CP-690550

Tofacitinib: A Review in Rheumatoid Arthritis

Sohita Dhillon1

© Springer International Publishing AG 2017

Abstract Tofacitinib (Xeljanz®) 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-na¨ıve 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

[email protected]

1 Springer, Private Bag 65901, Mairangi Bay, Auckland 0754, New Zealand
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-na¨ıve 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

⦁ 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 (Xeljanz®) 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.

⦁ 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
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- na¨ıve 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.

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].

⦁ 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].

⦁ 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 na¨ıve 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.

⦁ 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.

⦁ Compared with Placebo

⦁ 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

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
(months)

Treatment (no. of ptsc) Response ratesa (% pts) Remissiona,b LDAa,b Change from BL 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 ? MTXe (316) 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 ? MTXe (201) 52.6***f 35*j 22*j 12.5***f – 0.61***f,h [1.5]

ADA ? MTXe (204) 47.2***f 29*j 10*j 6.7*f - 0.49***f,h [1.5]
PL ? MTXi,e (108) 28.3 12j 2.5j 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 ? MTXe (134) 48.1***f 27.8*** 10.5** 8.8*f 20.8*** – 0.46***f [1.5]
PL ? MTXi,e (132) 24.4f 8.4 1.5 1.7f 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]
21 12 27 - 0.54j [1.6]

ADA ? MTXe (386) 71 44f,k

12 TOF 5 62 39 21 11 23 - 0.57j
TOF 5 ? MTXe 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]
PLi (122) 26.7f 12.5 5.8 4.4f 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
aMissing values imputed using nonresponse imputation
bProportion 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])
cFull analysis set [20–24] or modified intent-to-treat population [19]
dLeast-squares mean changes from BL; all BL values are means
eStable 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]
fPrimary [20] or coprimary [19, 21–24] endpoints; significance of coprimary endpoints was assessed using a step-down approach
gOwing to the step-down assessment of coprimary endpoints, and as no significant between-group difference was seen for radiographic progression, significance was not declared
hAssessed at month 3
iIn 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]
jValues estimated from graphs
kTOF ? 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

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 na¨ıve [18]

Study Treatment (no. of ITT pts) Timepoint (months)
LS mean change from BL in scores No radiographic 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**
TOF 10 ? MTX (316) 0.06*b (37.3) 0.02c (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**
PL ? MTX 0.92 0.29c 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)
MTX (186) \0.1***b (17.9)
0.8b (16.1) 0.1*** (9.1)
0.4 (8.4) 0.1* (8.8)
0.3 (7.7) 89.3***
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
aProportion of patients with a B 0.5 unit increase from BL in mTSS bCoprimary endpoints; significance assessed using a step-down approach cValues 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.

⦁ 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].

⦁ 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.

⦁ 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).
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].

⦁ 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

(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].

⦁ As Monotherapy in Methotrexate-Na¨ıve 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-na¨ıve 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-na¨ıve 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) ACR20 ACR50 ACR70 (% pts) (% pts) BL HAQ-DI [BL]c
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
aMissing values imputed using nonresponse imputation
bProportion of pts in remission (DAS28-ESR of \2.6) or with LDA (DAS28-ESR of B 3.2)
cLeast-squares mean changes from BL; all BL values are means
dCoprimary endpoints; significance of coprimary endpoints was assessed using a step-down approach
eMTX 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].

⦁ 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
(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].

⦁ 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-na¨ıve 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].

⦁ 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

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].

⦁ 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].

⦁ 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
\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].

⦁ 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].

⦁ 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%.

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].

⦁ 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.

⦁ 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
⦁ 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 na¨ıve 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-na¨ıve 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-na¨ıve 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
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

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 na¨ıve-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
reports; not relevant drug/indication) 12
Excluded during initial selection (e.g. preclinical study; reviews; case reports; not randomized trial) 8
Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials) 50
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 (Xeljanz®) 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.

References

⦁ O’Shea JJ, Laurence A, McInnes IB, et al. Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol. 2013;9(3):173–82.
⦁ Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommenda- tions for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960–77.
⦁ Winthrop KL, Strand V, van der Heijde DM, et al. The unmet need in rheumatology: reports from the Targeted Therapies meeting 2016. Clin Exp Rheumatol. 2016;34(4 Suppl 98):69–76.
⦁ Hodge JA, Kawabata TT, Krishnaswami S, et al. The mechanism of action of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(2):318–28.
⦁ Pfizer Ltd. Xeljanz (tofacitinib): summary of product character- istics. 2017. ⦁ http://www.ema.europa.eu/docs/en_GB/document_

library/EPAR_-_Product_Information/human/004214/WC50022 4911.pdf. Accessed 31 Oct 2017.
⦁ Scott LJ. Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. Drugs. 2013;73(8):857–74.
⦁ Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm. 2010;7:41.
⦁ Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32.
⦁ Maeshima K, Yamaoka K, Kubo S, et al. The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon- gamma and interleukin-17 production by human CD4 ? T cells. Arthritis Rheum. 2012;64(6):1790–8.
⦁ Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1311–6.
⦁ Conaghan PG, Ostergaard M, Bowes MA, et al. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate- naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques. Ann Rheum Dis. 2016;75(6):1024–33.
⦁ LaBranche TP, Jesson MI, Radi ZA, et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012;64(11): 3531–42.
⦁ Kitano M, Kitano S, Sekiguchi M, et al. Early effect of tofacitinib on osteoclast regulator in rheumatoid arthritis [abstract no. AB0394]. Ann Rheum Dis. 2016;75(Suppl 2):1040.
⦁ van Vollenhoven R, Choy E, Lee EB, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: changes in lymphocytes and lymphocyte subset counts and reversibility after up to 8 years of tofacitinib treatment [abstract no. THU0199]. Ann Rheum Dis. 2016;75(Suppl 2).
⦁ McInnes IB, Kim HY, Lee SH, et al. Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a ran- domised study. Ann Rheum Dis. 2014;73(1):124–31.
⦁ Isaacs JD, Zuckerman A, Krishnaswami S, et al. Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials. Arthritis Res Ther. 2014;16(4):R158.
⦁ Winthrop KL, Silverfield J, Racewicz A, et al. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann Rheum Dis. 2016;75(4):687–95.
⦁ Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86.
⦁ Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495–507.
⦁ Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adali- mumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, ran- domised controlled trial. Lancet. 2017;390(10093):457–68.
⦁ van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559–70.
⦁ van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19.
⦁ Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159(4):253–61.
⦁ Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451–60.
⦁ Fleischmann R, Mease PJ, Schwartzman S, et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group. Clin Rheumatol. 2017;36(1):15–24.
⦁ Landewe RB, Connell CA, Bradley JD, et al. Is radiographic progression in modern rheumatoid arthritis trials still a robust outcome? Experience from tofacitinib clinical trials. Arthritis Res Ther. 2016;18(1):212.
⦁ Strand V, van Vollenhoven RF, Lee EB, et al. Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis. Rheumatology (Oxford). 2016;55(6):1031–41.
⦁ Strand V, Kremer JM, Gruben D, et al. Tofacitinib in combina- tion with conventional disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: patient-reported out- comes from a phase III randomized controlled trial. Arthritis Care Res (Hoboken). 2017;69(4):592–8.
⦁ Strand V, Burmester GR, Zerbini CA, et al. Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patient-reported outcomes from a phase III trial. Arthritis Care Res (Hoboken). 2015;67(4):475–83.
⦁ Strand V, Mysler E, Moots RJ, et al. Tofacitinib with and without methotrexate versus adalimumab with methotrexate for the treatment of rheumatoid arthritis: patient-reported outcomes from a phase 3b/4 randomized trial [abstract no. 1906]. Arthritis Rheumatol. 2017;69(Suppl 10).
⦁ Strand V, Kremer J, Wallenstein G, et al. Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. Arthritis Res Ther. 2015;17:307.
⦁ Strand V, Lee EB, Fleischmann R, et al. Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial. RMD Open. 2016;2(2):e000308.
⦁ Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41(5):837–52.
⦁ Wollenhaupt J, Silverfield J, Lee EB. Tofacitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in open-label, long-term extension studies over 9 years [abstract no. 522]. Arthritis Rheumatol. 2017;69(Suppl 10).
⦁ van der Heijde D, Wollenhaupt J, Cohen SB, et al. Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib: data from an open-label long-term extension study over 3 years [abstract no. 533]. 2017;69(Suppl 10).
⦁ Charles-Schoeman C, Burmester G, Nash P, et al. Efficacy and safety of tofacitinib following inadequate response to conven- tional synthetic or biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2016;75(7):1293–301.
⦁ Hall S, Nash P, Rischmueller M, et al. Efficacy of tofacitinib in patients who are inadequate responders to disease-modifying antirheumatic drugs according to early versus late duration of

rheumatoid arthritis: post-hoc analysis of data from phase 3 trials [abstract no. 1609]. Arthritis Rheumatol. 2016;68(Suppl 10).
⦁ Dikranian A, Gonzalez-Gay MA, Wellborne F, et al. The efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index [abstract no. 2371]. Arthritis Rheumatol. 2017;69(Suppl 10).
⦁ Tesser J, Gu¨l A, Olech E, et al. Efficacy and safety of tofacitinib in patients with rheumatoid arthritis and inadequate response or intolerance to prior therapies [abstract no. 2493]. Arthritis Rheumatol. 2017;69(Suppl 10).
⦁ Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther. 2016. ⦁ https://doi.org/10.1186/s13075-016-0932-⦁ 2.
⦁ An Y, Li Z, Wu Q. Efficacy and safety of tofacitinib in chinese patients with active rheumatoid arthritis: subgroup analysis from a phase 3 study of tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs [abstract no. AB0514]. Ann Rheum Dis. 2015;74(Suppl 2).
⦁ Radominski SC, Cardiel MH, Citera G, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: pooled efficacy and safety analyses of phase 3 and long-term extension studies. Reumatol Clin. 2017;13(4):201–9.
⦁ Cohen SB, Koenig A, Wang L, et al. Efficacy and safety of tofacitinib in US and non-US rheumatoid arthritis patients: pooled analyses of phase II and III. Clin Exp Rheumatol. 2016;34(1):32–6.
⦁ Curtis JR, Schulze-Koops H, Takiya L, et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin Exp Rheumatol. 2017;35(3):390–400.
⦁ Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to
8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017;76(7):1253–62.
⦁ European Medicines Agency. Xeljanz (tofacitinib): assessment report. 2017. ⦁ http://www.ema.europa.eu/docs/en_GB/document_ ⦁ library/EPAR_-_Public_assessment_report/human/⦁ 004214/ ⦁ WC500224913.pdf. Accessed 31 Oct 2017.
⦁ Pope J, Keystone E, Jamal S, et al. Persistence of tofacitinib in the treatment of rheumatoid arthritis in open-label, long-term extension studies up to 8 years [abstract no. 1602]. Arthritis Rheumatol. 2016;68(Suppl 10).
⦁ Winthrop K, Wouters A, Choy E, et al. Assessment of immunogenicity of live zoster vaccination in rheumatoid arthritis patients on background methotrexate before and after initiating tofacitinib or placebo [abstract no. FRI0110]. Ann Rheum Dis. 2016;75(Suppl 2):468.
⦁ Nurmohamed M, Choy E, Charles-Schoeman C, et al. Impact of tofacitinib treatment compared with placebo or methotrexate on cardiovascular risk scores in six phase 3 randomized controlled trials [abstract no. 2966]. Arthritis Rheumatol. 2017;69(Suppl 10).
⦁ Schulze-Koops H, Strand V, Nduaka C, et al. Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. Rheumatology (Oxford). 2017;56(1):46–57.
⦁ Mariette X, Chen C, Biswas P, et al. Lymphoma in the tofacitinib rheumatoid arthritis clinical development program. Arthritis Care Res (Hoboken). 2017. ⦁ https://doi.org/10.1002/acr.23421.
⦁ Curtis JR, Lanas A, John A, et al. Factors associated with gas- trointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(12):1819–28.
⦁ Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet. 2017;389(10086):2338–48.
⦁ Eli Lilly Nederland B.V. Olumiant® (baricitinib): summary of
product characteristics. 2017. http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Product_Information/human/ 004085/WC500223723.pdf. Accessed 31 Oct 2017.
⦁ National Institute of Health and Care Excellence. Tofacitinib for moderate to severe rheumatoid arthritis: technology appraisal guidance. 2017. https://www.nice.org.uk/guidance/ta480. Acces- sed 31 Oct 2017.
⦁ National Institute of Health and Care Excellence. Baricitinib for moderate to severe rheumatoid arthritis. 2017. ⦁ https://www.nice. ⦁ org.uk/guidance/ta466. Accessed 31 Oct 2017.
⦁ Mocsai A, Kovacs L, Gergely P. What is the future of targeted therapy in rheumatology: biologics or small molecules? BMC Med. 2014;12:43.
⦁ Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234–43.
⦁ Strand V, Ahadieh S, French J, et al. Systematic review and meta- analysis of serious infections with tofacitinib and biologic dis- ease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362.
⦁ Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(10):2675–84.
⦁ Curtis JR, Xie F, Yun H, et al. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):1843–7.
⦁ Vieira MC, Zwillich SH, Jansen JP, et al. Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor inhibitors: results from a network meta-analysis. Clin Ther. 2016;38(12):2628–41.e5.
⦁ Bergrath E, Gerber RA, Gruben D, et al. Tofacitinib versus biologic treatments in moderate-to-severe rheumatoid arthritis patients who have had an inadequate response to nonbiologic DMARDs: systematic literature review and network meta-anal- ysis. Int J Rheumatol. 2017;2017:8417249.
⦁ Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652–62.
⦁ Weinblatt M, Taylor PC, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis [abstract no. 2352]. Arthritis. Rheumatol. 2017;69(Suppl 10):2352.
⦁ Eli Lilly and Co Ltd. Olumiant (baricitinib): UK summary of product characteristics. 2017. ⦁ https://www.medicines.org.uk/emc/ ⦁ medicine/32997#. Accessed 31 Oct 2017.
⦁ Souto A, Maneiro JR, Gomez-Reino JJ. Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology (Oxford). 2016;55(3):523–34.
⦁ Smith T, Harnett J, Gruben D, et al. Real-world experience with tofacitinib versus adalimumab and etanercept in biologic-naive patients with RA previously treated with methotrexate: data from a US administrative healthcare insurance claims database [ab- stract no. 2831]. Arthritis Rheumatol. 2017;69(Suppl 10).
⦁ Marengo MF, Suarez-Almazor ME. Improving treatment adher- ence in patients with rheumatoid arthritis: what are the options? Int J Clin Rheumtol. 2015;10(5):345–56.
⦁ Alten R, Kruger K, Rellecke J, et al. Examining patient prefer- ences in the treatment of rheumatoid arthritis using a discrete- choice approach. Patient Prefer Adherence. 2016;10:2217–28.