Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies.

BACKGROUND & AIMS: The pivotal phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. This analysis assessed ozanimod during TN and the ongoing open-label extension (OLE) in patients with active disease who were naive to advanced therapies (ATs). METHODS: TN was a randomized, double-blind, placebo-controlled trial consisting of 10-week induction period and 42-week maintenance period. Eligible patients could enter the OLE. Symptomatic efficacy was evaluated from induction through the OLE. Clinical, endoscopic, and mucosal outcomes were evaluated at the end of induction (Week [W] 10) and maintenance (W52) and at predefined OLE timepoints (OLE W46 and W94). Safety during TN was reported. RESULTS: This analysis included 616 AT-naive patients. Numerically greater proportions of patients receiving ozanimod than placebo achieved symptomatic response (39% vs 29%, 95% confidence interval, -0.1 to 18.8) by W2, with significant differences (56% vs 39%, 95% confidence interval, 6.3-26.3) achieved by W4. Patients receiving ozanimod showed significant improvements across efficacy outcomes versus placebo at W10 and W52 (P < .05, all endpoints). In patients on continuous ozanimod who entered the OLE in clinical response at W52, 91% maintained clinical response through OLE W94, and 74% achieved endoscopic improvement and 57% achieved mucosal healing at OLE W94. In ozanimod-treated patients without clinical response by W10 who received extended induction in the OLE, 62% achieved symptomatic response by OLE W10. Safety outcomes in AT-naive patients were consistent with the total TN population. CONCLUSIONS: Ozanimod is an effective, durable, and well-tolerated oral therapy for AT-naive ulcerative colitis patients. CLINICALTRIALS: gov, numbers NCT02435992 and NCT02531126.

Considerations for Colorectal Neoplasia Detection in Inflammatory Bowel Disease Clinical Trials.

BACKGROUND: High-quality colonoscopic surveillance can lead to earlier and increased detection of colorectal neoplasia in patients with inflammatory bowel disease (IBD). In IBD clinical trials, endoscopy is used to assess mucosal disease activity before and after treatment but also provides an opportunity to surveil for colorectal neoplasia during follow-up. SUMMARY: Best practices for colorectal cancer identification in IBD clinical trials require engagement and collaboration between the clinical trial sponsor, site endoscopist and/or principal investigator, and central read team. Each team member has unique responsibilities for maximizing dysplasia detection in IBD trials. KEY MESSAGES: Sponsors should work in accordance with scientific guidelines to standardize imaging procedures, design the protocol to ensure the trial population is safeguarded, and oversee trial conduct. The site endoscopist should remain updated on best practices to tailor sponsor protocol-required procedures to patient needs, examine the mucosa for disease activity and potential dysplasia during all procedures, and provide optimal procedure videos for central read analysis. Central readers may detect dysplasia or colorectal cancer and a framework to report these findings to trial sponsors is essential. Synergistic relationships between all team members in IBD clinical trials provide an important opportunity for extended endoscopic evaluation and colorectal neoplasia identification.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses.

BACKGROUND & AIMS: Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). METHODS: All patients who received ozanimod in TN (n = 796) and all eligible TN patients who entered the OLE (n = 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. RESULTS: On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. CONCLUSIONS: No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

Implementation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System in a randomized phase IIb study of abatacept in psoriatic arthritis.

OBJECTIVES: To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA. METHODS: We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365. MRIs at baseline and days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, osteitis, tenosynovitis, periarticular inflammation, bone erosions, joint space narrowing and bone proliferation were assessed using the PsAMRIS. A novel total inflammation score was tested. RESULTS: MRIs for 123 patients were included. On day 169, ABA10 and ABA30/10 significantly reduced MRI synovitis and tenosynovitis, respectively, vs placebo [differences -0.966 (P = 0.039) and -1.652 (P = 0.014), respectively]. Synovitis in the placebo group increased non-significantly from baseline to day 169, total inflammation and tenosynovitis decreased non-significantly and all measures improved significantly after a switch to ABA10 [-1.019, -0.940, -2.275 (P < 0.05), respectively, day 365 vs day 169]. Structural outcomes changed minimally across groups. CONCLUSION: Adults with PsA receiving ABA10 and ABA30/10 demonstrated significant resolution of inflammatory components of disease, confirmed by MRI, with synovitis and tenosynovitis improvements consistent with previously reported clinical responses for these doses. Results indicate that a reduction in OMERACT PsAMRIS inflammation scores may provide proof of tissue-level efficacy in PsA clinical trials. REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00534313.

Disease activity measures at baseline predict structural damage progression: data from the randomized, controlled AMPLE and AVERT trials.

OBJECTIVE: Data from two double-blind, randomized, Phase III studies were analysed to investigate the ability of Routine Assessment of Patient Index Data 3, DAS28 (CRP), modified (M)-DAS28 (CRP) and Simplified or Clinical Disease Activity Indices to predict structural damage progression in RA. METHODS: This post hoc analysis included data from the 2-year Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) trial in biologic-naïve patients with active RA (<5 years) and an inadequate response to MTX, and the 12-month treatment period of the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial in MTX-naïve patients with early RA (⩽2 years) and poor prognostic indicators. Adjusted logistic regression analysis assessed the relationship between baseline disease activity and structural damage progression (defined as change from baseline greater than the smallest detectable change) at 12 and 24 months in AMPLE and 6 and 12 months in AVERT. Areas under the receiver operating characteristic curves for the impact of baseline disease activity on structural damage progression were calculated. RESULTS: Adjusted logistic regression analyses included all randomized and treated patients in AMPLE (N = 646) and those who received abatacept plus MTX or MTX monotherapy in AVERT (N = 235). Baseline Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) scores significantly predicted structural progression at months 12 and 24 in AMPLE (P < 0.05) and months 6 and 12 in AVERT (P < 0.01), and were stronger predictors than Simplified or Clinical Disease Activity Indices. CONCLUSION: In this post hoc analysis of two patient populations with RA, Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) were good at predicting structural damage. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov: NCT00929864 (AMPLE); NCT01142726 (AVERT).

Poor prognostic factors in predicting abatacept response in a phase III randomized controlled trial in psoriatic arthritis.

In ASTRAEA (NCT01860976), abatacept significantly increased American College of Rheumatology criteria 20% (ACR20) responses at Week 24 versus placebo in patients with psoriatic arthritis (PsA). This post hoc analysis explored relationships between prospectively identified baseline characteristics [poor prognostic factors (PPFs) ] and response to abatacept. Patients were randomized (1:1) to receive subcutaneous abatacept 125 mg weekly or placebo for 24 weeks; those without ≥ 20% improvement in joint counts at Week 16 switched to open-label abatacept. Potential predictors of ACR20 response were identified by treatment arm using multivariate analyses. Likelihood of ACR20 response to abatacept versus placebo was compared in univariate and multivariate analyses in subgroups stratified by the PPF, as defined by EULAR and/or GRAPPA treatment guidelines. Odds ratios (ORs) were generated using logistic regression to identify meaningful differences (OR cut-off: 1.2). 424 patients were randomized and treated (abatacept n = 213; placebo n = 211). In abatacept-treated patients, elevated C-reactive protein (CRP), high Disease Activity Score based on 28 joints (CRP), presence of dactylitis, and ≥ 3 joint erosions were identified as predictors of response (OR > 1.2). In placebo-treated patients, only dactylitis was a potential predictor of response. In the univariate analysis stratified by PPF, ACR20 response was more likely (OR > 1.2) with abatacept versus placebo in patients with baseline PPFs than in those without; multivariate analysis confirmed this finding. Response to abatacept versus placebo is more likely in patients with features indicative of high disease activity and progressive disease; these characteristics are recognized as PPFs in treatment guidelines for PsA.

Correction to: On-drug and drug-free remission by baseline symptom duration: abatacept with methotrexate in patients with early rheumatoid arthritis.

The article "On-drug and drug-free remission by baseline symptom duration: abatacept with methotrexate in patients with early rheumatoid arthritis", written by Vivian P.Bykerk, was originally published Online First without open access.

On-drug and drug-free remission by baseline symptom duration: abatacept with methotrexate in patients with early rheumatoid arthritis.

Clinical outcomes in patients with early rheumatoid arthritis (RA) were assessed by baseline symptom duration in the Assessing Very Early Rheumatoid arthritis Treatment trial (ClinicalTrials.gov; NCT01142726). Patients with early, active RA were randomized to subcutaneous (SC) abatacept 125 mg/week plus methotrexate (MTX), SC abatacept alone, or MTX monotherapy for 12 months. All RA treatments were withdrawn after 12 months in patients with Disease Activity Score in 28 joints (C-reactive protein; DAS28-CRP) < 3.2. In this post hoc analysis, the proportion of patients achieving protocol-defined remission (DAS28-CRP < 2.6) or improvement in physical function at 12 and at both 12 and 18 months was assessed according to symptom duration (≤ 3 months, > 3 to ≤ 6 months, or > 6 months) and treatment group. No clinically significant differences were seen in baseline demographics or characteristics across symptom duration groups. Irrespective of baseline symptom duration, a numerically higher proportion of abatacept plus MTX-treated patients achieved DAS-defined remission at month 12 and sustained remission at month 18 compared with MTX monotherapy. A numerically higher proportion of abatacept plus MTX-treated patients with symptom duration ≤ 3 months maintained DAS-defined remission after complete treatment withdrawal from 12 to 18 months compared with longer symptom duration groups. This subgroup also had the fastest onset of clinical response (DAS28-CRP < 2.6) after initiation of treatment. Health Assessment Questionnaire-Disability Index response was similar regardless of baseline symptom duration. Overall, symptom duration of ≤ 3 months was associated with a faster onset of clinical response and higher rates of drug-free remission following treatment with abatacept plus MTX.

Measurement error in the assessment of radiographic progression in rheumatoid arthritis (RA) clinical trials: the smallest detectable change (SDC) revisited.

OBJECTIVES: To evaluate if the mean smallest detectable change (SDC) of multiple time intervals using the Bland & Altman (B&A) levels of agreement (LoA) method is an appropriate surrogate for the generalisability analysis method for estimating the overall SDC of radiological progression in rheumatoid arthritis (RA) trials. Secondly, to compare the SDC based on 95% LoA with the SDC based on 80% LoA, and to investigate the association between SDC and baseline damage and progression. METHODS: Fifteen datasets from randomised controlled trials in RA were scored by 13 experienced readers as pairs according to the modified Sharp/van der Heijde method. The SDC using the 95% and 80% LoA and the generalisability methods was calculated. RESULTS: 21 295 radiographic time points from 7643 patients were included. The mean (range) SDC for the LoA and the generalisability methods was 3.1 (2.3-4.3) and 3.2 (2.3-4.6) units, respectively. The mean ± SD difference between the two methods was -0.13 ± 0.28. The mean SDC including all intervals (n=31) was 3.0 ± 0.7 for 95% LoA and 2.0 ± 0.4 for 80% LoA. No relationship was observed between baseline damage and the SDC, whereas the SDC increased with increasing radiological progression. CONCLUSIONS: The mean of the interval SDCs obtained by the simple LoA method is a valid surrogate for the SDC obtained by complex generalisability methods. The SDC depends on the level of radiographic progression rather than on the level of absolute damage. In addition, the use of an SDC based on 80% rather than on 95% LoA is proposed.

Rate of adjudication of radiological progression in rheumatoid arthritis randomized controlled trials depending on preset limits of agreement: a pooled analysis from 15 randomized trials.

OBJECTIVE: The aim of this study is to provide data on the adjudication rate for a predetermined threshold of difference in change score between two readers in randomized controlled trials (RCTs). METHODS: Fifteen datasets from RCTs in RA were scored by 13 experienced readers as pairs according to the modified Sharp-van der Heijde method. The theoretical adjudication rates for thresholds of between 3 and 20 units were calculated. We investigated the influence of the number of time points within the same session, the length of the interval and disease duration on the adjudication rates. RESULTS: A total of 21,295 time points from 7643 patients from 15 databases were included in the analysis. The adjudication rate was inversely related to the threshold. Higher adjudication rates were observed with a higher number of time points, longer time intervals and in early versus established RA. The adjudication rates ranged from 0% to 22% depending on the scenario. CONCLUSION: With trained and experienced readers, the adjudication rate in RA RCTs is low even with very conservative adjudication thresholds.

Artificial intelligence in inflammatory bowel disease: implications for clinical practice and future directions.

Inflammatory bowel disease encompasses Crohn's disease and ulcerative colitis and is characterized by uncontrolled, relapsing, and remitting course of inflammation in the gastrointestinal tract. Artificial intelligence represents a new era within the field of gastroenterology, and the amount of research surrounding artificial intelligence in patients with inflammatory bowel disease is on the rise. As clinical trial outcomes and treatment targets evolve in inflammatory bowel disease, artificial intelligence may prove as a valuable tool for providing accurate, consistent, and reproducible evaluations of endoscopic appearance and histologic activity, thereby optimizing the diagnosis process and identifying disease severity. Furthermore, as the applications of artificial intelligence for inflammatory bowel disease continue to expand, they may present an ideal opportunity for improving disease management by predicting treatment response to biologic therapies and for refining the standard of care by setting the basis for future treatment personalization and cost reduction. The purpose of this review is to provide an overview of the unmet needs in the management of inflammatory bowel disease in clinical practice and how artificial intelligence tools can address these gaps to transform patient care.

Artificial Intelligence in Inflammatory Bowel Disease Endoscopy: Implications for Clinical Trials.

Artificial intelligence shows promise for clinical research in inflammatory bowel disease endoscopy. Accurate assessment of endoscopic activity is important in clinical practice and inflammatory bowel disease clinical trials. Emerging artificial intelligence technologies can increase efficiency and accuracy of assessing the baseline endoscopic appearance in patients with inflammatory bowel disease and the impact that therapeutic interventions may have on mucosal healing in both of these contexts. In this review, state-of-the-art endoscopic assessment of mucosal disease activity in inflammatory bowel disease clinical trials is described, covering the potential for artificial intelligence to transform the current paradigm, its limitations, and suggested next steps. Site-based artificial intelligence quality evaluation and inclusion of patients in clinical trials without the need for a central reader is proposed; for following patient progress, a second reading using AI alongside a central reader with expedited reading is proposed. Artificial intelligence will support precision endoscopy in inflammatory bowel disease and is on the threshold of advancing inflammatory bowel disease clinical trial recruitment.

Declining Enrolment and Other Challenges in IBD Clinical Trials: Causes and Potential Solutions.

BACKGROUND: Rates of enrolment in clinical trials in inflammatory bowel disease [IBD] have decreased dramatically in recent years. This has led to delays, increased costs and failures to develop novel treatments. AIMS: The aim of this work is to describe the current bottlenecks of IBD clinical trial enrolment and propose solutions. METHODS: A taskforce comprising experienced IBD clinical trialists from academic centres and pharmaceutical companies involved in IBD clinical research predefined the four following levels: [1] study design, [2] investigative centre, [3] physician and [4] patient. At each level, the taskforce collectively explored the reasons for declining enrolment rates and generated an inventory of potential solutions. RESULTS: The main reasons identified included the overall increased demands for trials, the high screen failure rates, particularly in Crohn's disease, partly due to the lack of correlation between clinical and endoscopic activity, and the use of complicated endoscopic scoring systems not reflective of the totality of inflammation. In addition, complex trial protocols with restrictive eligibility criteria, increasing burden of procedures and administrative tasks enhance the need for qualified resources in study coordination. At the physician level, lack of dedicated time and training is crucial. From the patients' perspective, long washout periods from previous medications and protocol requirements not reflecting clinical practice, such as prolonged steroid management and placebo exposures, limit their participation in clinical trials. CONCLUSION: This joint effort is proposed as the basis for profound clinical trial transformation triggered by investigative centres, contract research organizations, sponsors and regulatory agencies.

Identification of poor prognostic joint locations in an early rheumatoid arthritis cohort at risk of rapidly progressing disease: a post-hoc analysis of the Phase III AGREE study.

BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease with established poor prognostic factors such as seropositivity, joint damage, and high disease activity at an early, treatment-naïve stage of disease. However, few studies have examined if specific joint locations are correlated with these factors in such a population. This analysis explored the potential correlation of individual swollen and erosive joints with other disease characteristics at baseline and with remission rates in a post-hoc analysis of the Phase III randomized AGREE study. METHODS: Methotrexate (MTX)-naïve, erosive, RF- and/or ACPA-positive early RA patients (N = 509) were retrospectively evaluated. Baseline joint swelling was analyzed for large and small joints. Baseline erosions were analyzed for wrist, MCP1-5, IP1, PIP2-5 and MTP1-5. Remission rates were assessed after 6 months of treatment with abatacept (ABA) + MTX (N = 256) or MTX (N = 253). The following statistical tests were used: Chi-Square or Fisher's exact test (categorical variables); Student's t-test or Wilcoxon rank-sum test (continuous variables); continuity-corrected Chi-square test (efficacy remission endpoints). RESULTS: Baseline swelling was most frequent in wrist (91.9%) and MCP2 joint (89.1%), while baseline erosion was most frequent in MTP5 joint (43.5%). Swollen shoulder was significantly correlated (p < 0.0001) with swelling of almost all other large or medium joints. Baseline swelling in the knee, temporomandibular joint (TMJ), wrist and elbow was highly correlated (p < 0.001) with higher tender and swollen joint counts, higher DAS28(CRP) and higher SDAI and CDAI. Baseline swelling was not correlated with erosion per joint, except for MCP2. The largest difference in mean Boolean remission rates at 6 months was in patients with baseline swollen wrist favoring ABA + MTX (14.0% vs 4.4%; p < 0.001). CONCLUSIONS: Swelling in the large and medium joints (knee, TMJ, elbow and wrist) was highly correlated with severe disease activity while MCP2 swelling seemed to be correlated with joint damage. The correlation of joint locations at an early, treatment-naïve stage with poor prognostic factors, higher disease activity and joint damage, could establish a rapidly progressing anatomical pattern in early RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00122382, registered July 2005.

Prediction of flare following remission and treatment withdrawal in early rheumatoid arthritis: post hoc analysis of a phase IIIb trial with abatacept.

BACKGROUND: Drug-free remission is a desirable goal in rheumatoid arthritis (RA) for both patients and clinicians. The aim of this post hoc analysis was to investigate whether clinical and magnetic resonance imaging (MRI) variables in patients with early RA who achieved remission with methotrexate and/or abatacept at 12 months could predict disease flare following treatment withdrawal. METHODS: In the AVERT study of abatacept in early RA, patients with low disease activity at month 12 entered a 12-month period with all treatment discontinued (withdrawal, WD). This post hoc analysis assessed predictors of disease flare at WD+6months (mo) and WD+12mo of patients with Disease Activity Score in 28 joints (DAS28)-defined remission (DAS28[C-reactive protein (CRP)] <2.6) at withdrawal using univariate and multivariable regression models. Predictors investigated included the Health Assessment Questionnaire-Disability Index (HAQ-DI), pain, Patient Global Assessment; MRI synovitis, erosion, bone edema, and combined (synovitis + bone edema) inflammation scores. RESULTS: Remission was achieved by 172 patients; 100 (58%) and 113 (66%) patients had experienced a flare at WD+6mo and WD+12mo, respectively. In univariate analyses, higher HAQ-DI and MRI synovitis, erosion, bone edema, and combined inflammation scores at WD were identified as potential predictors of flare (P ≤ 0.01). In multivariable analysis, high scores at WD for HAQ-DI and MRI erosion were confirmed as independent predictors of flare at WD+6mo and WD+12mo (P < 0.01). CONCLUSION: In patients with early RA achieving clinical remission, patient function (HAQ-DI), and MRI measures of bone damage (erosion) predicted disease flare 6 and 12 months after treatment withdrawal. These variables may help identify patients with early RA in clinical remission as candidates for successful treatment withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010).

Poor Patient-Reported Outcomes and Impaired Work Productivity in Patients With Inflammatory Bowel Disease in Remission.

Background and Aims: This study aimed to evaluate associations between disease severity, patient-reported outcomes (PROs), and work productivity in patients with inflammatory bowel disease (IBD [Crohn's disease (CD) and ulcerative colitis (UC)]). Methods: Patients diagnosed with CD or UC enrolled in CorEvitas' IBD Registry (May 2017 to September 2019) were included (N = 1543; CD, n = 812; UC, n = 731). Disease severity was assessed using the Harvey-Bradshaw Index (CD) and partial Mayo Score (UC); psychosocial PROs (Patient-Reported Outcomes Measurement Information System [PROMIS]) and work productivity (Work Productivity and Activity Impairment [WPAI]) were assessed. Univariable and multivariable regression analyses assessed associations between PROs and disease severity. Results: Among CD patients, 67.4% were in remission, 19.2% had mild disease, and 13.4% had moderate/severe disease; among UC patients, 52.7% were in remission, 35.3% had mild disease, and 12.0% had moderate/severe disease. For CD patients in remission, unadjusted percentages of patients with PROMIS scores outside normal limits ranged from 18.9% (depression) to 34.9% (fatigue). For CD patients in remission, 54.3% reported work productivity loss, and 57.1% reported activity impairment. The unadjusted percentage of UC patients in remission with scores outside normal limits ranged from 15.7% (depression) to 28.7% (fatigue) for PROMIS and 10.5% (absenteeism) to 43.5% (activity impairment) for WPAI. Impairment increased with IBD severity. Congruently, adjusted estimates showed significant impairment in PROMIS and WPAI scores for CD and UC patients in remission. Conclusion: In this real-world analysis, IBD patients across the spectrum of activity, from remission to severe disease, experienced impaired psychosocial function and reduced work productivity. Impairment, even among patients in remission, indicates an unmet need in this patient population.

Background Glucocorticoid Therapy Has No Impact on Efficacy and Safety of Abatacept or Adalimumab in Patients with Rheumatoid Arthritis.

To date, the impact of background glucocorticoids (GC) on the efficacy and safety of abatacept or adalimumab in patients with active rheumatoid arthritis (RA) is not clearly established. This post hoc analysis of (AMPLE) trial (NCT00929864) compared efficacy and safety outcomes over 2 years in patients treated with abatacept or adalimumab plus background methotrexate (MTX), who continued GC (≤10 mg/day) versus those who were not receiving GC (no-GC). Of 646 randomized patients, 317 received abatacept + MTX (161 GC, 156 no-GC) and 326 received adalimumab + MTX (162 GC, 164 no-GC). At Year 2, the adjusted mean changes from baseline in Disease Activity Score (DAS28 C-reactive protein (CRP)) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were not significantly different in the GC versus no-GC subgroups receiving abatacept or adalimumab. A similar proportion of patients achieved remission, HAQ-DI score improvement ≥0.3 and radiographic progression rates. No clinically meaningful safety differences were observed between GC versus no-GC subgroups either with abatacept or adalimumab. In patients with active RA of similar baseline disease activity treated with abatacept or adalimumab plus background MTX, there was no additional value of background GC on clinical, functional or radiographic outcomes over two years.

Baseline Objective Inflammation by Magnetic Resonance Imaging as a Predictor of Therapeutic Benefit in Early Rheumatoid Arthritis With Poor Prognosis.

OBJECTIVE: High magnetic resonance imaging (MRI)-detected inflammation is associated with greater progression and poorer outcomes in rheumatoid arthritis (RA). This analysis aimed to determine if baseline MRI inflammation was related to clinical response and remission in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) study. METHODS: AVERT was a phase IIIb, randomized, controlled trial with a 12-month, double-blind treatment period enrolling patients with early (≤2 years' duration), anti-citrullinated peptide-positive methotrexate (MTX)-naive RA. In this post hoc analysis, patients in the abatacept plus MTX (n = 114) and MTX (n = 111) arms with available MRI results were stratified into low and high baseline MRI inflammation groups based on previously developed cutoffs of synovitis and osteitis on unilateral hand-wrist contrast-enhanced MRI. Simplified Disease Activity Index (SDAI) remission (≤3.3), Clinical Disease Activity Index (CDAI) remission (≤2.8), Boolean remission, and Disease Activity Score in 28 joints using the C-reactive protein level (<2.6) were assessed. RESULTS: Overall, 100 of 225 patients (44.4%) had high baseline MRI inflammation. In patients with high baseline MRI inflammation, a significantly greater proportion achieved remission at 12 months with abatacept plus MTX versus MTX across SDAI (45.1% versus 16.3%; P = 0.0022), CDAI (47.1% versus 20.4%; P = 0.0065), and Boolean indices (39.2% versus 16.3%; P = 0.0156). In patients with low baseline MRI inflammation, remission rates were not significantly different with abatacept plus MTX versus MTX (SDAI: 39.7% versus 32.3%; P = 0.4961). CONCLUSION: In seropositive, MTX-naive patients with early RA and presence of objectively measured high inflammation by MRI, indicating poor prognosis, remission rates were higher with abatacept plus MTX treatment versus MTX.

Determining MRI Inflammation Targets When Considering a Rheumatoid Arthritis Treat-to-Target Strategy: Results of a Randomized, Placebo-Controlled Trial.

INTRODUCTION: Magnetic resonance imaging (MRI) is increasingly used in patients with rheumatoid arthritis (RA) to determine residual inflammation after treatment and as a predictor of structural damage progression. Establishing an optimal threshold of inflammatory activity that predicts lower risk of structural damage progression may inform treatment decisions. This post hoc analysis investigated whether patients with RA at low risk of structural damage progression can be identified based on MRI inflammation thresholds. METHODS: Hand and wrist MRI was performed at baseline, and at months 6 and 12 in a phase 3b, randomized, active-controlled, double-blind trial of abatacept in early RA (AVERT). Pathologies were scored using the OMERACT RA MRI Score. Data were stratified into two risk subgroups (less and more severe inflammation) for structural damage progression (erosion change > 0.5) based on baseline inflammation. In this post hoc analysis, log odds ratios of probability of progression {adjusted for baseline Disease Activity Score in 28 joints [C-reactive protein; DAS28 (CRP)]} were compared between subgroups to test the performance of inflammation thresholds. RESULTS: There were 351 randomized and treated patients with baseline MRIs, of whom 276 (78.6%) and 235 (67.0%) had MRIs available at months 6 and 12, respectively. The DAS28 (CRP)-adjusted probabilities of progression from baseline to month 12 based on scores at baseline, and from months 6 to 12 based on month 6 scores, were significantly lower among patients with less inflammation (P < 0.0001-0.0459), independent of clinical disease activity. Predefined thresholds of synovitis ≤ 3 (total score 21), osteitis ≤ 3 (total score 69) and total inflammation score (osteitis double-weighted) ≤ 9 were associated with a lower likelihood of structural damage progression in unadjusted analyses. CONCLUSION: Levels of MRI-determined inflammatory activity below defined thresholds were independently associated with a lower risk of structural damage progression in early RA, providing a potential trial endpoint for levels of inflammation not associated with progression. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01142726. FUNDING: Bristol-Myers Squibb.

Body mass index and treatment response to subcutaneous abatacept in patients with psoriatic arthritis: a post hoc analysis of a phase III trial.

Objective: This post hoc analysis of the phase III Active PSoriaTic Arthritis RAndomizEd TriAl (ASTRAEA) evaluated the effect of baseline body mass index (BMI) on subsequent response to subcutaneous (SC) abatacept in patients with psoriatic arthritis (PsA). Methods: In ASTRAEA, patients with active PsA were randomised (1:1) to receive blinded weekly SC abatacept 125 mg or placebo for 24 weeks. Treatment response at week 24 was assessed by the proportions of patients achieving American College of Rheumatology 20% improvement response, Disease Activity Score in 28 joints (DAS28 (C reactive protein (CRP))) ≤3.6 and <2.6, Health Assessment Questionnaire-Disability Index reduction from baseline ≥0.35 and radiographic non-progression (defined as change from baseline ≤0 in PsA-modified total Sharp/van der Heijde score). Responses were stratified by baseline BMI (underweight/normal, <25 kg/m2; overweight, 25-30 kg/m2; obese, >30 kg/m2) and compared in univariate and multivariate models. Results: Of 212/213 and 210/211 patients with baseline BMI data in the abatacept and placebo groups, respectively, 15% and 19% were underweight/normal, 36% and 27% were overweight, and 49% and 54% were obese. After adjusting for baseline characteristics, there were no significant differences for any outcome measure at week 24 with abatacept in the overweight or obese versus underweight/normal subgroup. In the placebo group, patients in the obese versus underweight/normal subgroup were significantly less likely to achieve DAS28 (CRP) <2.6 at week 24 (OR 0.26; 95% CI 0.08 to 0.87; p=0.03). Conclusion: BMI does not impact clinical or radiographic response to SC abatacept in patients with PsA. Trial registration number: NCT01860976.