ORIGINAL RESEARCH

Safety and Efficacy of Tofacitinib in Patientswith Active Psoriatic Arthritis: Interim Analysisof OPAL Balance, an Open-Label, Long-TermExtension Study

Peter Nash . Laura C. Coates . Alan J. Kivitz . Philip J. Mease . Dafna D. Gladman .

Jose A. Covarrubias-Cobos . Oliver FitzGerald . Dona Fleishaker . Cunshan Wang .

Joseph Wu . Ming-Ann Hsu . Sujatha Menon . Lara Fallon . Ana Belen Romero . Keith S. Kanik

Received: February 21, 2020 / Published online: June 6, 2020� The Author(s) 2020

ABSTRACT

Introduction: Tofacitinib is an oral Januskinase inhibitor for the treatment of psoriaticarthritis (PsA). We report the interim safety,tolerability, and efficacy of tofacitinib in PsApatients in OPAL Balance, a 3-year, open-label,long-term extension study (data cut-off: August2017; database not locked, data may change).

Methods: Eligible patients from two phase (P) 3(P3) tofacitinib PsA studies (OPAL Broaden,NCT01877668; OPAL Beyond, NCT01882439)entered OPAL Balance B 3 months after com-pleting the P3 study or discontinuing for rea-sons other than study-drug-related adverseevents (AEs). Patients received open-labeltofacitinib 5 mg twice daily (BID), with adjust-ments to 10 mg BID permitted post-month(M) 1. Certain concomitant conventional syn-thetic disease-modifying antirheumatic drugswere allowed. Primary endpoints were inci-dence/severity of AEs and laboratory abnor-malities, and changes from baseline inlaboratory parameters (reported up to M36 andM30, respectively). Efficacy (clinical/patient-reported outcomes) was reported through M30.

Ana Belen Romero was affiliated with Pfizer Inc at thetime of analysis.

Digital Features To view digital features for this articlego to: https://doi.org/10.6084/m9.figshare.12163389.

Electronic Supplementary Material The onlineversion of this article (https://doi.org/10.1007/s40744-020-00209-4) contains supplementary material, which isavailable to authorized users.

P. NashSchool of Medicine, Griffith University, Brisbane,QLD, Australia

L. C. CoatesNuffield Department of Orthopaedics,Rheumatology and Musculoskeletal Sciences,University of Oxford, Oxford, UK

A. J. KivitzDepartment of Rheumatology, Altoona Center forClinical Research, Duncansville, PA, USA

P. J. MeaseSwedish Medical Center/Providence St JosephHealth and University of Washington, Seattle, WA,USA

D. D. GladmanDepartment of Medicine, University of Toronto andKrembil Research Institute, Toronto WesternHospital, Toronto, ON, Canada

J. A. Covarrubias-CobosUnidad Rheumatologica Las Americas S.C.P, Merida,Mexico

O. FitzGeraldConway Institute for Biomolecular Research, Schoolof Medicine, University College Dublin, Dublin,Ireland

Rheumatol Ther (2020) 7:553–580

https://doi.org/10.1007/s40744-020-00209-4

Results: A total of 686 patients were treated; atdata cut-off, 68.2% remained in the study.Mean (range) treatment duration was 641(1–1032) days; total treatment duration was1153.2 patient-years. By M36, 79.6, 13.8, and8.6% of patients reported AEs, serious AEs, anddiscontinuations due to AEs, respectively. Fivedeaths occurred; one within the risk period(incidence rate [IR; patients with events/100patient-years] 0.1). IRs for AEs of special interestwere: all (non-serious and serious) herpes zoster,1.7; serious infections, 0.9; opportunistic infec-tions, 0.3 (all disseminated/multi-dermatomalherpes zoster); malignancies excluding non-melanoma skin cancer (NMSC), 0.8; NMSC, 1.0;major adverse cardiovascular events, 0.3; pul-monary embolisms, 0.1; and arterial throm-boembolisms, 0.4. No patients had deep veinthrombosis. Alanine aminotransferase andaspartate aminotransferase levels were elevatedC 3-fold the upper limit of normal in 4.0 and2.2% of patients, respectively. Changes in lab-oratory parameters were generally stable overtime, although lymphocyte counts decreasedslightly. Efficacy was maintained through M30.Conclusions: In this interim analysis of OPALBalance, tofacitinib safety and efficacy inpatients with PsA appeared to be consistentwith those of the P3 studies. Efficacy wasmaintained over time.Trial Registration: ClinicalTrials.gov identifier:NCT01976364.

PLAIN LANGUAGE SUMMARY

In many countries, tofacitinib is an approvedmedicine that can be used to treat psoriaticarthritis (PsA). In the study reported here (OPALBalance), adult patients with PsA tooktofacitinib for up to 3 years. We report a plan-ned interim analysis, i.e., an analysis of infor-mation collected before the study finished. Thisearly information suggests that the safety oftofacitinib, and how well it improved symp-toms and quality of life (efficacy), was similar inthis long study as in shorter studies. Informa-tion from the finished study will be reportedlater. OPAL Balance started on 17 February2014. This interim analysis includes informa-tion collected by 31 August 2017. Before join-ing, patients had finished a 6-month or12-month tofacitinib study (OPAL Broaden orOPAL Beyond). Patients in OPAL Balance took a5 mg tofacitinib pill twice a day, but if PsAsymptoms did not improve after 1 month, theycould take a 10 mg pill twice a day. They couldalso take other medicines (includingmethotrexate or corticosteroids). Of the 686patients who took tofacitinib, 546 (80%) expe-rienced side effects over 3 years. These wereconsidered serious for 95 patients (14%) andcaused 59 patients (9%) to leave the study. Fivepatients died from causes not related totofacitinib. Known tofacitinib side effects,including shingles (herpes zoster), seriousinfections (needing hospitalization), infectionsin patients with weakened immune systems,cancer, heart (cardiovascular) problems, andvein blockages (embolisms), were each reportedby fewer than 20 patients. Most blood testresults and tofacitinib efficacy were stable over2.5 years.

Keywords: Long-term extension; Psoriaticarthritis; Tofacitinib

D. Fleishaker � C. Wang � J. Wu � M.-A. Hsu �S. Menon � K. S. KanikPfizer Inc, Groton, CT, USA

L. Fallon (&)Pfizer Inc, Montreal, QC, Canadae-mail: lara.fallon@pfizer.com

A. B. RomeroPfizer Inc, Barcelona, Spain

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Key Summary Points

Why carry out this study?

Psoriatic arthritis (PsA) is a chronic diseasethat requires long-term treatment.

Tofacitinib is an oral Janus kinaseinhibitor for the treatment of PsA.

This interim analysis of the OPAL Balancelong-term extension study reports thelong-term safety (up to month 36) andefficacy (up to month 30) of open-labeltofacitinib in patients with PsA.

What was learned from this study?

The long-term safety and efficacy oftofacitinib in patients with PsA appearedto be consistent with those of prior PsAphase 3 studies, and efficacy wasmaintained over time.

INTRODUCTION

Psoriatic arthritis (PsA) is a chronic, immune-mediated, inflammatory, musculoskeletal dis-ease, manifesting as peripheral arthritis, enthe-sitis, dactylitis, spondylitis, and skin and nailpsoriasis [1, 2]. Current pharmacologic thera-pies for PsA include conventional syntheticdisease-modifying antirheumatic drugs(csDMARDs; e.g., methotrexate [MTX]), bio-logic DMARDs (i.e., biologic inhibitors of tumornecrosis factor [TNFi], interleukin-12/23 andinterleukin-17, and cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin), andtargeted synthetic DMARDs (e.g., apremilastand Janus kinase [JAK] inhibitors) [3–5].

Tofacitinib is an oral JAK inhibitor for thetreatment of PsA. The efficacy and safety oftofacitinib 5 and 10 mg twice daily (BID) inpatients with PsA have been reported in twophase 3 randomized controlled trials: OPALBroaden (ClinicalTrials.gov identifier:NCT01877668), a 12-month study in patients

with PsA who were naıve to TNFi therapy andhad experienced an inadequate response to C 1csDMARD (422 patients randomized and trea-ted), and OPAL Beyond (ClinicalTrials.govidentifier: NCT01882439), a 6-month study inpatients with PsA who had experienced aninadequate response to C 1 TNFi therapy(395 patients randomized, 394 treated) [6, 7].

In both OPAL Broaden and OPAL Beyond,tofacitinib efficacy was superior to placebo atmonth 3 (end of the placebo-controlled period),as demonstrated by American College ofRheumatology (ACR) 20 response rates andmean changes from baseline in the HealthAssessment Questionnaire-Disability Index(HAQ-DI). Rates of adverse events (AEs) werenumerically more frequent with tofacitinibthan with placebo up to month 3 [6, 7].

Patients from OPAL Broaden and OPALBeyond were eligible to enter OPAL Balance(ClinicalTrials.gov identifier: NCT01976364), along-term extension (LTE) study designed toassess the long-term safety, tolerability, andefficacy of tofacitinib treatment in PsA. Twoprevious interim analyses of OPAL Balance haveshown that the long-term safety profile oftofacitinib in patients with PsA was generallysimilar to that of OPAL Broaden and OPALBeyond. Efficacy was maintained over time[8, 9].

In this third interim analysis of the OPALBalance study (data cut-off: 31 August 2017), wereport results on the long-term safety (up tomonth 36) and efficacy (up to month 30) oftofacitinib in adult patients with PsA.

METHODS

Study Design and Treatment

OPAL Balance is a phase 3, open-label LTE studyconducted in 124 centers across 16 countries. Itwas designed to evaluate the safety, tolerability,and efficacy of tofacitinib over 36 months inpatients with PsA who had previously partici-pated in the qualifying phase 3 studies OPALBroaden [6] and OPAL Beyond [7].

Patients in OPAL Broaden and OPAL Beyondwere randomized to receive tofacitinib

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5 mg BID, tofacitinib 10 mg BID, placeboadvancing to tofacitinib 5 or 10 mg BID after3 months, or adalimumab 40 mg subcuta-neously every 2 weeks (OPAL Broaden only).Upon entry into OPAL Balance, all patientsreceived open-label tofacitinib 5 mg BID,regardless of previous treatment in the qualify-ing studies (Electronic Supplementary Material[ESM] Fig. S1). Patients entering OPAL Balancefrom OPAL Broaden received the first dose ofopen-label tofacitinib C 1 week after the lastinjection of placebo or adalimumab. At themonth 1 visit and at additional visits, thetofacitinib dose could be increased to 10 mg BIDfor reasons of inadequate control of PsA symp-toms; the dose could subsequently be reducedback to 5 mg BID at any time due to safetyevents, at the investigator’s discretion. Con-comitant csDMARD treatment according tolocal standard-of-care, stable doses of concomi-tant oral corticosteroids (B 10 mg prednisonedaily or equivalent) or nonsteroidal anti-inflammatory drugs, or cyclo-oxygenase 2inhibitors were allowed, but not required.

All data retrieved up to and including 31August 2017 (study start date: 17 February 2014)were included in this interim analysis. Dataincluded in this analysis are not from a lockeddatabase; therefore, some values may changewith the final, locked study database.

The study was conducted in accordance withthe International Conference on Harmoniza-tion Good Clinical Practice guidelines, theprinciples of the Declaration of Helsinki, andapplicable local regulatory requirements andlaws. The study protocol was approved by theInstitutional Review Boards and/or Indepen-dent Ethics Committee at each study center (seeESM). An independent Data Safety MonitoringBoard external to the study sponsor reviewedsafety data on a cumulative basis, and SafetyEndpoint Adjudication Committees providedstandardized safety assessment for selectedevents. All patients provided written, informedconsent.

Patients

Full patient inclusion and exclusion criteria forthe qualifying studies have been reported pre-viously [6, 7]. In brief, patients eligible to enterOPAL Broaden and OPAL Beyondwere C 18 years of age (C 20 years in Taiwan),had been diagnosed with PsA for C 6 months,met the ClASsification criteria for PsoriaticARthritis (CASPAR) [10], and had active arthritisand plaque psoriasis at screening. Patients fromthese two studies were eligible to enter OPALBalance B 3 months after completing the qual-ifying study or discontinuing for reasons otherthan study-drug-related AEs. Patients whoenrolled into OPAL Balance[ 14 days after theend of the study visit of the qualifying studymust have had sufficient evidence of PsA diseaseactivity to warrant the use of tofacitinib, dis-continued all disallowed concomitant medica-tions, and had no evidence of active, latent, orinadequately treated infection with Mycobac-terium tuberculosis. Additional exclusion criteriafor these patients included the following labo-ratory assessments at the LTE screening visitor B 3 months prior to the LTE baseline visit:evidence of hematopoietic disorders or evidenceof hemoglobin levels\10 g/dL; absolute whiteblood cell count of\3.0 9 103/mm3; absoluteneutrophil count (ANC) of B 1.5 9 103/mm3;absolute lymphocyte count (ALC) of\1.0 9 103/mm3; and platelet count of\100 9 103/mm3. The following laboratoryassessments at the LTE screening visit only werealso considered as exclusion criteria for patientswho enrolled in OPAL Balance[ 14 daysafter the end of the qualifying study:estimated creatinine clearance\ 40 mL/min(Cockcroft–Gault equation); and total bilirubin,alanine aminotransferase (ALT), or aspartateaminotransferase (AST) [1.5-fold the upperlimit of normal (ULN).

Trial Objectives and Interim AnalysisEndpoints

The primary objective of OPAL Balance was toevaluate the long-term safety and tolerability oftofacitinib in adult patients with PsA.

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Evaluating the long-term efficacy of tofacitinibwas a secondary objective.

The primary endpoints included in thisinterim analysis were the incidence and severityof AEs, the incidence of laboratory abnormali-ties, and changes from baseline in laboratoryparameters during treatment. AEs were reportedup to month 36, including serious AEs (SAEs),severe AEs (AEs that interfere significantly witha patient’s usual function), discontinuationsand dose reductions due to AEs, deaths, and AEsof special interest (herpes zoster, serious infec-tions, tuberculosis [TB], opportunistic infec-tions, gastrointestinal perforations, interstitiallung disease, inflammatory bowel disease,malignancies [all malignancies, malignanciesexcluding non-melanoma skin cancer (NMSC),and NMSC], major adverse cardiovascularevents [MACE], venous thromboembolism[VTE] events [pulmonary embolism (PE) anddeep vein thrombosis (DVT)], and arterialthromboembolism (ATE) events]. PE, DVT, andATE events were based on selected events in anarrow Standardized Medical Dictionary forRegulatory Activities (MedDRA) Query (SMQ)for embolic and thrombotic events. Laboratoryabnormalities (elevations in ALT and AST, andthe proportions of patients meeting discontin-uation criteria) were reported up to month 36.Changes from baseline in laboratory parameterswere reported up to month 30 and includedALT, AST, hemoglobin, ALC, ANC, creatinine,and creatine kinase assessed at months 1 and 3,and every 3 months thereafter. Percentagechanges from baseline in absolute CD16?56cells (a subset of lymphocytes) were assessed atmonth 3, and every 3 months thereafter untilmonth 30. Percentage changes from baseline inhigh-density lipoprotein cholesterol (HDL-cholesterol), low-density lipoprotein cholesterol(LDL-cholesterol), total cholesterol, andtriglycerides were assessed in patients atmonths 3 and 6, and every 6 months thereafteruntil month 30, during visits requiring fastinglipid panels. Absolute mean values for theselaboratory parameters were also reported up tomonth 30 (ESM Fig. S2).

Secondary and other endpoints reported inthis interim analysis included the efficacy datalisted here, and these were reported up to

month 30 (as sample sizes were too small[N B 50] for meaningful analysis beyond thispoint). Rheumatologic and dermatologic end-points included: response rates of ACR20,ACR50, and ACR70 (the percentages of patientsreporting a C 20%, C 50%, and C 70%improvement, respectively, in ACR criteria);Psoriatic Arthritis Response Criteria (PsARC;improvement in two of the following four cri-teria, one of which must be joint pain or swel-ling, without worsening in any measure: C 30%improvement in tender joint counts [68 joints]or swollen joint counts [66 joints], and C 20%improvement in Patient or Physician GlobalAssessment of Arthritis) [11]; Psoriasis Area andSeverity Index 75% improvement (PASI75; thepercentage of patients reporting a C 75%improvement in PASI, calculated in patientswith plaque psoriasis affecting C 3% of bodysurface area at baseline and with a baseline PASIscore [ 0); and changes from baseline inPhysician Global Assessment of Psoriasis (PGA-PsO; range: 0 [clear] to 4 [severe]; assessed inpatients with baseline PGA-PsO [ 0), LeedsEnthesitis Index (LEI; range 0–6; higher scoresindicate more affected sites; assessed in patientswith baseline LEI [ 0), and Dactylitis SeverityScore (DSS; range 0–60; higher scores indicategreater severity; assessed in patients with base-line DSS [ 0). Composite endpoints included:rates of achievement of minimal disease activity(MDA; defined as a patient meeting at least fiveof the seven MDA criteria) [12]; and changesfrom baseline in Disease Activity in PsoriaticArthritis (DAPSA; higher scores indicate higherdisease activity), Composite Psoriasis DiseaseActivity Index (CPDAI; range 0–15; higherscores indicate more severe disease activity;calculated in patients with plaque psoriasisaffecting C 3% of body surface area at baseline),and Psoriatic ArthritiS Disease Activity Score(PASDAS; higher scores indicate higher diseaseactivity). The following patient-reported out-comes (PROs) were also assessed: rates ofHAQ-DI response (decrease from baseline inHAQ-DI C 0.35; assessed in patients with base-line HAQ-DI C 0.35); and changes from base-line in HAQ-DI (range 0–3; higher scoresindicate greater disability), Patient Assessmentof Arthritis Pain (Pain; Visual Analog Scale [VAS]

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0–100 mm; higher scores indicate more severearthritis pain), Functional Assessment ofChronic Illness Therapy-Fatigue (FACIT-F) totalscore (range 0–52; lower scores indicate morefatigue), Dermatology Life Quality Index (DLQI;range 0–30; higher values indicate a greaterimpact on quality of life), Short Form-36 HealthSurvey Version 2 (SF-36v2) Physical ComponentSummary (PCS) and Mental Component Sum-mary (MCS) scores and eight norm-baseddomain scores (physical functioning, role-physical, bodily pain, general health, vitality,social functioning, role-emotional, and mentalhealth; lower scores indicate a worse healthoutcome), and EuroQol five dimensions, threelevels (EQ-5D-3L) dimension scores (mobility,self-care, usual activities, pain/discomfort, anx-iety/depression; higher scores indicate greaterimpact on dimension) and EQ-VAS (‘‘Your ownhealth state today’’ measured using a VAS0–100 mm; lower scores indicate a worse healthstate).

Statistical Analysis

This was an open-label study with no formalhypothesis testing. Safety and efficacy end-points were summarized using a singletofacitinib group (all tofacitinib group), whichincluded all patients who received at least onedose of tofacitinib in OPAL Balance. This wasthe main analysis group, since patients wereable to switch tofacitinib doses between 5 and10 mg BID per the investigator’s discretion, aspermitted by the study protocol. For all efficacyand safety endpoints, only observed values wereused, and no imputation was applied to missingvalues.

To provide information on potential dose-related effects, post-hoc analyses, includingaverage total daily dose (ATDD; i.e., sum of totaldaily doses of tofacitinib received divided by thenumber of days of treatment) and constantdaily dose were also performed based on treat-ment assignment algorithms. The averagetofacitinib 5 mg BID and average tofacitinib10 mg BID groups included all patients whoreceived an ATDD of\ 15 mg and C 15 mg,respectively, from day 1 through the data cut-

off in OPAL Balance. The constant tofacitinib5 mg BID group included all patients in thestudy who started on tofacitinib 5 mg BID andstayed on tofacitinib 5 mg BID (as per sponsor’ssmoothing algorithm), until switching totofacitinib 10 mg BID or discontinuing thestudy. Exposure and events captured after adose switch were excluded from the analysis.Therefore, unlike the all tofacitinib group,which included all exposure and eventsregardless of whether patients switchedbetween tofacitinib 5 and 10 mg BID duringOPAL Balance, the constant tofacitinib 5 mg BIDgroup represented a group of patients who onlyreceived tofacitinib 5 mg BID during their par-ticipation in OPAL Balance.

Patient demographics, baseline disease char-acteristics, and baseline values for all efficacy orhealth outcome endpoints came from thebaseline of the qualifying study (OPAL Broadenor OPAL Beyond), disregarding the enrollmentgap. For safety endpoints, baseline values fromthe qualifying study were used for patients whoenrolled B 14 days after the final visit of thequalifying study, whereas baseline values fromOPAL Balance were used for patients whoenrolled[14 days after the final visit of thequalifying study.

Incidence rates (IRs) were calculated forSAEs, discontinuations due to AEs, deaths, andselected AEs of special interest. These wereexpressed as the number of patients with eventsper 100 patient-years (PY) and were estimatedby dividing the number of patients with eventsduring their risk periods by the sum of exposuretimes of patients during the risk period, thenmultiplying it by 100 (exposure times being thetime from exposure to treatment to the firstevent for patients with event, or to the end ofthe risk period for patients without event, inPY). The risk period was defined as the timefrom exposure to treatment to the patient’s lastdose plus 28 days or to the date of last obser-vation, whichever was earlier. This approachprovided exposure-adjusted IRs that accountedfor differing follow-up times between patientsand quantified the risk of developing an eventduring the treatment and immediate post-treatment (up to 28 days) periods. Inclusion ofall events (numerator) without regard to elapsed

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time may inflate IR estimations because theexposure time (denominator) is not similarlyincreased. The 95% confidence intervals (CIs) ofIRs were calculated based on Exact Poisson dis-tribution. Any events that occurred outside therisk period, although not included in the cal-culation of IRs, were summarized forcompleteness.

RESULTS

Patients

In total, 686 patients were treated in OPALBalance (363 patients from OPAL Broaden, 323from OPAL Beyond). At the data cut-off for thisinterim analysis (31 August 2017), 468 (68.2%)patients remained in the study, 190 (27.7%)patients had discontinued, and 28 (4.1%)patients had completed 36 months of treatment(ESM Fig. S3); the mean (range) duration oftofacitinib treatment for the all tofacitinibgroup was 614 (1–1032) days. The total durationof tofacitinib treatment was 1153.2 PY for theall tofacitinib group (Table 1). Six patients didnot receive tofacitinib 5 mg BID at studyentry due to protocol deviations; therefore,680 patients were included in the constanttofacitinib 5 mg BID group, and the total dura-tion of tofacitinib treatment (constant tofaci-tinib 5 mg BID) was 686.9 PY in this group.Overall, the most common reasons for patientsdiscontinuing from the study included thatthey were no longer willing to participate (58/190 patients [30.5%]), had insufficient clinicalresponse (37/190 patients [19.5%]), had an AErelated to the study drug (33/190 patients[17.4%]), or had an AE not related to the studydrug (21/190 [11.1%]). Additional reasons fordiscontinuation included patients that were lostto follow-up (9/190 [4.7%]), had protocol vio-lations (8/190 [4.2%]), died (4/190 [2.1%]),withdrew due to pregnancy (4/190 [2.1%]), nolonger met eligibility criteria (2/190 [1.1%]),had a medication error without associated AE(1/190 [0.5%]), or discontinued due to ‘other’reasons (13/190 [6.8%]).

Patient demographics and baseline diseasecharacteristics (from the qualifying studies) are

shown in Table 1. In the all tofacitinib group,the mean duration of PsA was 7.6 years. Aslightly lower proportion of patients in theaverage tofacitinib 10 mg BID group (15.8%)received oral corticosteroids on day 1 of OPALBalance, compared with the average tofacitinib5 mg BID (21.6%) and constant tofacitinib5 mg BID groups (19.1%). Most patients(675 [98.4%]) were receiving concomitantcsDMARDs on day 1 of OPAL Balance (mostcommonly MTX); 86 (12.7%) later discontinuedand did not restart csDMARD treatment. Meandoses of concomitant oral corticosteroids andMTX were 6.4 mg/day and 18.5 mg/week,respectively, for the all tofacitinib group; doseswere similar across all treatment groups. Of the686 patients in OPAL Balance, 21 (3.1%)enrolled[14 days after the end of study visit ofthe qualifying study; therefore, baseline valuesfor safety endpoints for these patients weretaken from the LTE screening visit.

Safety

Treatment-Emergent AEs and SAEsIn the all tofacitinib group, 2189 all-causalityAEs were reported in 546 (79.6%) patients up tomonth 36; 95 (13.8%) patients reported SAEs,73 (10.6%) experienced severe AEs, 59 (8.6%)discontinued due to AEs, and 212 (30.9%)reduced their dose or temporarily discontinuedtofacitinib due to AEs. The IR (95% CI) for SAEsoccurring within the risk period was7.8 (6.2–9.6) per 100 PY for the all tofacitinibgroup (Table 2); IRs were generally similar acrossthe other treatment groups, with overlapping95% CIs. The IR (95% CI) for discontinuationsdue to AEs during the risk period was 3.8(2.7–5.1) per 100 PY for the all tofacitinib group;IRs (95% CI) per 100 PY were numerically lowerin the average tofacitinib 10 mg BID group(2.0 [1.0–3.7]) than in the average tofacitinib5 mg BID group (5.1 [3.5–7.1]), with 95% CIsmarginally overlapping (Table 2). AEs thatoccurred in C 5% of all tofacitinib patientsincluded upper respiratory tract infection,nasopharyngitis, urinary tract infection, bron-chitis, and hypertension (ESM Table S1).

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Table 1 Patient demographics and baseline disease characteristics

Patient demographics andbaseline diseasecharacteristicsa

All tofacitinibdoses(N = 686)

Average tofacitinib5 mg BIDb

(N = 407)

Average tofacitinib10 mg BIDb

(N = 279)

Constant tofacitinib5 mg BIDc

(N = 680)

Total duration,d PY 1153.2 664.2 489.1 686.9

Demographics

Age (years), mean (SD) 48.8 (11.8) 49.4 (11.8) 48.0 (11.7) 48.8 (11.8)

Female, n (%) 370 (53.9) 224 (55.0) 146 (52.3) 367 (54.0)

White, n (%) 646 (94.2) 384 (94.3) 262 (93.9) 641 (94.3)

BMI (kg/m2), mean (SD) 29.6 (6.1) 29.6 (6.2) 29.7 (5.9) 29.7 (6.1)

Smoking history, n (%)

Never smoked 431 (62.8) 258 (63.4) 173 (62.0) 429 (63.1)

Smoker 121 (17.6) 82 (20.1) 39 (14.0) 118 (17.4)

Ex-smoker 134 (19.5) 67 (16.5) 67 (24.0) 133 (19.6)

Baseline disease characteristics

Duration of PsA (years),

mean (SD)

7.6 (7.2) 7.7 (7.4) 7.5 (6.8) 7.6 (7.2)

Tender joint count (68),

mean (SD)

20.8 (14.4) 19.5 (13.5) 22.8 (15.3) 20.8 (14.4)

Swollen joint count (66),

mean (SD)

11.9 (9.6) 10.9 (8.7) 13.2 (10.7) 11.9 (9.6)

Plaque psoriasis affecting

body surface area C 3%,

n (%)

475 (69.2) 286 (70.3) 189 (67.7) 472 (69.4)

PASI,e median (range)

[N1]7.3 (0.3–66.0)

[474]

6.3 (0.3–66.0)

[285]

8.8 (0.9–46.0)

[189]

7.2 (0.3–66.0)

[471]

Presence of enthesitis

(LEI[ 0), n (%)

458 (66.8) 264 (64.9) 194 (69.5) 453 (66.6)

LEI,f mean (SD) [N2] 2.8 (1.6) [458] 2.5 (1.4) [264] 3.3 (1.7) [194] 2.8 (1.6) [453]

Presence of dactylitis

(DSS[ 0), n (%)

366 (53.4) 206 (50.6) 160 (57.3) 363 (53.4)

DSS,g mean (SD) [N3] 8.4 (8.2) [366] 8.1 (8.0) [206] 8.9 (8.4) [160] 8.4 (8.2) [363]

HAQ-DI, mean (SD) 1.2 (0.7) 1.2 (0.7) 1.2 (0.7) 1.2 (0.7)

CRP[ 2.87 mg/L, n (%) 416 (60.6) 241 (59.2) 175 (62.7) 413 (60.7)

CRP, mean (SD) 11.9 (20.5) 11.2 (18.9) 12.8 (22.6) 11.9 (20.6)

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Table 1 continued

Patient demographics andbaseline diseasecharacteristicsa

All tofacitinibdoses(N = 686)

Average tofacitinib5 mg BIDb

(N = 407)

Average tofacitinib10 mg BIDb

(N = 279)

Constant tofacitinib5 mg BIDc

(N = 680)

Concomitant oral

corticosteroid use, n (%)

132 (19.2) 88 (21.6) 44 (15.8) 130 (19.1)

Oral corticosteroid dose

(mg/day),h mean (SD) [N4]6.4 (2.7) [131] 6.2 (2.5) [87] 6.7 (3.1) [44] 6.4 (2.7) [129]

Concomitant csDMARD

use, n (%)

675 (98.4) 398 (97.8) 277 (99.3) 669 (98.4)

Methotrexate 548 (79.9) 330 (81.1) 218 (78.1) 543 (79.9)

Methotrexate dose (mg/

week),h mean (SD) [N4]18.5 (7.0) [481] 18.7 (7.0) [296] 18.1 (6.8) [185] 18.5 (7.0) [475]

Otheri,j 128 (18.7) 68 (16.7) 60 (21.5) 127 (18.7)

Baseline diabetes mellitus,

n (%)

88 (12.8) 54 (13.3) 34 (12.2) 87 (12.8)

Baseline hypertension, n (%) 255 (37.2) 158 (38.8) 97 (34.8) 254 (37.4)

Baseline metabolic

syndrome,k n (%)

279 (40.7) 170 (41.8) 109 (39.1) 277 (40.7)

ATDD average total daily dose, BID twice daily, BMI body mass index, CRP C-reactive protein, csDMARD conventionalsynthetic disease-modifying antirheumatic drug, DSS Dactylitis Severity Score, HAQ-DI Health Assessment Questionnaire-Disability Index, HDL high-density lipoprotein, LEI Leeds Enthesitis Index, PASI Psoriasis Area and Severity Index,PsA psoriatic arthritis, PY patient-years, SD standard deviationa Baseline demographics and disease characteristics were taken from the baseline of the qualifying study (OPAL Beyond orOPAL Broaden). Concomitant medications were those taken on day 1 of OPAL Balance. N is the number of patients ineach treatment groupb Average dosing was based on an ATDD of tofacitinib: patients who received an ATDD\ 15 mg/day were assigned tothe average tofacitinib 5 mg BID group; patients who received an ATDD C 15 mg/day were assigned to the averagetofacitinib 10 mg BID groupc Constant tofacitinib 5 mg BID included all patients who started OPAL Balance on tofacitinib 5 mg BID and stayed ontofacitinib 5 mg BID (as per sponsor’s smoothing algorithm) until switching to tofacitinib 10 mg BID or discontinuing the study.Assessments (including exposure and adverse events) after a dose switch to tofacitinib 10 mg BID were excluded from the analysisd Total duration (in PY) is calculated as the sum of durations of treatment in days across all patients in a group divided by365.25. Duration of treatment (in days) is defined as date of last dose - date of first dose ? 1e Among patients with plaque psoriasis affecting body surface area C 3% and PASI[ 0 at baseline, denoted as N1f Among patients with LEI[ 0 at baseline, denoted as N2g Among patients with DSS[ 0 at baseline, denoted as N3h Among patients evaluable for the dosing summary, denoted as N4i ‘Other’ concomitant csDMARDs used on day 1 were chloroquine, hydroxychloroquine, leflunomide, and sulfasalazinej In total, 128 patients used ‘other’ csDMARDs on day 1, with one patient taking two different ‘other’ csDMARDsk Meets metabolic syndrome definition by meeting C 3 of 5 criteria: abdominal obesity based on elevated waist circum-ference; triglyceride C 150 mg/dL and/or concomitant lipid-lowering agent taken; HDL-cholesterol\ 40 mg/dL formales and\ 50 mg/dL for females; systolic blood pressure C 130 mmHg and/or diastolic blood pressure C 85 mmHgand/or concomitant anti-hypertensive drug treatment taken; and glucose C 100 mg/dL and/or concomitant anti-diabeticdrug treatment taken

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DeathsThere were five deaths reported up to month 36in the all tofacitinib group (Table 2); four of thefive deaths occurred after the 28-day risk period(one death due to chronic obstructive pul-monary disease [COPD] occurred within the riskperiod). The IR (95% CI) for deaths occurringwithin the risk period in the all tofacitinibgroup was 0.1 (0.0–0.5) per 100 PY (Table 2).The causes of death were acute cardiac failuresecondary to hypertensive heart disease, car-diovascular insufficiency leading to suddencardiac death, COPD, pancreatic adenocarci-noma, and PE (all n = 1; ESM Table S2). Thepatients who died from acute cardiac failure andcardiovascular insufficiency both had a historyof hypercholesterolemia and hypertension; thepatient with cardiovascular insufficiency alsohad diabetes mellitus. The patient who diedfrom COPD discontinued tofacitinib uponexacerbation of COPD. Of the patients who diedoutside the 28-day risk period, only one patientdiscontinued tofacitinib because of the condi-tion that caused their death (pancreatic adeno-carcinoma). The patient who died from acutecardiac failure (following post-elective surgeryfor myocardial infarction) had discontinuedtofacitinib due to an infection, while thepatient with a PE was reported to have discon-tinued tofacitinib due to non-serious AEs ofviral upper respiratory tract infection and lowerrespiratory tract infection. The reason for dis-continuation of tofacitinib for the patient whodied from cardiovascular insufficiency isunknown.

AEs of Special InterestThe IRs for select AEs of special interest occur-ring within the risk period up to month 36 arereported in Table 2.

The IR (95% CI) for all (non-serious andserious) herpes zoster was 1.7 (1.0–2.6) per100 PY for the all tofacitinib group, which wasgenerally similar across the other treatmentgroups (overlapping 95% CI). Of the 19 patientsin the all tofacitinib group who reported herpeszoster within the risk period, one case of facialherpes zoster was an SAE. This event occurredon day 83 in a 67-year-old white male patientwho had previously completed 11 months of

treatment with tofacitinib 5 mg BID in OPALBroaden and was receiving the same dose inOPAL Balance; tofacitinib treatment was per-manently discontinued, and the event subse-quently resolved. One severe event of herpeszoster occurred in a 61-year-old white femalepatient who had previously completed5 months of treatment with tofacitinib5 mg BID in OPAL Beyond and was receivingthe same dose in OPAL Balance at the onset ofthe event on day 43; tofacitinib was temporarilydiscontinued, and the event resolved. Fourpatients with herpes zoster, including threepatients with multi-dermatomal herpes zosterand one with disseminated herpes zoster, wereadjudicated as having opportunistic infections(IR 0.3, 95% CI 0.1–0.9); these were the onlyopportunistic infections reported in the study.Five patients with herpes zoster were receivingconcomitant glucocorticoids; none of thesepatients had adjudicated opportunistic infec-tions. In the all tofacitinib group, 11 patientsreported serious infections within the risk per-iod, with an IR (95% CI) of 0.9 (0.5–1.7) per 100PY; this was generally similar across the othertreatment groups (overlapping 95% CI). Fourpatients (one of whom was living in Russia, acountry with a high burden of TB [13]), reportedAEs of latent TB where a previously negativeQuantiFERON response became positive; nocases of active TB were reported.

In the all tofacitinib group, the IR (95% CI)for adjudicated malignancies (excluding NMSC)was 0.8 (0.4–1.5) per 100 PY, and the IR(95% CI) for NMSC was 1.0 (0.5–1.7) per 100 PY.These were generally similar across the othertreatment groups (95% CI overlapping), withthe exception that the IR (95% CI) per 100 PYfor malignancies (excluding NMSC) for theaverage tofacitinib 10 mg BID group(0.2 [0.0–1.1]) was numerically lower than thatfor the average tofacitinib 5 mg BID group(1.2 [0.5–2.3]), with 95% CI marginally over-lapping. These malignancies (20 in total,including NMSC, in the all tofacitinib groupwithin the risk period) included one case ofpancreatic adenocarcinoma (diagnosed on day85 of tofacitinib treatment in OPAL Balance,after 12 months of adalimumab treatment inthe OPAL Broaden qualifying study; the patient

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Table 2 Incidence rates for all-causality serious adverse events, discontinuations due to adverse events, deaths, and selectadverse events of special interest occurring within the risk period up to month 36

Safety outcomesa All tofacitinibdoses(N = 686)

Average tofacitinib5 mg BIDb

(N = 407)

Average tofacitinib10 mg BIDb

(N = 279)

Constant tofacitinib5 mg BIDc

(N = 680)

SAEsd

n (%) 85 (12.4) 51 (12.5) 34 (12.2) 48 (7.1)

Total PY exposure, years 1093.3 631.5 461.8 659.7

IR (95% CI), per 100 PY 7.8 (6.2–9.6) 8.1 (6.0–10.6) 7.4 (5.1–10.3) 7.3 (5.4–9.7)

n1 (%) 9 (1.3) 6 (1.5) 3 (1.1) 5 (0.7)

Discontinuations due to AEse

n (%) 44 (6.4) 34 (8.4) 10 (3.6) 29 (4.3)

Total PY exposure, years 1167.1 671.9 495.2 693.9

IR (95% CI), per 100 PY 3.8 (2.7–5.1) 5.1 (3.5–7.1) 2.0 (1.0–3.7) 4.2 (2.8–6.0)

n1 (%) 15 (2.2) 10 (2.5) 5 (1.8) 8 (1.2)

Deaths

n (%) 1 (0.1) 1 (0.2) 0 1 (0.1)

Total PY exposure, years 1169.6 673.9 495.7 695.5

IR (95% CI), per 100 PY 0.1 (0.0–0.5) 0.2 (0.0–0.8) 0.0 (0.0–0.7) 0.1 (0.0–0.8)

n1 (%) 4 (0.6) 4 (1.0) 0 3 (0.4)

Herpes zoster (non-serious and serious)

n (%) 19 (2.8) 10 (2.5) 9 (3.2) 9 (1.3)

Total PY exposure, years 1149.0 663.3 485.7 687.8

IR (95% CI), per 100 PY 1.7 (1.0–2.6) 1.5 (0.7–2.8) 1.9 (0.9–3.5) 1.3 (0.6–2.5)

n1 (%) 1 (0.1) 1 (0.2) 0 1 (0.1)

Serious infections

n (%) 11 (1.6) 7 (1.7) 4 (1.4) 6 (0.9)

Total PY exposure, years 1167.7 672.9 494.8 694.6

IR (95% CI), per 100 PY 0.9 (0.5–1.7) 1.0 (0.4–2.1) 0.8 (0.2–2.1) 0.9 (0.3–1.9)

n1 (%) 1 (0.1) 0 1 (0.4) 0

Adjudicated opportunistic infections

n (%) 4 (0.6) 1 (0.2) 3 (1.1) 1 (0.1)

Total PY exposure, years 1166.3 672.2 494.1 693.8

IR (95% CI), per 100 PY 0.3 (0.1–0.9) 0.2 (0.0–0.8) 0.6 (0.1–1.8) 0.1 (0.0–0.8)

n1 (%) 0 0 0 0

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Table 2 continued

Safety outcomesa All tofacitinibdoses(N = 686)

Average tofacitinib5 mg BIDb

(N = 407)

Average tofacitinib10 mg BIDb

(N = 279)

Constant tofacitinib5 mg BIDc

(N = 680)

Adjudicated malignancies (excluding NMSC)

n (%) 9 (1.3) 8 (2.0) 1 (0.4) 6 (0.9)

Total PY exposure, years 1168.7 673.3 495.4 695.2

IR (95% CI), per 100 PY 0.8 (0.4–1.5) 1.2 (0.5–2.3) 0.2 (0.0–1.1) 0.9 (0.3–1.9)

n1 (%) 3 (0.4) 2 (0.5) 1 (0.4) 1 (0.1)

Adjudicated NMSC

n (%) 11 (1.6) 7 (1.7) 4 (1.4) 7 (1.0)

Total PY exposure, years 1157.9 665.0 492.9 687.3

IR (95% CI), per 100 PY 1.0 (0.5–1.7) 1.1 (0.4–2.2) 0.8 (0.2–2.1) 1.0 (0.4–2.1)

n1 (%) 1 (0.1) 1 (0.2) 0 1 (0.1)

Adjudicated MACE

n (%) 3 (0.4) 2 (0.5) 1 (0.4) 2 (0.3)

Total PY exposure, years 1167.6 672.2 495.4 694.5

IR (95% CI), per 100 PY 0.3 (0.1–0.8) 0.3 (0.0–1.1) 0.2 (0.0–1.1) 0.3 (0.0–1.0)

n1 (%) 2 (0.3) 2 (0.5) 0 1 (0.1)

PEf

n (%) 1 (0.1) 1 (0.2) 0 (0.0) 1 (0.1)

Total PY exposure, years 1168.7 673.0 495.7 694.7

IR (95% CI), per 100 PY 0.1 (0.0–0.5) 0.2 (0.0–0.8) 0.0 (0.0–0.7) 0.1 (0.0–0.8)

n1 (%) 1 (0.1) 1 (0.2) 0 1 (0.1)

DVTf

n (%) 0 0 0 0

Total PY exposure, years 1169.6 673.9 495.7 695.5

IR (P95% CI), per 100 PY 0.0 (0.0–0.3) 0.0 (0.0–0.6) 0.0 (0.0–0.7) 0.0 (0.0–0.5)

n1 (%) 0 0 0 0

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received concomitant MTX during OPAL Bal-ance) and one case of non-Hodgkin’s B-celllymphoma (day 585 of treatment in OPAL Bal-ance, after 11 months of tofacitinib 5 mg BIDtreatment in OPAL Broaden; the patient alsoreceived MTX in OPAL Broaden but switched tosulfasalazine due to lack of efficacy, and thepatient later discontinued sulfasalazine in OPALBroaden due to improvement).

The IR (95% CI) of adjudicated MACE was0.3 (0.1–0.8) per 100 PY in the all tofacitinibgroup, which was generally similar across theother treatment groups (overlapping 95% CI).In the all tofacitinib group, three non-fatalMACE occurred within the risk period; thesewere myocardial infarction, ischemic stroke,and stress cardiomyopathy. Two fatal cases of

MACE occurred outside the risk period; thesewere acute cardiac failure and cardiovascularinsufficiency.

In the all tofacitinib group, the IR (95% CI)of PE was 0.1 (0.0–0.5) per 100 PY, with onepatient experiencing a non-fatal PE within therisk period. This patient, a 66-year-old whitemale, was also included in the averagetofacitinib 5 mg BID and constant tofacitinib5 mg BID groups. The patient had previouslyreceived tofacitinib 10 mg BID in OPALBroaden. He experienced a PE on day 439, washospitalized, and temporarily discontinuedtofacitinib 5 mg BID; once he had recovered(day 448), the patient was discharged from thehospital and resumed tofacitinib treatment. Itwas noted that two of the patient’s brothers had

Table 2 continued

Safety outcomesa All tofacitinibdoses(N = 686)

Average tofacitinib5 mg BIDb

(N = 407)

Average tofacitinib10 mg BIDb

(N = 279)

Constant tofacitinib5 mg BIDc

(N = 680)

ATEf

n (%) 5 (0.7) 2 (0.5) 3 (1.1) 2 (0.3)

Total PY exposure, years 1163.3 671.3 492.0 693.9

IR (95% CI), per 100 PY 0.4 (0.1–1.0) 0.3 (0.0–1.1) 0.6 (0.1–1.8) 0.3 (0.0–1.0)

n1 (%) 0 (0.0) 0 (0.0) 0 (0.0) 3 (0.4)

AE adverse event, ATDD average total daily dose, ATE arterial thromboembolism, BID twice daily, CI confidence interval,DVT deep vein thrombosis, IR incidence rate,MACE major adverse cardiovascular events,MedDRAMedical Dictionary forRegulatory Activities, NMSC non-melanoma skin cancer, PE pulmonary embolism, PY patient-years, SAE serious adverseevent, SMQ Standardized MedDRA Querya Crude IRs (number of patients with events per 100 PY) were calculated by the inclusion of events occurring within therisk period, defined as time from first dose to 28 days after the last tofacitinib dose or the last observation date, whicheverwas shorter. The total PY exposure was the denominator for the IR calculation. n is the number of patients with an eventwithin the risk period; these patients are included in the IR calculations. n1 is the number of patients with an event outsidethe risk period; these patients are not included in the IR calculations. N is the number of patients in each treatment groupb Average dosing was based on an ATDD of tofacitinib: patients who received an ATDD\ 15 mg/day were assigned tothe average tofacitinib 5 mg BID group; patients who received an ATDD C 15 mg/day were assigned to the averagetofacitinib 10 mg BID groupc Constant tofacitinib 5 mg BID included all patients who started OPAL Balance on tofacitinib 5 mg BID and stayed ontofacitinib 5 mg BID (as per sponsor’s smoothing algorithm) until switching to tofacitinib 10 mg BID or discontinuing the study.Assessments (including exposure and adverse events) after dose switch to tofacitinib 10 mg BID were excluded from the analysisd One male patient reported that his partner experienced a spontaneous abortion; this SAE has not been included in thistable because it was not reported in a treated patiente Includes four patients who withdrew due to maternal exposure and three patients who died; excludes one patient who hadan AE that was not considered as treatment emergent and one patient who had missing dataf The events were based on selected events in narrow SMQ for embolic and thrombotic events

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died from PE, but investigations for coagulopa-thy disorders had not been carried out in eitherthe patient or his brothers. One fatal PE occur-red outside the risk period in a 45-year-oldfemale patient in the average tofacitinib5 mg BID and constant tofacitinib 5 mg BIDgroups. The patient had previously receivedtofacitinib 5 mg BID in OPAL Beyond. Thepatient had developed non-serious AEs of viralupper respiratory tract infection and lower res-piratory tract infection, which reportedly led tothe temporary discontinuation of tofacitinib5 mg BID on day 170; 29 days after discontinu-ing tofacitinib, the patient experienced the PE(considered to be the result of deep veinembolism) and died. The IR (95% CI) for ATEevents was 0.4 (0.1–1.0) for the all tofacitinibgroup; of the total of five patients withATE events, two were in the average tofacitinib5 mg BID group and three in the averagetofacitinib 10 mg BID group.

Finally, there were no reports of DVT, gas-trointestinal perforations, interstitial lung dis-ease, or inflammatory bowel disease.

Laboratory ParametersIn the all tofacitinib, average tofacitinib5 mg BID, average tofacitinib 10 mg BID, andconstant tofacitinib 5 mg BID groups, ALTwas elevated C 3-fold the ULN in 27 (4.0%),19 (4.7%), 8 (2.9%), and 14 (2.4%) patients,respectively, while AST was elevated C 3-foldthe ULN in 15 (2.2%), 10 (2.5%), 5 (1.8%), and9 (1.5%) patients, respectively (ESM Table S3).

Up to month 36, in the all tofacitinib group,seven (1.0%) patients met any protocol criteriafor discontinuing the study due to changes inlaboratory parameters: one patient due to twosequential hemoglobin values of\8.0 g/dL ordecreases of[ 30% from baseline value; onepatient due to two sequential plateletcounts\ 75 9 103/mm3; one patient due totwo sequential increases in serum crea-tinine[50% and an increase[0.5 mg/dL overthe average of screening and baseline; onepatient due to two sequential ALT or AST ele-vations C 5-fold the ULN regardless of total

bilirubin or accompanying signs or symptoms;two patients due to a confirmed positive urinepregnancy test; and one patient due to multiplecriteria, including two sequential ALT or ASTelevations C 5-fold the ULN regardless of totalbilirubin or accompanying signs or symptoms,two sequential ALT or AST elevations C 3-foldthe ULN with at least one total bilirubinvalue[2-fold the ULN, and two sequential ALTor AST elevations C 3-fold the ULN, accompa-nied by signs or symptoms consistent withhepatic injury. Additionally, 17 (2.5%) patientsmet the monitoring criterion of a creatinekinase elevation[ 5-fold the ULN; however, nopatients met the discontinuation criterionof two sequential creatine kinase elevations[10-fold the ULN. Furthermore, no patientsmet the criteria for Hy’s law.

ALT and AST showed a slight increase frombaseline through month 27 in all treatmentgroups, with values decreasing slightly atmonth 30 (Fig. 1a, b). Changes from baseline inhemoglobin remained generally stable throughmonth 24, then increased up to month 30, inpatients in the all tofacitinib group. A similartrend was observed in patients in the averagetofacitinib 5 mg BID and constant tofacitinib5 mg BID groups, whereas in the averagetofacitinib 10 mg BID group, hemoglobindeclined slightly up to month 21 and thenincreased and returned to baseline by month 30(Fig. 1c). In all treatment groups, ALC declinedfrom baseline and stabilized by month 24(Fig. 1d), while ANC appeared relativelystable up to month 30 after an initial decline atmonth 1 (Fig. 1e). Up to month 36, no patientin the all tofacitinib group met the discontinuationcriterion of confirmed (i.e., two or more consecu-tive measurements) ALC\0.5 9 103/mm3,and ANC\ 0.5 9 103/mm3. In all treatmentgroups, changes from baseline in creatinineremained relatively stable until month 24(Fig. 1f). Changes from baseline in creatinekinase showed an increase until month 9 in theall tofacitinib group, after which the valuesremained generally stable until month 30(Fig. 1g). The trend was similar in the average

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Fig. 1 Mean (standard error [SE]) change from baseline inalanine aminotransferase (a), aspartate aminotransferase (b),hemoglobin (c), absolute lymphocyte count (d), absoluteneutrophil count (e), creatinine (f), and creatine kinase (g),and mean (SE) percentage change from baseline in absoluteCD16?56 (h), high-density lipoprotein-cholesterol (i), low-density lipoprotein-cholesterol (j), total cholesterol (k), andtriglycerides (l), up tomonth 30. The dashed line represents thetimebetweenthebaseline(month0)andmonth1ormonth3,asbaseline refers to the baseline visit of the qualifying study forpatients who enrolled within the 14-day window from the lastvisit of the qualifying study, or the baseline visit of this long-termextension (LTE) study for patients who enrolled outside of the14-daywindowfromthelastvisitof thequalifyingstudy.Dataarepresented to month 30 because sample sizes were too small(N B 50) for meaningful analysis beyond this point. N is thenumber of patients evaluable at each time point. Only evaluable

patients at a visit of interest were included in the analysis andmissing values were not imputed. aAverage dosing was based onan average total daily dose (ATDD) of tofacitinib: patients whoreceived an ATDD\ 15 mg/day were assigned to the averagetofacitinib 5 mg twice daily (BID) group; patients who receivedanATDD C 15 mg/daywereassignedtotheaveragetofacitinib10 mg BID group. bThe constant tofacitinib 5 mg BID groupincluded all patients who started OPAL Balance on tofacitinib5 mg BID and stayed on tofacitinib 5 mg BID (as per sponsor’ssmoothing algorithm) until switching to tofacitinib 10 mg BIDordiscontinuing the study.Assessments (including exposure andadverse events) after dose switch to tofacitinib 10 mg BID wereexcluded from the analysis. D change from baseline, ALCabsolute lymphocyte count, ALT alanine aminotransferase,ANC absolute neutrophil count, AST aspartate aminotrans-ferase, ATDD average total daily dose, BID twice daily, HDLhigh-density lipoprotein, LDL low-density lipoprotein

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tofacitinib 5 mg BID and constant tofacitinib5 mg BID groups, whereas values continued toincrease slightly to month 21 in the averagetofacitinib 10 mg BID group, after which levelsdecreased to be similar to those in the othertreatment groups. Levels of CD16?56 cellsappeared to fluctuate throughout the study(Fig. 1h). HDL-cholesterol, LDL-cholesterol,total cholesterol, and triglyceride levelsincreased at month 3, then appeared to be gen-erally stable up to month 30 (Fig. 1i–l). Absolute

mean values for these laboratory parameters arereported in ESM Fig. S2.

Efficacy

Rheumatologic and Dermatologic OutcomesAcross all treatment groups, the proportions ofpatients who had an ACR20, ACR50, ACR70,and PsARC response were maintained up tomonth 30 (Fig. 2a–d). These proportions

Fig. 1 continued

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were generally higher in the average tofacitinib5 mg BID and constant tofacitinib 5 mg BIDgroups versus the average tofacitinib 10 mg BIDgroup up to month 21; however, it must benoted that patient numbers were smaller in thelatter group. Improvements in skin outcomes(i.e., PASI75 response rates and changes frombaseline in PGA-PsO; Fig. 2e, f) were also main-tained over time, as were improvements frombaseline in LEI and DSS (Fig. 2g, h).

Composite OutcomesThe proportions of patients who achieved MDAwere maintained up to month 30; these werealso generally higher in the average tofacitinib5 mg BID and constant tofacitinib 5 mg BIDgroups versus the average tofacitinib 10 mg BIDgroup (Fig. 3a). Improvements from baseline inDAPSA were also generally maintained up tomonth 30 (Fig. 3b), while improvements in

Fig. 1 continued

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Fig. 2 Proportion (SE) of patients reporting ACR20 (a),ACR50 (b), ACR70 (c), PsARC (d), and PASI75a response(e), and mean (SE) changes from baseline in PGA-PsOb (f),LEIc (g), and DSSd (h), up to month 30. The dashed linerepresents the time between the baseline (month 0) andmonth 1, as baseline refers to the baseline of the qualifyingstudy for all patients regardless of their enrollment gapsbetween the qualifying studies and this study. Data arepresented to month 30 because sample sizes were too small(N B 50) for analysis of efficacy outcomes beyond this point.N is the number of patients evaluable at each time point. Onlyevaluable patients at a visit of interest were included in theanalysis andmissing valueswere not imputed. aAmongpatientswith plaque psoriasis affecting body surface area C 3% andPASI[ 0 at baseline. bAmong patients with PGA-PsO[ 0at baseline. cAmong patients with LEI[ 0 at baseline.dAmong patients with DSS[ 0 at baseline. eAverage dosing

was based on an ATDD of tofacitinib: patients who receivedan ATDD\ 15 mg/day were assigned to the averagetofacitinib 5 mg BID group; patients who received anATDD C 15 mg/day were assigned to the average tofacitinib10 mg BID group. fThe constant tofacitinib 5 mg BID groupincluded all patients who startedOPALBalance on tofacitinib5 mgBIDand stayed on tofacitinib5 mgBID (as per sponsor’ssmoothing algorithm) until switching to tofacitinib10 mgBIDor discontinuing the study. Assessments (includingexposure and adverse events) after dose switch to tofacitinib10 mg BID were excluded from the analysis. D Change frombaseline, ACR20/50/70 American College of RheumatologyC 20%, C 50%, or C 70% response criteria, DSS DactylitisSeverity Score, LEI Leeds Enthesitis Index, PASI PsoriasisArea and Severity Index, PASI75 C 75% PASI improvementfrom baseline, PGA-PsO Physician Global Assessment ofPsoriasis, PsARC Psoriatic Arthritis Response Criteria

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CPDAI and PASDAS continued over time(Fig. 3c, d).

Patient-Reported OutcomesThe proportions of patients who achievedHAQ-DI response (decrease from baseline inHAQ-DI C 0.35) were generally constant up tomonth 30 (Fig. 4a), and improvements from

baseline were maintained over time in HAQ-DI,Pain, FACIT-F total score, and DLQI (Fig. 4b–e).Improvements from baseline in SF-36v2 PCS,MCS (Fig. 4f, g), and eight norm-based domainscores (ESM Fig. S4), as well as all EQ-5D-3Ldimensions and EQ-VAS (ESM Fig. S5), were alsogenerally maintained over time.

Fig. 2 continued

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Fig. 3 Proportion of patients (SE) reporting MDA (a),and mean (SE) changes from baseline in DAPSA (b),CPDAIa (c), and PASDAS (d), up to month 30. Thedashed line represents the time between the baseline(month 0) and month 1, as baseline refers to the baselineof the qualifying study for all patients regardless of theirenrollment gaps between the qualifying studies and thisstudy. Data are presented to month 30 because sample sizeswere too small (N B 50) for analysis of efficacy outcomesbeyond this point. N is the number of patients evaluable ateach time point. Only evaluable patients at a visit ofinterest were included in the analysis and missing valueswere not imputed. aAmong patients with plaque psoriasisaffecting C 3% of body surface area at baseline. bAveragedosing was based on an ATDD of tofacitinib: patients who

received an ATDD\ 15 mg/day were assigned to theaverage tofacitinib 5 mg BID group; patients who receivedan ATDD C 15 mg/day were assigned to the averagetofacitinib 10 mg BID group. cThe constant tofacitinib5 mg BID group included all patients who started OPALBalance on tofacitinib 5 mg BID and stayed on tofacitinib5 mg BID (as per sponsor’s smoothing algorithm) untilswitching to tofacitinib 10 mg BID or discontinuing thestudy. Assessments (including exposure and adverse events)after dose switch to tofacitinib 10 mg BID were excludedfrom the analysis. D Change from baseline, CPDAIComposite Psoriasis Disease Activity Index, DAPSADisease Activity in PSoriatic Arthritis, MDA minimaldisease activity, PASDAS Psoriatic Arthritis DiseaseActivity Score

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Fig. 4 Proportion (SE) of patients achieving HAQ-DIresponsea (a), and mean (SE) changes from baseline inHAQ-DI (b), Pain (Patient Assessment of Arthritis Pain;c), FACIT-F total score (d), DLQI (e), SF-36v2 PCS (f),and SF-36v2 MCS (g), up to month 30. The dashed linerepresents the time between the baseline (month 0) andmonth 1, as baseline refers to the baseline of the qualifyingstudy for all patients regardless of their enrollment gapsbetween the qualifying studies and this study. Data arepresented to month 30 because sample sizes were too small(N B 50) for analysis of efficacy outcomes beyond thispoint. N is the number of patients evaluable at each timepoint. Only evaluable patients at a visit of interest wereincluded in the analysis and missing values were notimputed. aDecrease from baseline HAQ-DI C 0.35,among patients with HAQ-DI C 0.35 at baseline.bAverage dosing was based on an ATDD of tofacitinib:

patients who received an ATDD\ 15 mg/day wereassigned to the average tofacitinib 5 mg BID group;patients who received an ATDD C 15 mg/day wereassigned to the average tofacitinib 10 mg BID group. cTheconstant tofacitinib 5 mg BID group included all patientswho started OPAL Balance on tofacitinib 5 mg BID andstayed on tofacitinib 5 mg BID (as per sponsor’s smooth-ing algorithm) until switching to tofacitinib 10 mg BID ordiscontinuing the study. Assessments (including exposureand adverse events) after dose switch to tofacitinib 10 mgBID were excluded from the analysis. D Change frombaseline, DLQI Dermatology Life Quality Index, FACIT-FFunctional Assessment of Chronic Illness Therapy-Fatigue, HAQ-DI Health Assessment Questionnaire-Disability Index, MCS Mental Component Summary,PCS Physical Component Summary, SF-36v2 Short Form-36 Health Survey Version 2

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DISCUSSION

This interim analysis of the LTE study OPALBalance provides safety and efficacy data up tomonth 36 and 30, respectively, for tofacitinibin[650 patients with PsA.

Overall, the safety profile of tofacitinib inthis study (AEs and laboratory abnormalitiesassessed up to month 36, and changes frombaseline in laboratory parameters assessed up tomonth 30) was similar to that reported in thequalifying phase 3 studies (6 and 12 months in

duration) [6, 7], with efficacy maintained up tomonth 30. The safety profile in OPAL Balancewas consistent with that reported in OPALBroaden and OPAL Beyond [6, 7], and with theknown long-term safety profile of tofacitinib inpatients with rheumatoid arthritis (RA) [14, 15].

Up to month 36, 79.6% of all tofacitinibpatients in OPAL Balance reported AEs. IRs forSAEsweresimilar forall tofacitinibpatients (7.8per100 PY) and the three treatment groups (8.1, 7.4,and 7.3 per 100 PY for the average tofacitinib5 mg BID, average tofacitinib 10 mg BID,

Fig. 4 continued

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and constant tofacitinib 5 mg BID groups,respectively). The IR for discontinuations due toAEs for all tofacitinib patients was 3.8 per 100 PY;this was numerically lower in patients in theaverage tofacitinib 10 mg BID group comparedwith the average tofacitinib 5 mg BID group (2.0and 5.1 per 100 PY, respectively). It should benoted that while the proportions of patientsreceiving concomitant csDMARDs were similaracross treatment groups, the proportions ofpatients receiving concomitant oral corticos-teroids were slightly lower in the averagetofacitinib 10 mg BID group (15.8%) versus theaverage tofacitinib 5 mg BID (21.6%) and con-stant tofacitinib 5 mg BID (19.1%) groups,which may have impacted the rates of AEs. Ingeneral, IRs for SAEs and discontinuations dueto AEs appeared to be lower in patients with PsAthan in patients with RA treated withtofacitinib, with IRs for the all tofacitinib groupreported as 9.0–9.4 per 100 PY for SAEs and6.8–7.5 per 100 PY for discontinuations due toAEs [14, 15].

The most common AEs in OPAL Balancewere similar to those reported in the two phase3 PsA tofacitinib studies (OPAL Broaden andOPAL Beyond) and in ORAL Sequel, the globalLTE study of tofacitinib in patients with RA forup to 9.5 years [6, 7, 15]. Upper respiratory tractinfection, nasopharyngitis, urinary tract infec-tion, and bronchitis were the most commonAEs in this interim analysis of OPAL Balance(PsA) and in ORAL Sequel (RA), occurring inC 5% of patients in the all tofacitinib groups[15].

Of the select AEs of special interest, IRs werehighest for all herpes zoster events (non-seriousand serious; 1.7 per 100 PY in the all tofacitinibgroup), with 19 patients experiencing herpeszoster up to month 36, within the risk period.Of these, one was an SAE (facial herpes zoster)and four were adjudicated as opportunisticinfections (including three cases of multi-dermatomal herpes zoster, and one case of dis-seminated herpes zoster). IRs for herpes zoster,as well as for serious infections (0.9 per 100 PYin the all tofacitinib group), were similar acrosstreatment groups. IRs for these short-latencyevents appeared to be lower in patients with PsAthan in patients with RA, reported as 3.4–4.4 per

100 PY for herpes zoster and 2.4–2.7 per 100 PYfor serious infections [14–16]. Long-latencyevents, such as malignancies (excluding NMSC),NMSC, and MACE, had IRs of 0.8, 1.0, and 0.3per 100 PY, respectively, in the all tofacitinibgroup; these were generally similar acrosstreatment groups (with the exception of malig-nancies [excluding NMSC], which were numeri-cally lower for the average tofacitinib 10 mg BIDgroup vs. the average tofacitinib 5 mg BIDgroup) and between patients with PsA and RA(IRs for RA have been reported as 0.8–0.9,0.6–0.7, and 0.4–0.6 per 100 PY, respectively)[14, 15, 17]. The IR for PE was 0.1 per 100 PY,with one patient experiencing a PE during therisk period; this was similar to the IR reportedfor patients with RA (0.1 per 100 PY) [15]. The IRfor ATE was 0.4 per 100 PY in the all tofacitinibgroup.

The long-term safety profile of tofacitinib inpatients with PsA appears to be generally com-parable with that of biologic treatments for PsA;however, comparisons must be made with cau-tion, due to differences in study designs, patientpopulations, disease activities and comorbidi-ties, and treatment exposure. Adalimumab hasbeen assessed in a 120-week open-label study(with data reported for 2 years of exposure) [18]and in a pooled analysis of clinical trials for upto 3.5 years [19]; secukinumab has been assessedin a 2-year follow-up of a randomized study[20]; and certolizumab pegol has been assessedin a pooled analysis of randomized and open-label studies across several indications (includ-ing PsA) for up to 7.8 years [21]. Proportions ofpatients with PsA experiencing AEs, SAEs, anddiscontinuations due to AEs, respectively, were91.6, 16.8, and 6.7% for adalimumab (2-yearopen-label treatment) [18], 84.5, 14.1, and 4.6%for secukinumab [20], and 93.4, 25.4, and12.7% for certolizumab pegol [21]. ConsideringAEs of special interest, the IR for herpes zosterappeared to be higher for tofacitinib than thatpreviously reported for certolizumab pegol(0.1 events per 100 PY) [21]; no cases of herpeszoster were reported with adalimumab orsecukinumab [18–20]. The following IRs (eventsper 100 PY) have been previously reported forserious infections: 2.4 for adalimumab (2-yearopen-label treatment) [18], 2.8 for adalimumab

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(pooled clinical trial data for up to 3.5 years)[19], and 1.6 for certolizumab pegol [21]. IRs(events per 100 PY) of opportunistic infections(excluding TB) were reported as 0.6 and 0.1 foradalimumab and certolizumab pegol, respec-tively [18, 21]. IRs (events per 100 PY) ofmalignancies were reported as 0.1–0.3 for adal-imumab (excluding lymphoma and NMSC) and0.5 for certolizumab pegol (excluding NMSC)[18, 19, 21]. IRs of NMSC ranged from 0 to 0.3events per 100 PY for adalimumab; no eventswere reported for certolizumab pegol[18, 19, 21]. Considering MACE, three patientswho received secukinumab for up to 2 yearsreported myocardial infarctions (IR 0.3 per100 PY), and four strokes occurred (IR 0.4 per100 PY) [20]. Four patients reported VTE (IR 0.3events per 100 PY), and three patients experi-enced PEs (IR 0.2 events per 100 PY) with cer-tolizumab pegol [21].

Laboratory parameters observed in OPALBalance were generally similar to those previ-ously observed in OPAL Broaden and OPALBeyond [6, 7]. Mean changes from baseline inALT and AST showed a slight and generallystable increase up to month 27, with valuesdecreasing slightly at month 30. Changes frombaseline in hemoglobin appeared to be mini-mal. Similar to the trend observed in OPALBroaden [6], patients who received averagetofacitinib 5 mg BID showed a small increase inhemoglobin levels, whereas those who receivedaverage tofacitinib 10 mg BID showed an initialdecrease in hemoglobin levels; this decreaselasted until month 21, with levels returning tobaseline by month 30. Changes from baseline inALC showed an increase at month 1 followed bya decrease over time, stabilizing by month 24.This trend was similar to that observed in long-term analyses of tofacitinib-treated patientswith RA, which showed an initial increase inALC followed by a decline to stable levels bymonth 48 [22]. In OPAL Balance, one patientwas diagnosed with a non-serious infection(pneumonia) prior to a measurement ofALC\ 0.5 9 103/mm3, and was being treatedwith antibiotics at the time of the visit; repeat test-ing6 dayslaterreportedALCat0.6 9 103/mm3. Nopatients reported at least two consecutive mea-surements of ALC\ 0.5 9 103/mm3 and,

therefore, these patients were not required bythe protocol to be discontinued from the study.This protocol requirement is in line with thetofacitinib prescribing information, which rec-ommends the discontinuation of tofacitinib ifALC is\0.5 9 103/mm3 (due to an increasedrisk of serious infections [14, 22]), dose reduc-tion or interruption of tofacitinib if ALC is0.5–0.75 9 103/mm3, and dose maintenance ifALC is[0.75 9 103/mm3 [23, 24]. Changesfrom baseline in ANC, creatinine and creatinekinase (both reported only in OPAL Beyond),and percentage changes from baseline in HDL-cholesterol, LDL-cholesterol, total cholesterol,and triglyceride levels appeared generally simi-lar to values observed up to month 12 in OPALBroaden and up to month 6 in OPAL Beyond[6, 7]. Levels of natural killer cells, measured byCD16?56 cells, fluctuated in OPAL Balance. Inan analysis of the effect of tofacitinib on lym-phocytes in patients with RA, short- and mid-term (up to 22 months) decreases in naturalkiller cells (CD3-/CD16?/CD56?) wereobserved; however, these were observed to haveincreased at month 50 in the long-term studyORAL Sequel [22].

The efficacy of tofacitinib in patients withPsA was maintained up to month 30, which wasa continuation of the improvements observedin OPAL Broaden and OPAL Beyond [6, 7],although it should be noted that these datareflect only those patients who remained in thestudy. Some patients discontinued from thestudy, and others switched to a MTX with-drawal sub-study from month 24; these patientswere therefore not followed beyond this timepoint. Although it appeared that a greater pro-portion of patients in the average tofacitinib5 mg BID and constant tofacitinib 5 mg BIDgroups achieved ACR20, ACR50, ACR70, PASI75responses, and MDA compared with patients inthe average tofacitinib 10 mg BID group, thismay be due to the comparatively low number ofpatients in the latter group.

This interim analysis of OPAL Balance has anumber of limitations. Patients were eligible forenrollment into the LTE study if they hadcompleted the phase 3 qualifying studies or haddiscontinued these studies due to non-study-drug-related AEs. The study population

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therefore represents patients who were knownto respond to, and tolerate, tofacitinib (oradalimumab, for those who received adali-mumab in OPAL Broaden). The lack of a placebogroup prevented the direct determination of theimpact of tofacitinib on safety outcomes. Onlyobserved values were used in the analyses,without imputation for missing values. Further,sample sizes for laboratory parameters and effi-cacy outcomes were low beyond month 30, asmany patients had not yet reached this timepoint; this resulted in a large standard error inthese values after this time point. The treatmentalgorithms used to assess potential dose-relatedeffects also had their own limitations. Animportant limitation of the ATDD method isthat a patient is assigned to the same categorythroughout their experience in the program,and thus events may be attributed to a dosecategory that is different from the actual dosereceived at the time of the event. Additionally,this approach narrows the differences betweenthe point estimates for both doses, bringingthem closer to each other and confounding theability to evaluate differences between them. Asthe constant daily dose method excludedexposure and events that occurred after a doseswitch, it resulted in a shorter overall exposureto tofacitinib and the risk of confounding bythe reasons for discontinuation or dose change.Because of the exposure differences amongdefined treatment groups, percentages forevents of interest are presented for descriptivepurposes only and should not be used to com-pare treatment groups. Finally, as this is aninterim analysis only, full details of the safetyand efficacy of long-term tofacitinib use inpatients with PsA are yet to be elucidated.Comparisons between this analysis and theprior RA analyses must be made with cautionbecause of the differences in PY of exposure totofacitinib, as patients with PsA have beenobserved for up to 36 months, and patients withRA were observed for up to 9.5 years. Addition-ally, the sample size of OPAL Balance (686patients in the all tofacitinib group) was smallerthan that of the RA LTE study, ORAL Sequel(4481 patients in the all tofacitinib group) [15].

CONCLUSIONS

The results of this third interim analysis of theLTE study OPAL Balance support the long-termsafety and efficacy of tofacitinib in patients withactive PsA. The safety and efficacy of tofacitinib5 and 10 mg BID in patients with PsA appearedto be consistent with that observed in thequalifying studies, OPAL Broaden and OPALBeyond. Laboratory parameters generallyremained consistent over time. Efficacy acrossvarious PsA disease domains and PROs was alsomaintained over time in those patientsremaining in the study.

ACKNOWLEDGEMENTS

The authors would like to thank the patientsand investigators involved in OPAL Balance.

Funding. This study and the Rapid ServiceFee were sponsored by Pfizer Inc.

Medical Writing Assistance. Medical writ-ing support, under the guidance of the authors,was provided by Mark Bennett, PhD, andChristina Viegelmann, PhD, CMC Connect,McCann Health Medical Communications andwas funded by Pfizer Inc, New York, NY, USA inaccordance with Good Publication Practice(GPP3) guidelines (Ann Intern Med.2015;163:461–4).

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authorship Contributions. PN, AJK, PJM,JAC-C, DF, CW, JW, M-AH, SM, and KSK con-tributed to the conception/design of the study,acquisition of the data, and data analysis. Allauthors contributed to the interpretation of thedata, critically revised each draft of the manu-script for intellectual content, provided finalapproval of the version submitted for

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publication, and accept accountability for theaccuracy and integrity of the work.

Disclosures. Peter Nash has receivedresearch grants from, is a consultant for, and is amember of the speakers’ bureau for AbbVie,Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead,Janssen, MSD, Novartis, Pfizer Inc, Roche,Sanofi, and UCB. Laura C. Coates has receivedresearch grants from AbbVie, Celgene, Eli Lilly,Janssen, Novartis, and Pfizer Inc, and hasreceived consulting fees from AbbVie, Amgen,Boehringer Ingelheim, Biogen, Celgene, EliLilly, Gilead, Janssen, Novartis, Pfizer Inc, andUCB. Laura C. Coates is also a member of thejournal’s Editorial Board. Alan J. Kivitz hasreceived consulting fees from Gilead, Pfizer Inc,Regeneron, Sanofi, and Sun Pharma, is a mem-ber of the speakers’ bureau for AbbVie, Celgene,Eli Lilly, Flexion, GSK, Horizon, Merck, Novar-tis, Pfizer Inc, Regeneron, and Sanofi, is anadvisory committee member for AbbVie, Boeh-ringer Ingelheim, Flexion, Genzyme, Janssen,Pfizer Inc, Regeneron, Sanofi, and UCB, and is ashareholder of Novartis and Pfizer Inc. Philip J.Mease has received research grants and con-sulting fees from AbbVie, Amgen, Bristol-MyersSquibb, Celgene, Eli Lilly, Galapagos, Gilead,GSK, Janssen, Novartis, Pfizer Inc, Sun Pharma,and UCB, and is a member of the speakers’bureau for AbbVie, Amgen, Bristol-MyersSquibb, Celgene, Eli Lilly, Genentech, Janssen,Novartis, Pfizer Inc, and UCB. Dafna D. Glad-man has received research grants and/or con-sulting fees from AbbVie, Amgen, Bristol-MyersSquibb, Celgene, Eli Lilly, Galapagos, Gilead,Janssen, Novartis, Pfizer Inc, and UCB. Jose A.Covarrubias-Cobos has received research grantsfrom Bristol-Myers Squibb, Eli Lilly, Janssen,and Pfizer Inc. Oliver FitzGerald has receivedresearch grants and/or consulting fees fromAbbVie, Amgen, Bristol-Myers Squibb, Celgene,Eli Lilly, Janssen, Novartis, Pfizer Inc, and UCB.Dona Fleishaker, Cunshan Wang, Joseph Wu,Ming-Ann Hsu, Sujatha Menon, Lara Fallon,and Keith S. Kanik are employees and share-holders of Pfizer Inc. Ana Belen Romero was anemployee and shareholder of Pfizer Inc at thetime of this analysis, and is currently anemployee of LEO Pharma.

Compliance with Ethics Guidelines. Thestudy was conducted in accordance with theInternational Conference on HarmonizationGood Clinical Practice guidelines, the principlesof the Declaration of Helsinki, and applicablelocal regulatory requirements and laws. Thestudy protocol was approved by the Institu-tional Review Boards and/or Independent EthicsCommittee at each study center (see ESM). Allpatients provided written, informed consent.

Data Availability. Upon request, and sub-ject to certain criteria, conditions, and excep-tions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for moreinformation), Pfizer will provide access to indi-vidual de-identified participant data from Pfizer-sponsored global interventional clinical studiesconducted for medicines, vaccines, and medicaldevices (1) for indications that have beenapproved in the US and/or EU, or (2) in pro-grams that have been terminated (i.e., devel-opment for all indications has beendiscontinued). Pfizer will also consider requestsfor the protocol, data dictionary, and statisticalanalysis plan. Data may be requested from Pfizertrials 24 months after study completion. The de-identified participant data will be made avail-able to researchers whose proposals meet theresearch criteria and other conditions, and forwhich an exception does not apply, via a secureportal. To gain access, data requestors mustenter into a data access agreement with Pfizer.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, you

578 Rheumatol Ther (2020) 7:553–580

will need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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