) [5]; during B 9.4 years’ (B 114 months)
therapy with tofacitinib (5 or 10 mg twice daily with or
without DMARDs) in the LTEs, 5.7 and 3.3% of patients
had increases in ALT and AST of C 3 times the ULN,
respectively [34].
5.4 Compared with Adalimumab
The 12-month ORAL Strategy study showed that the tol-
erability profile of tofacitinib plus methotrexate was gen-
erally similar to that of adalimumab plus methotrexate,
with no new safety concerns reported in either combination
therapy group or in the tofacitinib monotherapy group [20].
In tofacitinib monotherapy, tofacitinib plus methotrexate
and adalimumab plus methotrexate recipients, treatment-
emergent AEs occurred in 59, 61 and 66% of patients,
respectively, treatment-related AEs in 26, 30 and 35% of
patients and SAEs in 9, 7 and 6% of patients; corre-
sponding AE-related withdrawal rates were 6, 7 and 10%.
Tofacitinib: A Review
Most AEs in all treatment groups were of mild to moderate
severity, with the most common being URTI (7, 10 and 8%
with tofacitinib, tofacitinib plus methotrexate and adali-
mumab plus methotrexate, respectively), nasopharyngitis
(6, 4 and 5%), UTI (3, 4 and 4%), nausea (3, 4 and 4%) and
increase in ALT levels (2, 6 and 7%). AEs of special
interest also occurred at generally similar rates in tofaci-
tinib, tofacitinib plus methotrexate and adalimumab plus
methotrexate recipients, including serious infections (2, 3
and 2%, respectively), HZ (1, 2 and 2%), TB (0, 1 and 0%)
and malignancies (excluding NMSC;\1, 0 and 0%) [20].
6 Dosage and Administration of Tofacitinib
In the EU, oral tofacitinib in combination with methotrexate
is indicated for the treatment of moderate to severe active
RA in adult patients who have responded inadequately to, or
who are intolerant of, one or more DMARDs [5]. Tofaci-
tinib may be administered as monotherapy in patients who
are intolerant of methotrexate or when treatment with
methotrexate is inappropriate. The recommended dosage of
tofacitinib is 5 mg administered twice daily, with or without
food. No dosage adjustment is needed when tofacitinib is
coadministered with methotrexate or when given to patients
with mild [creatinine clearance (CLCR) 50–80 mL/min] or
moderate (CLCR 30–49 mL/min) renal impairment or mild
hepatic impairment (Child Pugh A) [5]. However, tofaci-
tinib dosage should be reduced to 5 mg once daily in
patients with severe renal impairment (CLCR\30 mL/min)
or moderate hepatic impairment (Child Pugh B), and when
coadministering tofacitinib with potent CYP3A4 inhibitors
(e.g. ketoconazole) or drugs that are both moderate inhibi-
tors of CYP3A4 and potent inhibitors of CYP2C19 (e.g.
fluconazole) [5].
Tofacitinib is contraindicated in patients with active TB,
serious (e.g. sepsis) or opportunistic infections, in patients
with severe hepatic impairment, and during pregnancy and
lactation. Regular monitoring of patients is recommended,
and temporary or permanent discontinuation of tofacitinib
may be required for the management of AEs and laboratory
abnormalities associated with tofacitinib therapy (Sect. 5).
[5]. Local prescribing information should be consulted for
further information, including dosage and administration
details, contraindications, warnings and precautions.
7 Place of Tofacitinib in the Management
of Rheumatoid Arthritis
Management strategies for RA have changed substantially
since the 1990s when there were few and minimally
effective therapeutic agents and available antirheumatic
therapies were started late during the course of the disease
[2, 53]. Today, disease modification has become a
cornerstone of RA management and is a key requirement
for all modern antirheumatic agents [2]. A variety of
pharmacotherapeutic options are available, including
(i) csDMARDs, such as methotrexate (anchor drug) and
sulfasalazine (ii) bDMARDs, including TNF inhibitors
(e.g. adalimumab, etanercept) and IL-6 inhibitors (e.g.
tocilizumab) (iii) biosimilars, including infliximab and
etanercept biosimilars (iv) and targeted synthetic DMARDs
(tsDMARDs), such as JAK inhibitors (e.g. tofacitinib,
baricitinib).
Current EU treatment guidelines recommend adopting a
treat-to-target approach for the management of RA, with
the aim of achieving remission or sustained low disease
activity [2]. Treatment should be initiated soon after
diagnosis, with the choice of therapy based on disease
activity and other patient factors (e.g. progression of
structural damage), comorbidities, safety profile of agents,
and medical and societal costs. Methotrexate should be part
of the first treatment strategy in patients with active RA,
unless contraindicated or not tolerated, in which case
another csDMARD (leflunomide or sulfasalazine) may be
used. If the treatment target is not achieved within
3–6 months and in the absence of unfavourable prognostic
factors, switching to a, or the addition of another,
csDMARD is recommended. When unfavourable prog-
nostic factors are present (e.g. moderate to high activity,
high acute phase reactant levels or high swollen joint
counts), a bDMARD or tsDMARD should be combined
with the csDMARD; current practice is to start with a
bDMARD, owing to the long-term experience with these
agents. If the treatment target is still not reached, use of any
other bDMARD or tsDMARD is recommended [2].
Recently, two tsDMARDs tofacitinib [20] and barici-
tinib [54] have been approved in the EU for the treatment
of patients with moderate to severe active RA, and have
been included as treatment options in the current EU [2]
and NICE [55, 56] treatment guidelines (consult individual
guidelines for further details). Tofacitinib is a potent,
selective JAK inhibitor that preferentially inhibits sig-
nalling by heterodimeric cytokine receptors that associate
with JAK3 and/or JAK1 (Sect. 2). It is an organic small
molecule with convenient oral twice daily dosing relative
to bDMARDs, which are proteinaceous molecules admin-
istered subcutaneously or intravenously [57]. An extensive
phase 3–4 ORAL trial programme in patients with RA
showed that tofacitinib (monotherapy and/or combination
therapy with csDMARDs) was effective in reducing signs
and symptoms of disease and improving HR-QOL in a
range of patient populations, including patients naı̈ve to
methotrexate, patients with inadequate response to
cs/bDMARDs and patients with inadequate response to

TNF inhibitors (Sect. 4). Tofacitinib monotherapy was
more effective than methotrexate or placebo, but was
generally less effective than combination therapy with
tofacitinib or adalimumab plus methotrexate; the two
combination therapies were noninferior to each other [20].
Tofacitinib had a rapid onset of response with improve-
ments in signs and symptoms, and physical function gen-
erally evident within 2–4 weeks of treatment and benefits
sustained during long-term therapy (B 96 months) (Sect.
4).
In terms of structural preservation, tofacitinib
monotherapy was superior to methotrexate monotherapy in
inhibiting progression of structural damage (assessed by
mTSS) in ORAL Start in methotrexate-naı̈ve patients [18],
with treatment benefits maintained for up to 24 months
(Sect. 4.3). In ORAL Scan in patients with inadequate
response to methotrexate [21], although the addition of
tofacitinib to background methotrexate did not demonstrate
superiority over the addition of placebo in inhibiting pro-
gression of structural damage (assessed by mTSS), signif-
icantly more patients receiving tofacitinib experienced no
radiographic disease progression (Sect. 4.1.1.2). Moreover,
patients with unfavourable prognostic factors experienced
greater benefits with tofacitinib than placebo, according to
post hoc analyses (Sect. 4.1.1.2). In addition, when data
from both studies were analysed using a trimmed analysis
(to assess the effect of outliers), a significant (p B 0.05)
benefit of tofacitinib over placebo in terms of mTSS was
seen in both ORAL Start and ORAL Scan [26]. It was
suggested that the difference in structural preservation
outcomes between the ORAL Start and ORAL Scan studies
may be because of differences in the sensitivity of the two
study populations in terms of revealing a treatment benefit
over the short treatment duration [46]. Patients with inad-
equate response to methotrexate may be less sensitive due
to a smaller potentially responsive subset and a lower rate
of structural progression than methotrexate-naı̈ve patients
[46].
Tofacitinib was generally well tolerated in clinical
studies (Sect. 5), with a tolerability profile generally similar
to that of bDMARDs [58], such as adalimumab (Sect. 5.4).
During B 114 months’ therapy, the most common treat-
ment-emergent AEs with tofacitinib were infections and
infestations, of which URTI and nasopharyngitis were the
most frequent (Sect. 5). Infections were also the most
common SAEs, with pneumonia and HZ among the most
frequently reported (Sect. 5.1). A systematic review and
meta-analysis of data from 66 randomized controlled trials
and 22 LTE studies of bDMARDs and tofacitinib
S. Dhillon
suggested that the risk of serious infections with tofacitinib
was generally similar to that with bDMARDs (risk ratio
versus placebo of 2.2 for tofacitinib 5 mg twice daily vs.
1.0–2.27 for bDMARDs) [59].
However, the incidence of HZ (Sect. 5.1) was approxi-
mately 1.5- to 2-fold higher in tofacitinib recipients than
patients receiving placebo or bDMARDs [60], which
appears to be a class effect [58]. Similar results were seen
in a real-world study (based on 2006–2013 US Medicare
data and 2010–2014 US Marketscan data), which showed
that the risk of HZ was 2-fold higher with tofacitinib than
bDMARDs (hazard ratio 2.01 vs. 1.0–1.17) [61]. Impor-
tantly, in clinical studies, HZ was manageable, with the
majority of patients recovering and no HZ-related deaths
reported with tofacitinib [46]. Although an understanding
of the biological mechanism of the increased risk of viral
reactivation with tofacitinib is currently lacking, it has been
suggested that tofacitinib-mediated inhibition of IFN sig-
nalling via JAK1 receptor may play a role, as antiviral
defences in humans rely upon IFN signalling [60].
Tofacitinib did not appear to increase the risk of
malignancies, GI perforations or MACE during long-term
therapy (Sect. 5). Changes in laboratory parameters with
tofacitinib were generally mild or moderate, and reversible
with treatment interruption (Sect. 5).
Although assessed for B 114 months, the overall clinical
experience with tofacitinib is less than that with
bDMARDs. In addition, apart from a head-to-head com-
parison of tofacitinib with adalimumab (in addition to
background methotrexate) in ORAL Strategy [20], there
are no direct comparisons of tofacitinib and bDMARDs.
However, indirect network meta-analyses suggest that the
efficacy and safety profile of tofacitinib is generally similar
to that of bDMARDs [62, 63]. There are also no clinical
trials comparing the efficacy of tofacitinib with that of oral
baricitinib once daily, which preferentially inhibits JAK1
and JAK2 and has demonstrated efficacy in similar clinical
settings [54]. In one clinical study (RA-BEAM), when
added to background methotrexate, baricitinib was more
effective than adalimumab in reducing signs and symptoms
of disease and inhibiting progression of structural joint
damage in patients with active RA who had inadequate
response to methotrexate [64]. Although not directly
compared, the tolerability profile of baricitinib appears to
be generally similar to that of tofacitinib, with both agents
associated with an increased risk of HZ [58]. Baricitinib
has also been associated with cases of deep vein throm-
bosis (DVT) and pulmonary embolism (PE) (5 cases during
6637 PY experience) [65], and the summary of product
Tofacitinib: A Review
characteristics (SPC) carries a warning regarding the same
(UK SPC [66]). A signal for DVT and PE has not been
confirmed with tofacitinib despite longer clinical experi-
ence than that with baricitinib.
Drug survival or the time to discontinuation of medi-
cations is largely determined by the efficacy and tolera-
bility of a drug, and assesses the long-term impact of
medication on the course of the disease [67]. Early results
in the clinical setting showed that tofacitinib had a median
drug survival of 5 years (Sect. 5). In the real-world setting,
persistence at 12 months was found to be generally similar
for tofacitinib, adalimumab and etanercept in a retrospec-
tive US cohort study in bDMARD naı̈ve-patients with RA
who had received prior methotrexate [68]. Additional
studies would help to determine how tofacitinib compares
with bDMARDs in this respect during long term therapy.
In addition to the efficacy and tolerability of antirheu-
matic drugs, the convenience of drug intake, as determined
by the frequency and route of administration, may impact
patients’ adherence to treatment and ultimately to the
failure or success of therapy [69, 70], particularly if the
drugs have similar efficacy and tolerability (e.g.
bDMARDs and tsDMARDs [62, 63]). Tofacitinib has
convenient oral twice daily administration, which may be
preferred by patients, potentially increasing satisfaction
and adherence, and thereby improving clinical outcomes. A
recent study examining patient preferences in the treatment
of RA using a discrete-choice approach suggested that an
oral DMARD that does not have to be combined with
methotrexate and is not administered (only) every
1–2 weeks may be a favourable second-line option in
patients with RA [70]. Well-designed studies are needed to
assess adherence/compliance to therapy with tofacitinib
and any potential impact this may have on clinical
outcomes.
The cost-effectiveness of treatment is also an important
factor in determining the choice of therapy in RA, and
current NICE guidelines indicate that tofacitinib and
baricitinib are cost-effective after cs/bDMARDs in some
clinical settings [55, 56]. Additional well-designed cost-
effectiveness analyses would help to more definitively
position tofacitinib relative to cs/bDMARDs, including
biosimilar DMARDs.
In conclusion, B 114 months’ clinical experience in
patients with active RA showed that tofacitinib
monotherapy (as first- and second-line treatment) and
combination therapy with methotrexate (as second- and
third-line treatment) was effective and generally well tol-
erated. When added to background methotrexate, tofaci-
tinib and adalimumab were noninferior in terms of efficacy
and had generally similar tolerability profiles. Although
additional comparative studies are needed to more defini-
tively position tofacitinib relative to bDMARDs and other
tsDMARDs, current evidence indicates that oral tofacitinib
is a useful option for the treatment of patients with RA.
Data Selection Tofacitinib: 178 records identified
Duplicates removed 38
Excluded at initial screening (e.g. press releases; news 12
reports; not relevant drug/indication)
Excluded during initial selection (e.g. preclinical study; 8
reviews; case reports; not randomized trial)
Excluded during writing (e.g. reviews; duplicate data; 50
small patient number; nonrandomized/phase I/II trials)
Cited efficacy/tolerability articles 37
Cited articles not efficacy/tolerability 33
Search Strategy EMBASE, MEDLINE and PubMed from 2013 to
present. Previous Adis Drug Evaluation published in 2013 was
hand-searched for relevant data Clinical trial registries/databases
and websites were also searched for relevant data. Key words were
Tofacitinib, Xeljanz, CP-690550, rheumatoid arthritis, BID, twice
daily. Records were limited to those in English language. Searches
last updated 27 October 2017
Acknowledgements During the peer review process, the manufac-
turer of tofacitinib (XeljanzÒ) was also offered an opportunity to
review this article. Changes resulting from comments received were
made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any
external funding.
Conflict of interest Sohita Dhillon is a salaried employee of Adis/
Springer, is responsible for the article content and declares no rele-
vant conflicts of interest.
Additional information about this Adis Drug Review can be found at
http://www.medengine.com/Redeem/ED1CF06073837128.
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