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Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials.

ABSTRACT: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (??3), low (LDA; >?3-??6), moderate (MDA; >?6-??12), or high disease activity (HDA; >?12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ??0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (

SUBMITTER: Strand V

PROVIDER: S-EPMC6061070 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials.

Strand Vibeke V Lee Eun Bong EB Yazici Yusuf Y Dikranian Ara A Wilkinson Bethanie B Takiya Liza L Zang Chuanbo C Bananis Eustratios E Bergman Martin J MJ

Clinical rheumatology 20180414 8

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving ...[more]

PMID: 29656373

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Project description:INTRODUCTION:Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function. METHODS:This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP). RESULTS:Mean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of < 1.9 most closely approximated CDAI remission (≤ 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low disease activity (LDA) at month 6 reported normative HAQ-DI scores (< 0.5) at month 24 than did those with CDAI MDA/HDA. CONCLUSION:Regardless of treatment, in both MTX-naïve and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of < 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation. FUNDING:Pfizer Inc. TRIAL REGISTRATION:Clinicaltrials.gov identifiers: NCT01039688 and NCT00847613.

Project description:BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We examined the degree to which Patient Global Assessment of Disease Activity (PtGA) was driven by patient-reported assessments of pain (Pain), physical function, and fatigue in patients receiving tofacitinib 5 mg twice daily or placebo, each with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).MethodsThis post hoc analysis used data pooled from three randomized controlled trials in csDMARD-inadequate responder (csDMARD-IR) patients (ORAL Scan: NCT00847613; ORAL Standard: NCT00853385; ORAL Sync: NCT00856544). Using subgroup analysis from 2 × 2 tables, associations between PtGA and Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at month 3 were evaluated using Pearson's Phi correlation coefficients. To support the main analysis, associations between select patient-reported outcomes (PROs) were also evaluated in csDMARD-naïve (ORAL Start; NCT01039688) and biologic (b)DMARD-IR (ORAL Step; NCT00960440) patients.ResultsAcross csDMARD-IR treatment groups, low disease activity (defined as PtGA ≤ 20 mm), and moderate (≥ 30%) and substantial (≥ 50%) improvements from baseline in PtGA were associated with mild Pain (Visual Analog Scale score ≤ 20 mm), and moderate (≥ 30%) and substantial (≥ 50%) improvements from baseline in Pain; lack of Pain improvement was associated with little/no improvement in PtGA. In contrast, large proportions of csDMARD-IR patients who reported PtGA improvements did not report HAQ-DI or FACIT-F scores ≥ normative values (≤ 0.25 and ≥ 43.5, respectively) or changes in HAQ-DI or FACIT-F scores ≥ minimum clinically important difference (≥ 0.22 and ≥ 4.0, respectively). Generally, PtGA and Pain outcomes were moderately-to-strongly correlated at month 3 in csDMARD-IR patients, with weaker correlations evident between PtGA and HAQ-DI/FACIT-F outcomes. Similar findings were generally evident in csDMARD-naïve and bDMARD-IR patients.ConclusionsThis analysis supports the role of Pain as a key driver of PtGA in RA; physical function and fatigue play lesser roles in patients' perceptions of disease activity. These findings corroborate the importance of improved PROs and attainment of low symptom states for optimizing patient care.Trial registrationClinicaltrials.gov: NCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009); NCT01039688 (registered: December 25, 2009); NCT00960440 (registered: August 17, 2009).

Project description:ObjectiveAnalyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA).MethodsThis post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters.ResultsFive hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week.ConclusionEfficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week.Trial registrationClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

Project description:OBJECTIVE:Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. METHODS:Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (?) in C-reactive protein, HAQ-DI, Patient's/Physician's Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), ? in lipid/hepatic values, and liver parameter increases. RESULTS:Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or ? in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. CONCLUSION:Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.

Project description:IntroductionPatients with rheumatoid arthritis (RA) have decreased survival because of increased cardiovascular risk compared with the general population, and treatment with tocilizumab (TCZ) has been shown to increase lipid levels; however, the relationship between lipids and cardiovascular risk is unknown. This post hoc analysis expanded on previously reported 24-week results by characterizing statin use and subsequent changes in lipid parameters in patients with RA treated with intravenous or subcutaneous TCZ (TCZ-IV or TCZ-SC) over 2 years of treatment.MethodsData were collected from patients with moderate to severe active RA who received ≥1 dose of the study drug in seven international, randomized, double-blind, controlled phase 3 and 4 clinical trials of TCZ-IV or TCZ-SC. Lipid levels and safety events were assessed over 2 years of treatment. Data were summarized for all pooled treatment groups of the intention-to-treat populations in the TCZ-IV and TCZ-SC studies, and results were stratified by concomitant statin use.ResultsData from this descriptive, retrospective, pooled analysis indicated that statins can stabilize lipid levels without a clinically significant increase in adverse events. Approximately 30% of patients in the TCZ treatment arms who never received a statin demonstrated a shift in low-density-lipoprotein cholesterol (LDL-C) from <130 mg/dl at baseline to ≥130 mg/dl at 2 years. However, despite the increased potential cardiovascular risk, <15% of patients with LDL-C ≥100 mg/dl and <35% of patients with a total cholesterol:high-density-lipoprotein cholesterol ratio >5 at 2 years were receiving concomitant statins.ConclusionConcomitant statin use attenuated TCZ-mediated lipid increases; however, a large proportion of TCZ-treated patients potentially at risk of cardiovascular disease were untreated. These findings highlight the need for better understanding of potential risk associated with TCZ-mediated lipid elevations as well as implementation of RA-specific guidelines on the recognition and management of elevated risk of cardiovascular events in patients with RA.FundingF. Hoffmann-La Roche, Ltd.

Project description:AIM:We report tofacitinib efficacy and safety in Asia-Pacific patients who participated in the rheumatoid arthritis (RA) clinical development program. METHOD:This post-hoc analysis included pooled data from patients with RA in the Asia-Pacific region treated with tofacitinib with/without conventional synthetic disease-modifying antirheumatic drugs in Phase (P)1, 2, 3, and long-term extension (LTE) studies (one LTE ongoing; January 2016 data-cut). Efficacy was assessed over 24 months in patients who received tofacitinib 5 (N = 397) or 10 (N = 382) mg twice daily or placebo (N = 243) in three P2 and five P3 studies. Endpoints included American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) and Clinical Disease Activity Index (CDAI) remission rates, and change from baseline in Health Assessment Questionnaire-Disability Index (?HAQ-DI). Safety data pooled over 92 months from one P1, four P2, six P3, and two LTE studies for all tofacitinib doses (N = 1464) included incidence rates (IRs) (patients with events/100 patient-years) for adverse events (AEs) of special interest. RESULTS:At month 3, patients receiving tofacitinib 5/10 mg twice daily improved vs placebo in ACR20 (69.2%/77.9% vs 27.5%), ACR50 (36.9%/44.4% vs 9.5%), and ACR70 (15.1%/22.4% vs 2.7%) responses, remission rates for DAS28-4(ESR) (8.5%/18.5% vs 2.6%) and CDAI (6.1%/12.3% vs 0.5%), and ?HAQ-DI (-0.5/-0.6 vs -0.1); improvements were sustained through 24 months. IRs (95% CI) were 9.4 (8.5, 10.3) for serious AEs, 9.1 (8.3, 10.1) for discontinuations due to AEs, 3.7 (3.2, 4.3) for serious infections, 5.9 (5.2, 6.7) for herpes zoster, and 0.8 (0.6, 1.1) for malignancies (excluding non-melanoma skin cancer). CONCLUSION:In Asia-Pacific patients, tofacitinib improved signs/symptoms over 24 months. Safety over 92 months was generally consistent with global tofacitinib studies; however, infection IRs were higher in Asia-Pacific patients.

Project description:IntroductionEmerging evidence suggests psoriatic arthritis (PsA) with axial involvement (axPsA) and radiographic axial spondyloarthritis (r-axSpA) may possibly represent distinct disorders, with some differing clinical manifestations, genetic associations, and radiographic findings. Moreover, axPsA and r-axSpA may respond differently to therapies: guselkumab (interleukin [IL]-23p19 subunit inhibitor [i]) and ustekinumab (IL-12/23p40i) demonstrated improvements in axial symptoms in patients with PsA; however, neither risankizumab (IL-23p19i) nor ustekinumab demonstrated efficacy versus placebo in patients with r-axSpA. Current analyses aim to further understand potential molecular distinctions between axPsA and r-axSpA and examine the pharmacodynamic effects of guselkumab in patients with axPsA and those with PsA without axial involvement (non-axPsA).MethodsPost hoc analyses utilized biomarker data from blood and serum samples collected from a subset of participants in phase 3 studies of ustekinumab in r-axSpA and guselkumab in PsA (DISCOVER-1 and DISCOVER-2). Participants with axPsA were identified by investigator-verified sacroiliitis (imaging-confirmed) and axial symptoms. HLA mapping, serum cytokine analysis, and whole-blood RNA sequencing were conducted.ResultsRelative to r-axSpA, patients with axPsA had a lower prevalence of HLA-B27, HLA-C01, and HLA-C02 alleles and a higher prevalence of HLA-B13, HLA-B38, HLA-B57, HLA-C06, and HLA-C12 alleles. Compared with r-axSpA, patients with axPsA had elevated baseline levels of serum IL-17A and IL-17F cytokines, enrichment of IL-17 and IL-10 pathway-associated genes, and neutrophil gene markers. Across axPsA and non-axPsA cohorts, reductions in cytokine levels and normalization of pathway-associated gene expression with guselkumab treatment were comparable.ConclusionThe differences in HLA genetic associations, serum cytokines, and enrichment scores support the concept that axPsA and r-axSpA may be distinct disorders. The comparable pharmacodynamic effects of guselkumab on cytokine levels and pathway-associated genes observed in patients with axPsA and non-axPsA are consistent with demonstrated clinical improvements across PsA cohorts. These findings contribute to the understanding of potential genetic and molecular distinctions between axPsA and r-axSpA.Trial registrationClinicalTrials.gov identifiers, NCT03162796, NCT0315828, NCT02437162, and NCT02438787.

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Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials.

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Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials.

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