Brief Report: Remission Rates With Tofacitinib Treatment in Rheumatoid Arthritis: A Comparison of Various Remission Criteria.
ABSTRACT: Tofacitinib is an oral JAK inhibitor that is used for the treatment of rheumatoid arthritis (RA). In previous clinical trials of tofacitinib, a Disease Activity Score in 28 joints (DAS28)-based analysis was used to assess outcomes. In this study, remission rates according to various remission criteria were evaluated across 5 phase III randomized controlled studies.In all 5 studies, tofacitinib was administered at a dosage of 5 mg twice daily or 10 mg twice daily, either as monotherapy or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs. One of the studies included adalimumab 40 mg once every 2 weeks. In addition to the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]), a primary efficacy variable used in the phase III studies, disease activity was assessed post hoc by the 4-variable DAS28 using the C-reactive protein level (DAS28-4[CRP]), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and Boolean-based assessment.A total of 3,306 patients were analyzed (1,213 of these patients received tofacitinib 5 mg twice daily, 1,212 received tofacitinib 10 mg twice daily, 679 received placebo, and 202 received adalimumab 40 mg every 2 weeks). Remission rates varied according to the criteria used, with higher rates in the active-treatment groups for the DAS28-4(CRP) than for other scores. At month 3, remission rates with tofacitinib 5 mg twice daily were 18-22% using the DAS28-4(CRP), 5-10% using the DAS28-4(ESR), 4-7% using the SDAI, 5-6% using the CDAI, and 2-7% using the Boolean-based method. In contrast, the remission rates with placebo varied from 0% to 7%, with small differences between the DAS28-4(ESR) and the DAS28-4(CRP).Although tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily was effective compared with placebo in achieving disease remission, regardless of the disease activity measure, remission rates were substantially higher when the DAS28-4(CRP) was used. The presence or absence and type of acute-phase reactants in remission criteria were significant contributors to remission rates across treatment groups. This finding has important consequences for trial design and clinical practice.
Project description:This prospective one-year follow-up study was conducted from 835 visits in 178 rheumatoid arthritis (RA) patients. Tender-/swollen-joint count, Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score 28-ESR (DAS28-ESR), DAS28-CRP, Simplified Disease Activity Index (SDAI) and DAS28-monocyte chemotactic protein-1 (DAS28-MCP-1) scores were obtained every 3 months. Radiographs of hands and feet were acquired at baseline and one year. We evaluated the correlation and accuracy of activity scores in predicting remission, HAQ-DI changes and radiographic changes. DAS28-MCP-1 correlated strongly with DAS28-ESR, DAS28-CRP and SDAI scores (0.830, 0.899 and 0.931, respectively, with all P?<?0.001). Score changes of DAS28-MCP-1 were comparable to those of DAS28-ESR, DAS28-CRP and SDAI in predicting changes in HAQ-DI and bone erosion. DAS28-MCP-1 (<2.2) was better than DAS28-ESR (<2.6) in indicating modified American Rheumatism Association remission and 2011 American College of Rheumatology/European League Against Rheumatism remission (75.61% vs. 36.99% and 81.71% vs. 49.13%, respectively) with odds ratios of 5.28 and 4.62 (both P?<?0.001), respectively. We compared DAS28-MCP-1 with SDAI (?3.3) in indicating remission with odds ratios of 2.63 (P?=?0.002) and 0.98, respectively (and DAS28-MCP-1 with DAS28-CRP?<?2.5: 1.33 and 0.92). Therefore, DAS28-MCP-1 is useful as an alternative in assessing RA activity.
Project description:OBJECTIVE:Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post hoc analysis explored the relationship between early disease activity changes and the achievement of low disease activity (LDA) and remission targets with tofacitinib. METHODS:Data were from 2 randomized, double-blind, phase III studies. In the ORAL Start trial, methotrexate (MTX)-naive patients received tofacitinib 5 or 10 mg twice daily, or MTX, for 24 months. In the placebo-controlled ORAL Standard trial, MTX inadequate responder patients received tofacitinib 5 or 10 mg twice daily or adalimumab 40 mg every 2 weeks, with MTX, for 12 months. Probabilities of achieving LDA (using a Clinical Disease Activity Index [CDAI] score ?10 or the 4-component Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] ?3.2) at months 6 and 12 were calculated, given failure to achieve threshold improvement from baseline (change in CDAI ?6 or DAS28-ESR ?1.2) at month 1 or 3. RESULTS:In ORAL Start, 7.2% and 5.4% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to show improvement in the CDAI ?6 at month 3; of those who failed, 3.8% and 28.6%, respectively, achieved month 6 CDAI-defined LDA. In ORAL Standard, 18.8% and 17.5% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to improve CDAI ?6 at month 3; of those who failed, 0% and 2.9%, respectively, achieved month 6 CDAI-defined LDA. Findings were similar when considering improvements at month 1 or DAS28-ESR thresholds. CONCLUSION:In patients with an inadequate response to MTX, lack of response to tofacitinib after 1 or 3 months predicted a low probability of achieving LDA at month 6. Lack of an early response may be considered when deciding whether to continue treatment with tofacitinib.
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:Objectives:Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA. Methods:Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). 'Serotype' subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared. Results:Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups. Conclusion:Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients.
Project description:BACKGROUND:Reliable assessment of remission is important for the optimal management of rheumatoid arthritis (RA) patients. In this study, we used the multi-biomarker disease activity (MBDA) test to explore the role of biomarkers in predicting point remission and sustained remission. METHODS:RA patients on >?6?months stable therapy in stable low disease activity (DAS28-ESR ??3.2) were assessed every 3?months for 1?year. Baseline, intermittent (IR) and sustained (SR) remission were defined by DAS28-ESR, DAS28-CRP, simple disease activity index (SDAI), clinical disease activity index (CDAI) and ACR/EULAR Boolean criteria. Patients not fulfilling any remission criteria at baseline were classified as 'low disease activity state' (LDAS). Patients not fulfilling any remission criteria over 1?year were classified as 'persistent disease activity' (PDA). MBDA score was measured at baseline/3/6?months. The baseline MBDA score, the 6-month time-integrated MBDA score and MBDA biomarkers were used for analyses. The area under the receiver operating characteristic curve (AUROC) assessed the ability of the MBDA score to discriminate between remission and non-remission. Biomarkers were analysed at baseline using the Mann-Whitney test and over time using the Jonckheere-Terpstra trend test. RESULTS:Of 148 patients, 27% were in the LDAS, 65% DAS28-ESR remission, 51% DAS28-CRP remission, 40% SDAI remission, 43% CDAI remission and 25% ACR/EULAR Boolean remission at baseline. Over 1?year, 9% of patients were classified as PDA. IR and SR were achieved in 42%/47% by DAS28-ESR, 46%/29% by DAS28-CRP, 45%/20% by SDAI, 44%/21% by CDAI and 35%/9% by ACR/EULAR Boolean criteria, respectively. By all remission criteria, baseline MBDA score discriminated baseline remission (AUROCs 0.68-0.75) and IR/SR (AUROCs 0.65-0.74). The 6-month time-integrated MBDA score discriminated IR/SR (AUROCs 0.65-0.79). Baseline MBDA score and concentrations of IL-6, leptin, SAA and CRP were significantly lower in all baseline remission criteria groups vs LDAS. They and the 6-month time-integrated values were lower among patients who achieved IR/SR vs PDA over 1?year. CONCLUSIONS:This study demonstrated that the MBDA score and its biomarkers IL-6, leptin, SAA and CRP differentiated between small differences in disease activity (i.e. between low disease activity and remission states). They were also predictors of remission over 1 year.
Project description:Stringent remission criteria are crucial in rheumatoid arthritis (RA) assessment. Disease activity score in 28 joints (DAS28)-remission has not been included among American College of Rheumatology/European League Against Rheumatism definitions, because of its association with significant residual disease activity, partly due to high weighting of acute-phase reactants (APR). New, more stringent cut-points for DAS28-remission have recently been proposed that are suggested to reflect remission by clinical and simplified disease activity indices (clinical disease activity index (CDAI), simple disease activity index (SDAI)). However, their stringency in therapies directly influencing APR, like IL-6-blockers, has not been tested. We tested the new cut-points in patients with RA receiving tocilizumab.We used data from randomised controlled trials of tocilizumab and evaluated patients in remission according to new DAS28-C-reactive protein (DAS-CRP) and DAS-erythrocyte sedimentation rate (DAS-ESR) cut-points (1.9 and 2.2). We assessed their disease activity state using the CDAI, SDAI and Boolean criteria and analysed their individual residual core set variables, like swollen joint counts (SJC28).About 50% of patients in DAS28-CRP-remission (<1.9) fell into higher disease activity states when assessed with CDAI, SDAI or Boolean criteria. Also, 15% had three or more (up to eight) SJC. Even higher disease activity was seen in patients classified as being in DAS28-ESR-remission (<2.2).Even with new, more stringent cut-points, DAS28-remission is frequently associated with considerable residual clinical disease activity, indicating that this limitation of the DAS28 is related to score construction rather than the choice of cut-points.
Project description:OBJECTIVE: To compare, "in a real world," the performance of the most common composite activity indices in a cohort of PsA patients. METHODS: A total of 171 PsA patients were involved. The following variables were evaluated: peripheral joint assessment, patient reported of pain, physician and patient assessments of disease activity, patient general health status, dactylitis digit count, Leeds Enthesitis Index, Health Assessment Questionnaire (HAQ), physical and mental component summary score of the Medical Outcome Survey (SF-36), Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). To measure the disease activity, the Disease Activity Score (DAS28-ESR and DAS28-CRP), Simple Disease Activity Index (SDAI), Composite Psoriatic Disease Activity Index (CPDAI), disease activity in psoriatic arthritis (DAPSA), and Psoriatic Arthritis Disease Activity Score (PASDAS) have been calculated. The criteria for minimal disease activity (MDA) and remission were applied as external criterion. RESULTS: The ROC were similar in all the composite measures. Only the CPDAI showed less discriminative ability. There was a high degree of correlation between all the indices (P < 0.0001). The highest correlations were between DAPSA and SDAI (rho = 0.996) and between DAPSA and DAS28-CRP (rho = 0.957). CPDAI, DAPSA, and PASDAS had the most stringent definitions of remission and MDA category. DAS28-ESR and DAS28-CRP had the highest proportions in remission and MDA. CONCLUSIONS: Although a good concurrent validity and discriminant capacity of six disease activity indices were observed, the proportions of patients classified in the disease activity levels differed. In particular, the rate of patients in remission was clearly different among the respective indices.
Project description:BACKGROUND:We aimed to evaluate the prevalence of foot and/or ankle arthritis (FAA) and its impact on clinical indices in patients with rheumatoid arthritis (RA). METHODS:This cross-sectional study used data from the Korean College of Rheumatology Biologics & Targeted therapy registry to observe clinical outcomes of patients undergoing biologics therapy and conventional therapy. FAA was defined as ≥1 tender or swollen joint in the ankle and/or 1st-5th metatarsophalangeal (MTP) joints. Disease Activity Score 28 (DAS28), Routine Assessment of Patient Index Data 3 (RAPID3), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) were assessed. RESULTS:Among 2046 patients, 598 had FAA. The ankle joint was the most commonly involved joint in FAA (tender joint, 71.4%; swollen joint, 59.5%), followed by the third and second MTP joints. Patients with FAA showed higher DAS28, RAPID3, SDAI, and CDAI scores. FAA presence was significantly associated with non-remission as per DAS28-ESR (odds ratio, 3.4; 95% confidence interval, 2.0-5.8), DAS28-CRP (3.6, 2.4-5.3), SDAI (6.3, 2.8-14.6), CDAI (7.6, 2.4-24.3), and RAPID3 (5.6, 2.7-11.5) indices on adjusting for age, sex, disease duration, presence of rheumatoid factor, presence of anti-cyclic citrullinated peptide antibody, lung disease, use of methotrexate, and previous use of biological disease-modifying anti-rheumatic drugs. Patients with FAA were less likely to achieve remission of SDAI (n = 6, 1.0%) and CDAI (n = 3, 0.5%) than that of DAS28-ESR (n = 21, 3.5%), DAS28-CRP (n = 38, 6.4%), and RAPID3 (n = 12, 2.0%). CONCLUSIONS:FAA represents a severe disease activity and is an independent risk factor for non-remission in patients with RA.
Project description:Objective:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post hoc analysis evaluated patients receiving tofacitinib monotherapy or combination therapy, as well as those who switched from monotherapy to combination therapy (mono→combo) or vice versa (combo→mono) in long-term extension (LTE) studies. Methods:Data were pooled from open-label LTE studies (ORAL Sequel (NCT00413699; ongoing; data collected 14 January 2016) and NCT00661661) involving patients who participated in qualifying index studies. Efficacy outcomes included American College of Rheumatology 20/50/70 rates, change from baseline in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index and DAS28-4(ESR) and CDAI low disease activity and remission. Safety was evaluated over 96 months. Results:Of the 4967 patients treated, 35.4% initiated tofacitinib monotherapy, 64.6% initiated combination therapy, 2.6% were mono→combo switchers and 7.1% were combo→mono switchers. Patients who switched multiple times were excluded. Of those who initiated monotherapy and combination therapy, 87.8% (1543/1757) and 82.0% (2631/3210), respectively, remained on the same regimen throughout the study; efficacy was maintained. Incidence rates (IRs) for serious adverse events with tofacitinib 5 mg and 10 mg twice daily, respectively, were 9.42 and 8.41 with monotherapy and 8.36 and 10.75 with combination therapy; IRs for discontinuations due to AEs were 7.13 and 6.06 with monotherapy and 7.82 and 8.06 with combination therapy (overlapping CIs). For mono→combo and combo→mono switchers, discontinuations due to AEs were experienced by 0.8% and 0.9%, respectively, within 30 days of switching. Conclusion:Tofacitinib efficacy as monotherapy or combination therapy was maintained through month 48 and sustained to month 72, with minimal switching of treatment regimens. Safety was consistent over 96 months. Clinical trial registration:NCT00413699 (Pre-results) and NCT00661661 (Results).
Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (?12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (?17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.