Filgotinib, a Novel JAK1-Preferential Inhibitor for the Treatment of Rheumatoid Arthritis: An Overview from Clinical Trials

Tanaka Y, Kavanaugh A, Wicklund J, McInnes IB.
Mod Rheumatol. 2021 Mar 19:1-26. Epub ahead of print. DOI 10.1080/14397595.2021.1902617

Filgotinib is the latest JAKinib to enter the international market for the treatment of RA, receiving regulatory approval in Japan and Europe late last year. In this review paper, Tanaka Y et al. examine the clinical evidence supporting its use as a later-line treatment, in accordance with international RA management guidelines, and provide their expert opinions on JAKinibs from a clinical perspective. The core clinical programme evaluating filgotinib in patients with moderately-to-severely acti...

Upadacitinib in Rheumatoid Arthritis: A Benefit–Risk Assessment Across a Phase III Program

Conaghan PG, Mysler E, Tanaka Y, Da Silva-Tillmann B, Shaw T, Liu J, Ferguson R, Enejosa JV, Cohen S, Nash P, Rigby W, Burmester G.
Drug Saf. 2021 Feb 2. DOI: 10.1007/s40264-020-01036-w

Upadacitinib 15 mg has a favourable benefit–risk profile according to an assessment of data from the phase III SELECT clinical trial programme. In this review of data for the once-daily, oral JAK inhibitor, Conaghan PG, et al. provided insights into the benefit–risk profile of upadacitinib in approximately 4400 patients with RA. Based on pooled data from five pivotal studies, benefits and risks were assessed up to the time of regulatory submission, and additional long-term integra...

Keywords: JAK, Upadacitinib, Clinical, Phase 3

Filgotinib Versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and Inadequate Response to Methotrexate: A Phase III Randomised Clinical Trial

Combe B, Kivitz A, Tanaka Y, van der Heijde D, Simon JA, Baraf HSB, Kumar U, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy JS, Jahreis A, Genovese MC, Mozaffarian M, Landewé RBM, Bae S-C, Keystone EC, Nash P.
Ann Rheum Dis. 2021 Jan 27:annrheumdis-2020-219214

Filgotinib improved RA signs and symptoms, physical function, and inhibited radiographic progression. FIL 200mg plus MTX, but not FIL 100mg plus MTX showed non-inferiority to ADA plus MTX, based on DAS28(CRP) low disease activity. FIL was also well tolerated in RA patients with inadequate response to MTX. This 52-week, phase 3 randomised clinical trial (FINCH 1) evaluated the efficacy and safety of FIL in patients with RA randomised to FIL 200 or 100mg, ADA 40mg, or placebo, all with background...

Keywords: JAK, Filgotinib, Clinical, Efficacy

Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study

Smolen JS, Xie L, Jia B, Taylor PC, Burmester G, Tanaka Y, Elias A, Cardoso A, Ortmann R, Walls C, Dougados M.
Rheumatology 2020; doi:10.1093/rheumatology/keaa576

Three year follow up data for baricitinib demonstrated efficacy in populations that span the clinical disease continuum in RA, including DMARD-naïve, MTX-IR, csDMARD-IR, and bDMARD-IR and was well tolerated. This study evaluated achievement and maintenance of LDA, remission and physical functioning in patients treated with baricitinib for up to 3 years. Data were analysed from two 52-week, Phase 3 studies (RA-BEAM and RA-BEGIN), and one ongoing long-term extension (RA-BEYOND). Patients com...

Keywords: JAK, Baricitinib, Clinical, Phase 3

Safety Profile of Upadacitinib in Rheumatoid Arthritis: Integrated Analysis from the SELECT Phase III Clinical Programme

Cohen SB, van Vollenhoven RF, Winthrop KL, Zerbini CAF, Tanaka Y, Bessette L, Zhang Y, Khan N, Hendrickson B, Enejosa JV, Burmester GR.
Ann Rheum Dis 2020 DOI:10.1136/annrheumdis-2020-218510

This integrated Phase III safety analysis of UPA showed that UPA had a similar profile to ADA and MTX for serious infections, malignancies, and thromboembolic events. Patients receiving UPA had increased risk of HZ and creatine phosphokinase elevation versus ADA. This integrated Phase III safety analysis of UPA examined >3500 RA patients and 4000 patient-years of exposure. Data were pooled from 3834 patients in SELECT-NEXT, SELECT-BEYOND, SELECT-MONOTHERAPY, SELECT-COMPARE and SELECT-EARLY s...

Keywords: JAK, Upadacitinib, Clinical, Safety

Temporary Interruption of Baricitinib: Characterization of Interruptions and Effect on Clinical Outcomes in Patients With Rheumatoid Arthritis

Emery P, Tanaka Y, Cardillo T, Schlichting D, Rooney T, Beattie S, Helt C, Smolen JS.
Arth Res Ther 2020;22:115 doi.org/10.1186/s13075-020-02199-8

This study aimed to characterize temporary interruptions of baricitinib and describe their impact on efficacy and safety. Brief interruptions during phase 3 baricitinib trials were associated with minor increases in symptoms which were resolved following treatment. In life-long, chronic conditions such as RA, interruption of therapy is common for various reasons, such as side effects, non-compliance, or because a patient requires surgery. Concerns have been raised that these treatment breaks c...

Keywords: JAK, Baricitinib, Clinical, Efficacy

Tofacitinib in Combination with Methotrexate in Patients with Rheumatoid Arthritis: Patient-reported Outcomes from the 24-month Phase 3 ORAL Scan study

Strand V, van der Heijde D, Tanaka Y, Keystone E, Kremer J, Zerbini C A F, Cardiel M H, Cohen S, Nash P, Song Y-W, Tegzová D, Gruben D, Wallenstein G, Connell C A, Fleischmann R.
Clin Exp Rheumatol . Sep-Oct 2020;38(5):848-857. Epub 2019 Dec 19.

In the ORAL SCAN study, patients receiving TOF 5 mg or 10 mg BID reported significant improvements in patient-reported outcomes at month 3 compared with placebo, which were maintained through 24 months of treatment. RA causes a significant health and socioeconomic burden and affects all aspects of health related quality of life. ORAL Scan included patients with active RA and inadequate response to MTX who were randomised to receive TOF 5 mg or 10 mg BID plus MTX or PBO. This study evaluated the ...

Keywords: JAK, Tofacitinib, Clinical, PRO

Efficacy and Safety of Peficitinib (ASP015K) in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III Randomised, Double-Blind, Placebo-Controlled Trial (RAJ4) in Japan

Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Iwasaki M, Katayama K, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Shiomi T, Yamada E, van der Heijde D.
Ann Rheum Dis 2019 DOI: 10.1136/annrheumdis-2019-215164

Peficitinib (PEF) 100 and 150 mg demonstrated robust clinical and structural efficacy in patients with RA who have an inadequate response to MTX. In Japan, two JAK inhibitors, TOF and BARI are currently available for RA patients with an inadequate response to conventional therapies. This randomized phase 3 study (RAJ4), assessed the efficacy and safety of two PEF doses in combination with MTX compared to PBO, in Japanese MTX-IR. Patients were randomized 1:1:1 to PBO, PEF 100 mg and 150 mg with...

Keywords: JAK, Peficitinib, Clinical, Phase 3

Clinical Outcomes in Patients Switched from Adalimumab to Baricitinib Due to Non-Response and/or Study Design: Phase III Data in Patients with Rheumatoid Arthritis

Tanaka Y, Fautrel B, Keystone EC, Ortmann RA, Xie L, Zhu B, Issa M, Patel H, Gaich CL, de Bono S, Rooney TP, Taylor PC.
Ann Rheum Dis. 2019 Jul;78(7):890-898.

Switching from ADA to BARI without a lengthy washout period can be executed with acceptable safety and tolerability and was associated with maintained disease control. Switching therapies in RA is commonplace in myriad scenarios including inadequate responses, intolerances and patient preference. Assessing the safety and efficacy of new treatments such as BARI, in the context of use as a replacement therapy, is beneficial. A previous study (RA-BEACON) has demonstrated that safely switching fro...

Keywords: JAK, Baricitinib, Clinical, Phase 3

Efficacy and Safety of Filgotinib for Patients With Rheumatoid Arthritis With Inadequate Response to Methotrexate: FINCH 1 Primary Outcome Results

Combe BG, Kivitiz AJ, Tanaka Y, van der Heijde D, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy JS, Mozaffarian N, Landewé RBM, Bae SC, Keystone EC, Nash P.
EULAR 2019 Abstract LB0001 Presentation

Filgotinib is an orally administered, selective inhibitor of JAK1. Filgotinib has shown good efficacy and was well tolerated for the treatment of rheumatoid arthritis (RA) in Phase 2 studies.The objective of this Phase 3 study was to evaluate the efficacy and safety of filgotinib treatment in patients with RA who have had an inadequate response to methotrexate (MTX).

Keywords: JAK, Filgotinib, Clinical, Phase 3

Upadacitinib as Monotherapy in Patients with Active Rheumatoid Arthritis and Inadequate Response to Methotrexate (SELECT-MONOTHERAPY): A Randomised, Placebo-Controlled, Double-Blind Phase 3 Study

Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, Zhang Y, Damjanov N, Friedman A, Othman AA, Camp HS, Cohen S.
Lancet. 2019 Jun 8;393(10188):2303-2311

UPA monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing MTX in MTX inadequate-responder patients with RA. Despite its proven effectiveness and safety, many patients are unable to tolerate MTX due to its side-effects. Therapies that can be used without concomitant MTX therefore, have an important place in RA management. In previous studies, UPA has shown efficacy in combination with stable background csDMARDs in RA patients who are DMA...

Keywords: JAK, Upadacitinib, Clinical, Efficacy

Safety Profile of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis with Over 1.6 Years Median Time in Treatment: An Integrated Analysis of Phase 2 and 3 Trials

Harigai M, Takeuchi T, Smolen JS, Winthrop KL, Nishikawa A, Rooney TP, Saifan CG, Issa M, Isaka Y, Akashi N, Ishii T, Tanaka Y.
Mod Rheumatol. 2019 Feb 20:1-23. DOI: 10.1080/14397595.2019.1583711

In this integrated analysis, BARI showed an acceptable safety profile in Japanese patients with up to 3.2 years of exposure. Other than incidences of herpes zoster (HZ), no major differences were noted with BARI safety in Japanese patients with RA, compared to the patients in the integrated database. BARI has previously demonstrated significant clinical efficacy and acceptable safety. Japanese patients who participated in the BARI clinical development programme, were comparable to those from th...

Keywords: JAK, Baricitinib, Clinical, Safety

Tofacitinib in Combination with Methotrexate in Patients with Rheumatoid Arthritis: Clinical Efficacy, Radiographic and Safety Outcomes from the 24-Month Phase 3 ORAL Scan Study

van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Stanley Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R, ORAL Scan investigators.
Arthritis Rheumatol. 2019 Jun;71(6):878-891

RA patients receiving TOF 5 or 10 mg BID plus MTX showed sustained clinical and radiographic treatment effects through months 12-24. The safety profile was consistent with previous TOF studies. The 12-month data from the ORAL Scan study have been previously reported. This report assesses durability of responses, including structural damage progression, and safety with TOF through 24 months. Patients were randomized 4:4:1:1 to receive TOF 5 or 10 mg BID, or PBO advanced to TOF with stable, ba...

Keywords: JAK, Tofacitinib, Clinical, Safety

Characterization and Changes of Lymphocyte Subsets in Baricitinib-Treated Patients With Rheumatoid Arthritis: An Integrated Analysis.

Tanaka Y, McInnes IB, Taylor PC, Byers NL, Chen L, de Bono S, Issa M, Macias WL, Rogai V, Rooney TP, Schlichting DE, Zuckerman SH, Emery P.
Arthritis Rheumatol. 2018 Dec;70(12):1923-1932. doi: 10.1002/art.40680

This review shows that changes in lymphocyte subsets were largely within normal reference ranges and were not associated with efficacy or safety end points. BARI is a selective JAK1/JAK2 inhibitor, approved for the treatment of moderate to severe RA. BARI treatment is associated with changes to circulating lymphocyte and lymphocyte subsets, however detailed analyses of these effects, and their relevance to efficacy and safety is lacking. This study investigated the changes in lymphocyte cell s...

Keywords: JAK, Baricitinib, Clinical, Safety

Tocilizumab Discontinuation After Attaining Remission in Patients with Rheumatoid Arthritis who were Treated with Tocilizumab Alone or in Combination with Methotrexate: Results from a Prospective Randomised Controlled Study (the second year of the SURPRISE study)

Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Takeuchi T, the SURPRISE study group.
Ann Rheum Dis 2018; 77:1268–1275 DOI: 10.1093/rheumatology/key121

The second-year results from the SURPRISE study show that low disease activity (LDA) can be maintained after discontinuation of tocilizumab with continued methotrexate after remission is achieved. Discontinuation of biologic agents in patients who have achieved remission or low disease activity (LDA) is desirable from a risk–benefit point of view. Compared with TNF inhibitors, little is known regarding TCZ-free remission or LDA, but studies indicate that only a small proportion of patien...

Keywords: IL-6, Tocilizumab, Clinical, Efficacy

Thromboembolism with Janus Kinase (JAK) Inhibitor for Rheumatoid Arthritis: How Real is the Risk?

Scott IC, Hider SL, Scott DL.
Drug Safety 2018 Jul;41(7):645–53

Current data suggests that JAK inhibitors may increase the risk of thromboembolism and pulmonary thrombosis (PT) in RA. Two JAK inhibitors – baricitinib (BARI) and tofacitinib (TOF) – are considered effective treatments for RA, however, there are concerns about the thromboembolic risks associated with them. In August 2017, the summary of product characteristics for BARI was revised to include a warning of developing DVT and pulmonary embolism (PE), with recommendations that BARI sho...

Keywords: JAK, Baricitinib, Clinical, Safety

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy

Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, Hirose T, Nduaka CI, Wang L, Mendelsohn AM, Fan H, Chen C, Bananis E.
Arthritis Rheumatol 2017;69(10):1960–68

The results of this analysis of patients with herpes zoster (HZ) within the global tofacitinib (TOF) RA programme suggest that there is likely to be a greater HZ risk in patients receiving TOF and glucocorticoids compared with patients receiving TOF monotherapy. The global TOF RA development programme comprised 2 Phase 1, 9 Phase 2, 6 Phase 3 and 2 long-term extension studies. These studies included 6192 patients; data were reviewed to identify cases of HZ. Crude incidence rates of number of pa...

Keywords: JAK, Tofacitinib, Clinical, Safety

Patient-reported Outcomes from a Phase 3 Study of Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis: Secondary Analyses from the RA-BEAM Study

Keystone EC, Taylor PC, Tanaka Y, Gaich C, DeLozier AM, Dudek A, Velasco Zamora J, Covarrubias Cobos JA, Rooney T, de Bono S, Arora V, Linetzky B, Weinblatt ME.
Ann Rheum Dis 2017;76(11):1853-1861. doi: 10.1136/annrheumdis-2017-211259

This paper describes the patient-reported outcome (PRO) data collected in RA-BEAM, a Phase 3 study of baricitinib compared with both placebo and adalimumab in patients with RA and an inadequate response to MTX. PRO measures evaluated include health-related quality of life (HRQOL), physical function, disability, fatigue, sleep, mental health status, work productivity and work activity impairment. The RA-BEAM study demonstrated that patients treated with baricitinib experienced a greater impro...

Keywords: JAK, Baricitinib, Clinical, PRO

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

Cohen BS, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Shoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J.
Ann Rheum Dis 2017;76:1253-1262. DOI 10.1136/annrheumdis-2016-210457

This analysis of exposure to tofacitinib, an oral JAKi for the treatment of RA, for up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. Adverse events were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. Data were collated into an integrated safety summary of tofacitinib in adult patients with active RA, and included data spanning the tofacitinib clinical programme: from 2 P...

Keywords: JAK, Tofacitinib, Clinical, Safety

Discontinuation of Tofacitinib after achieving Low Disease Activity in Patients with Rheumatoid Arthritis: a Multicentere, Observational Study

Kubo S, Yamaoka K, Amano K, Nagano S, Tohma S, Suematsu E, Nagasawa H, Iwata K and Tanaka Y.
Rheumatology. Doi 10.1093/rheumatology/kex068

This study showed that in patients who achieved low disease activity (LDA), it is possible to discontinue tofacitinib without flare in approximately one-third of patients. Patients from the tofacitinib Phase 3 programme and long-term extension study were enroled. Discontinuation was based on physician-patient decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib free at post-treatment Week 52. Of 64 patients treated with tofacitin...

Keywords: JAK, Tofacitinib

Efficacy and Safety of Sirukumab in Patients with Active Rheumatoid Arthritis Refractory to Anti-TNF Therapy (SIRROUND-T): A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multinational, Phase 3 Study

Aletaha D, Bingham CO 3rd, Tanaka Y, Agarwal P, Kurrasch R, Tak PP and Popik S.
Lancet 2017;pii:S0140-6736(17)30401-4

In this Phase 3 multicentre, randomised controlled trial in patients with active RA who were refractory or intolerant to previous biological treatment with at least one TNF inhibitor, sirukumab 50 mg every four weeks (Q4W) or 100 mg every two weeks (Q2W) was well tolerated and significantly improved signs and symptoms of disease. Patients were randomised 1:1:1 to placebo (n=294), sirukumab 50 mg Q4W (n=292) or sirukumab 100 mg Q2W (n=292), while continuing any concomitant DMARDs. Of the 878 ran...

Keywords: IL-6, Sirukumab, Clinical, Phase 3

Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study

Tanaka Y, Emoto K, Cai Z, et al.
J Rheumatol. 2016;43(3):504–511.

Clinical trials have shown baricitinib once daily to be effective in patients with RA. However, this Janus kinase (JAK) 1/JAK2 inhibitor has not been evaluated in a Japanese population. In this 12-week, placebo-controlled study, 145 Japanese patients were enrolled and received placebo, 1 mg, 2 mg, 4 mg or 8 mg oral baricitinib daily. Efficacy results were encouraging and consistent with earlier trials. Significantly more baricitinib patients achieved ACR20 response at Week 12 of treatment compa...

Keywords: JAK, Baricitinib, Clinical, Phase 3

Efficacy and safety of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy: Results from a randomized phase II trial

Takeuchi T, Tanaka Y, Yamanaka H, Amano K, Nagamine R, Park W, Shiozawa K, Tsukano M, Wei J, Shao J, Togo O, Mashimo H.
Modern Rheumatology. 2015 Sep 10:1-9. [Epub ahead of print]

This Phase II study assessed the safety and efficacy of olokizumab in Asian patients with moderate-to-severe rheumatoid arthritis, previously exposed to anti-TNF therapy. After 12 weeks of treatment, olokizumab was found to rapidly improve disease activity in patients who had previously failed anti-TNF therapy. There was also a significant decrease in ACR20 and ACR50 responder rates at week 12. The safety findings were consistent with the safety profile expected for this drug class. These findin...

Keywords: IL-6, Olokizumab, Clinical, Phase 2

Comparison of the efficacies of abatacept and tocilizumab in patients with rheumatoid arthritis by propensity score matching

Kubo S, Nakayamada S, Nakano K, Hirata S, Fukuyo S, Miyagawa I, Hanami K, Saito K, Tanaka Y.
Annals of the Rheumatic Diseases. 2015 Aug 5. doi:pii: annrheumdis-2015-207784. 10.1136/annrheumdis-2015-207784. [Epub ahead of print]

This study compared the clinical outcomes at one year after the treatment either abatacept or tocilizumab in routine clinical practice. This study employed propensity score matching and demonstrated that abatacept and tocilizumab had comparable continuing efficacies, and that treatment with the drugs resulted in comparable clinical and functional remission rates. Additionally, abatacept and tocilizumab showed similar effectiveness with or without MTX. While clinical efficacies, including SDAI,...

Keywords: IL-6, Tocilizumab, Clinical, Efficacy

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

Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S.
Modern Rheumatology. 2015 Jul;25(4):514-21. doi: 10.3109/14397595.2014.995875.

The oral Janus kinase (JAK) inhibitor, Tofacitinib, preferentially inhibits signalling by heterodimeric receptors associated with JAK3 and/or JAK1, blocking signalling for several cytokines. The purpose of this study was to evaluate the efficacy of tofacitinib monotherapy versus placebo in Japanese patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARDs). Data on response rates – ACR20/50/70, DAS28-4(ESR), and HAQ-DI – laboratory parameters and adverse eve...

Keywords: JAK, Tofacitinib, Clinical, Phase 2

Efficacy and Safety of Tofacitinib as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis: A 12-Week, Randomized, Phase 2 Study

Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S.
Mod Rheumatol. 2014 Dec 11:1–25. [Epub ahead of print]

In Japan, the biologic DMARDs infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, as well as tocilizumab and abatacept are approved for use in patients with active RA and an inadequate response to existing therapies. However, not all patients respond to these therapies adequately, creating an unmet need for therapeutic options with alternative mechanisms of action. The oral JAK inhibitor tofacitinib has demonstrated efficacy as monotherapy or in combination with DMARDs for th...

Keywords: JAK, Tofacitinib, Clinical, Phase 2

Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve-month data from a twenty-four–month phase III randomized radiographic study

van der Heijde D, Tanaka Y, Fleischmann R, et al.
Arthritis & Rheumatism 2013; 65(3):559-70

The ORAL Scan trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This is the 12-month interim results published for the ORAL Scan study, a 24-month, phase 3 study that compared the effects of tofacitinib and placebo on structural preservation in patients with active RA despite methotrexate therapy. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to 5 or 10 mg tofaciti...

Keywords: JAK, Tofacitinib, Clinical, Phase 3