Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib in long-term studies.
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ABSTRACT: Objectives
Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis).Methods
In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis.Results
For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n = 269).Conclusion
Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years.Trial registration
ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661.
SUBMITTER: van der Heijde D
PROVIDER: S-EPMC8023998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC6251846 | biostudies-literature
Project description:BackgroundThe detection of statistically significant reductions in radiographic progression during clinical studies in patients with rheumatoid arthritis (RA) has become increasingly difficult over the past decade due to early-escape study designs and declining rates of progression in control-group patients. We investigated the impact of extremes of radiographic data (outliers) and baseline prognostic factors on detection of treatment effects, to provide guidance on future analysis of joint structural data in RA clinical trials.MethodsData were from two, phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib in adult patients with moderate to severe RA: ORAL Scan (NCT00847613) and ORAL Start (NCT01039688). These studies detected significant reductions in radiographic progression with tofacitinib 10 mg twice daily (BID) plus background methotrexate (ORAL Scan), and with tofacitinib 5 or 10 mg BID as monotherapy (ORAL Start). We evaluated mean changes from baseline in van der Heijde modified total Sharp score (mTSS) at month 6 and month 12, using analysis of covariance (ANCOVA). A trimmed analysis was used to deal with extremes of data. The impact of baseline prognostic factors on radiographic progression was evaluated using ANCOVA to analyze the mean change from baseline in mTSS for each factor in turn.ResultsThe analysis included data from 720 patients from ORAL Scan and 880 patients from ORAL Start. Trimmed analyses were unbiased for the true mean estimate and enabled us to remove the effect of influential extreme observations in the data set. Almost all patients had at least one poor prognostic factor at baseline (e.g., high level of disease activity, or positive for rheumatoid factor). The strongest predictor of treatment effect was the severity of radiographic damage at baseline.ConclusionsA trimmed analysis can establish whether any significant inhibition of structural damage is being driven by extremes of data, and should be one of the sensitivity analyses of choice for structural data in RA clinical trials. Furthermore, analysis of radiographic data based on baseline prognostic factors may reveal increased treatment effects. Application of these methods to analysis of radiographic data from clinical trials in patients with RA, allows a more complete interpretation of data.Trial registrationClinicaltrials.gov NCT00847613 (registered 17 February 2009) and NCT01039688 (registered 23 December 2009).
| S-EPMC5034418 | biostudies-literature
Project description:Demonstrating inhibition of the structural damage to joints as a statistically significant difference in radiographic progression as measured by the van der Heijde modified Total Sharp Score (mTSS) is a common objective in trials for rheumatoid arthritis treatments. The frequently used analysis of the covariance model with missing data imputed using linear extrapolation (analyses of covariance, ANCOVA+LE) may not be ideal for long-term extension studies or for paediatric studies. The random coefficient (RC) model may represent a better alternative.A two-arm (active treatment and placebo) setting with a week 44 study period was considered. RC model, ANCOVA+LE and ANCOVA with last observation carried forward imputation were compared under different scenarios in bias, root mean square error (RMSE), power and type I error rate.The RC model outperformed ANCOVA+LE in metrics measuring bias, RMSE, power and type I error rate under the evaluated scenarios. ANCOVA and RC provide similar performance when there are no missing data. With missing data, RC+observed (OBS) provides similar or better results than ANCOVA+LE in power and bias.Our simulations support that RC is both a more sensitive and a more precise alternative to the commonly used ANCOVA+LE as a primary method for analysing mTSS in long-term extension and paediatric studies with a higher likelihood of missing data. The RC model can provide a reference at time points with missing data by estimating a slope; mTSS change by one unit change in time. ANCOVA+LE is recommended as a sensitivity analysis.
| S-EPMC10083852 | biostudies-literature
Project description:BackgroundPreclinical data suggest that tofacitinib would protect bone health in patients with rheumatoid arthritis (RA).ObjectiveTo assess fracture risk in tofacitinib RA clinical trials.DesignPost hoc analysis.MethodsWe analyzed pooled data of phase I/II/III and long-term extension studies ('P123LTE cohort'), pooled data of placebo-controlled portions of phase III studies (phase III placebo-controlled cohort), and data from ORAL Surveillance [phase IIIb/IV randomized, open-label trial evaluating tofacitinib 5/10 mg twice daily (BID) vs tumor necrosis factor inhibitor (TNFi) in patients ⩾ 50 years with ⩾ 1 additional cardiovascular risk factor].ResultsIn the phase III placebo-controlled cohort, incidence rates (IRs) [95% confidence interval (CI)] of fracture were 2.11 (1.09-3.68), 2.56 (1.23-4.71), and 4.43 (1.78-9.12) per 100 patient-years (PYs) for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively [tofacitinib 5 mg BID vs placebo: hazard ratio (HR) (95% CI) = 0.55(0.18-1.65); tofacitinib 10 mg BID vs placebo: HR (95% CI) = 0.72 (0.26-2.01)]. In P123LTE, IRs (95% CI) were 2.62 (2.29-2.99) and 2.26 (2.02-2.52) per 100 PY for average tofacitinib 5 and 10 mg BID, respectively. In ORAL Surveillance, IRs (95% CI) were 2.79 (2.34-3.30), 2.87 (2.40-3.40), and 2.27 (1.87-2.74) per 100 PY for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and TNFi, respectively. In ORAL Surveillance, the risk of fracture was numerically higher than TNFi for tofacitinib 5 mg BID [HR (95% CI) = 1.23 (0.96-1.58)] and tofacitinib 10 mg BID [HR (95% CI) = 1.26 (0.97-1.62)]. In ORAL Surveillance, independent predictors of all and osteoporotic fractures with tofacitinib or TNFi included age ⩾ 65, female sex, history of fracture/osteoporosis, and baseline oral corticosteroid use.ConclusionThis post hoc analysis showed numerically lower fracture risk with tofacitinib versus placebo and numerically greater risk versus TNFi. We did not identify any tofacitinib-specific predictors of fractures, and predictors of fracture were generally aligned with prior literature in the general population and patients with RA. Patients with fracture risk factors should be adequately monitored and treated.Clinical trial registrationNCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT02831855, NCT00413699, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00661661, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT01262118, NCT01484561, NCT02281552, NCT02147587, NCT02092467.
| S-EPMC9806361 | biostudies-literature
Project description:ObjectiveTofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib.MethodsData were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long-term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time-varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated.ResultsFifty-two MACE occurred in 4,076 patients over 12,873 patient-years of exposure (incidence rate 0.4 patients with events per 100 patient-years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk.ConclusionIn this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.
| S-EPMC6754249 | biostudies-literature
Project description:ObjectivePhase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction.MethodsPatients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson's correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression.ResultsA total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson's correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001).ConclusionsIn this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach.Clinical trial registration numbersEudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results.
| S-EPMC7427775 | biostudies-literature
Project description:ObjectivesTo evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib.MethodsPhase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05).ResultsWe identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)).ConclusionsWithin the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.
| S-EPMC4893093 | biostudies-literature
Project description:Background and objectivesPreclinical interstitial lung disease (pILD) may represent the early stages of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the characteristics, clinical outcomes, and risk factors associated with fibrosis progression in RA-ILD, including pILD and ILD, remain poorly understood.MethodsBaseline data were compared between patients with RA-ILD and those with RA alone. Multivariate logistic regression and Cox regression analyses were performed to identify risk factors associated with the prevalence and imaging progression of RA-ILD, respectively.ResultsAmong the 371 enrolled RA patients, 32.3% had RA-ILD. Multiple logistic regression analyses identified age over 60.0 years (OR 2.22), smoking (OR 2.09), diabetes mellitus (DM) (OR 3.09), mixed connective tissue disease (MCTD) (OR 2.98), serum lactate dehydrogenase (LDH) levels exceeding 250.0 U/L (OR 6.73), and positive anti-cyclic citrullinated peptide (anti-CCP) antibody (OR 2.06) as independent risk factors for RA-ILD (p< 0.05 or 0.01). Among the 98 RA-ILD patients who underwent follow-up for a median duration of 19.1 months, 51.0% demonstrated fibrotic progression on high-resolution computed tomography (HRCT). Multiple Cox regression analysis identified DM (HR 2.03), Disease Activity Score in 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) greater than 5.1 (HR 2.21), and baseline HRCT scores exceeding 5.0 (HR 2.30) as independent risk factors for fibrosis progression in RA-ILD (p< 0.05 or 0.01).ConclusionNearly one-third of RA patients in this cohort had prevalent pILD or ILD, and half of them demonstrated imaging progression during follow-up. DM, higher DAS28-ESR, and advanced HRCT scores were identified as independent risk factors for progressive fibrosis in RA-ILD.
| S-EPMC10556458 | biostudies-literature
Project description:Although the rapid onset of effect of glucocorticoids (GCs) allows rapid control of rheumatoid arthritis (RA) symptoms, their chronic use may be associated with several adverse events. The 2022 update of EUALR recommendations for the management of patients with RA suggests to reduce and discontinue oral GCs as quickly as possible. Considering GCs as a "bridging therapy" to promptly reduce symptoms and control inflammation, fast-acting drugs such as tofacitinib could allow faster and safer tapering of GCs. The purpose of this pilot study was to evaluate the steroid-sparing effect of adding tofacitinib in patients with RA inadequately responsive to methotrexate taking concomitant GCs. In this open-label pilot study, we enrolled patients with moderate to severe RA on a stable dose of prednisone (5-12.5 mg/day) who started treatment with tofacitinib. After 1 month, in patients who achieved at least a moderate EULAR response (decrease of > 1.2 in DAS28_CRP), GCs was tapered according to a predetermined schedule until complete discontinuation at week 12. Disease activity was assessed after 4, 12, 24 and 48 weeks of treatment. The primary endpoint was the percentage of patients discontinuing GCs after 12 weeks of tofacitinib treatment. We enrolled 30 patients (26 F: 4 M, mean age 60 ± 13 years, mean disease duration 13.2 ± 7.8 years). The primary endpoint was achieved: 9 patients (30%) discontinued GCs at week-12. At week-24, other 12 patients (46%) withdrew GCs. The median prednisone dose decreased from 5 mg/day (interquartile range 5-10 mg) to 2.5 (0-5) mg/day at week 12 and 48 (p < 0.00001 vs baseline). At week 48, 12 out of 30 patients (40%) had discontinued prednisone. The percentage of patients achieving remission or low disease activity increased throughout the follow-up without any difference between patients who discontinued or not the GC. In this cohort of long-standing RA patients treated with tofacitinib, the discontinuation of glucocorticoids was achievable in up to 30% of patients. These results should encourage rheumatologists to consider GCs tapering and discontinuation of GCs, as suggested by the 2022 EULAR recommendations, an achievable goal.
| S-EPMC10511736 | biostudies-literature
Project description:ObjectiveThis study examined long-term outcomes of biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib discontinuation in patients with rheumatoid arthritis (RA).MethodsNinety-seven RA patients who desired drug discontinuation after sustained remission or low disease activity for at least 48 weeks due to stable treatment with biological drugs or tofacitinib were enrolled into this study. All patients were prospectively followed until disease flare or the end of the study. Discontinued drugs (previous drugs) were reintroduced to treat flares.ResultsFollowing bDMARD/tofacitinib discontinuation (mean follow-up, 2.1 years; standard deviation, 2.0), disease flare occurred at a crude incidence rate of 0.36 per person-year. The median time to flare was 1.6 years (95% confidence interval [CI] 0.9-2.6), and the cumulative flare probability was estimated to be 45% at 1 year, 64% at 3 years, and 80% at 5 years. No or little radiological progression was shown in 87.1% of patients who maintained remission for 3 years. A Fine‒Gray competing risk regression analysis showed that predictive factors for a flare were longer RA duration at the start of bDMARD/tofacitinib treatment, previous failure of treatment with bDMARDs, and a shorter period of remission or low disease activity before drug discontinuation. Type of discontinued drug was not identified as a predictive factor after adjusting for other predictor variables. Restarting previous treatment regimens led to rapidly regaining disease control in 89% of flare patients within 1 month.ConclusionDiscontinuation of bDMARD/tofacitinib may be a feasible strategy in RA patients, especially patients with early treated and longer-controlled RA. Flares are manageable in most RA patients and radiological progression is rare for at least 3 years in patients with sustained remission after bDMARD/tofacitinib discontinuation.
| S-EPMC9223309 | biostudies-literature