Study Of Abatacept Research Articles

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

BackgroundDrug-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.MethodsIn 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.ResultsRemission 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).ConclusionIn 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 registrationClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010)

Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial.

Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months. Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat DiffuseCutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. Aftercompletion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months ofabatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406. Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-labelextension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (-6·6 [SD 6·4]), with further improvement seen during the open-label extension period (-9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (-3·7 [SD 7·6]), with a further improvement at month 18 (-6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo-abatacept group (12 adverse events, one serious adverse event) and in 11 patients in theabatacept-abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension. During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis. Bristol-Myers Squibb and National Institutes of Health.

Multicenter, observational clinical study of abatacept in Japanese patients with rheumatoid arthritis

The aim of this study was to assess abatacept in rheumatoid arthritis (RA) patient. Patients (20 men, 89 women, aged 61.9 ± 10.4 y) who responded inadequately to conventional synthetic disease-modifying anti-rheumatic drug were treated with abatacept for 24-months. Disease activity score in 28 joints (DAS28-CRP) was evaluated. Of 109 patients, 82 (75.2%) were on methotrexate (MTX; mean dosage 9.0 ± 2.7 mg/week); 48 (44.0%) were naive to biologics and 61 (56.0%) had failed biologics. The 1- and 2-year retention rates were 77% and 53%, respectively. At 24-months, the DAS28-CRP remission rates were 62.8% in the biologic-naïve patients, and 33.3% in the biologic-failure patients (p < .01), while the structural remission rates were 83.9% and 73.1%, respectively (p = .461). Abatacept was equally effective in RA patients who were and were not on concomitant MTX. Biologic-naïve was associated with better clinical outcome. Abatacept was effective in patients who showed decreasing anti-CCP antibody titers or serum MMP-3 levels during treatment. Infection was the most frequent adverse effect of abatacept therapy. In conclusion, abatacept is more effective in biologic-naïve than in biologic-failure RA patients with or without concomitant use of MTX. Abatacept is more effective in RA patients with than without decreasing serum MMP-3 or anti-CCP antibody titers during treatment.

Abstract P289: Effect of Abaptacept on Blood Pressure in Essential Hypertensive Subjects with Rheumatological Disorders

We previously showed that abatacept, an inhibitor of T cell co-stimulation, prevents and reverses experimental hypertension. We now investigated whether it lowers blood pressure (BP) in humans. Of 1624 subjects receiving this drug in our de-identified electronic health record, 320 had hypertension and adequate baseline and follow up data (1 month to 3 years). Use of glucocorticoids (GC), non-steroidal antiinflammatory agents (NSAIDs), and antihypertensive drugs (HTND) was scored with the WHO system. ΔBPs at 1, 3 and 6 months and 1, 2 and 3 years after abatacept were adjusted for concomitant changes in medications and weights (Wt) by multivariate regression. Subjects were 80.6% female, 88.4% white, age 62±1 y, BMI 30.9±0.4 Kg/m 2 and BP 128.2±0.8/74.6±0.5 mmHg. Significant changes in confounders over time included decreases in GC, NSAID and HTND over the initial months followed by rebound beyond baseline at 2 and 3 years, and increases in Wt in these late periods. Changes in adjusted BP were limited to an increase in systolic BP at 2 years (1.75±1.04, p&lt;0.05) and a decrease in diastolic BP at 3 years (-1.67±0.80, p&lt;0.02). 91 subjects (28.4%) had a decrease of MAP ≥5 mmHg in at least half of the periods. ΔBP in these “responders” vs all other subjects was -10.8±0.7/-7.6±0.4, MAP -8.6±0.4 vs +5.0±0.4/+2.3±0.2, MAP +3.2±0.2, but these groups did not differ in sex, age, race, obesity, use of concomitant immunomodulators, pressors or blockers of the renin-angiotensin system (RASB). However, pooled adjusted ΔBP differed between women and men (diastolic -0.72±0.26 vs +1.48±0.48, p=0.0002; MAP -0.29±0.26 vs +1.58±0.55, p=0.003); between subjects younger and older than 65 y (systolic -0.05±0.48 vs +1.88±0.58, p=0.021; MAP -0.39±0.33 vs +0.64±0.37, p=0.037); and between those with BMI≤25 and &gt;25 Kg/m 2 (systolic -1.31±0.79 vs +1.37±0.42, p&lt;0.008). Finally, Δsystolic BP was -0.15±0.53 in subjects not taking and +1.42±0.50 in those taking RASB, p=0.037. In summary, long term use of abatacept mildly reduces BP in lean women with essential hypertension and rheumatological disorders. The effect is attenuated by obesity and perhaps also by aging and treatment with RASB. Further studies of abatacept in resistant essential hypertension are warranted, particularly in women.

Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: A systematic review.

To determine the efficacy of differing biologic therapies amongst individual juvenile idiopathic arthritis (JIA) subtypes rather than JIA overall. A systematic literature review was conducted between January 1975 and November 2014. Studies included were randomised controlled trials, controlled trials, non-randomised prospective studies or case-control studies. Subjects were required to have a diagnosis of JIA and were ≤20 years of age at study entry. Studies were deemed suitable for inclusion only when the authors reported the efficacy of biologic drugs within individual ILAR subtypes rather than JIA overall. Of 7663 articles identified in the original search, 25 were deemed eligible for inclusion in this review. These articles included over 4000 participants classified as having JIA, with mean age groups ranging from 3 to 13 years. Systemic JIA was the largest represented subtype, whilst the persistent oligoarthritis subtype was represented by the lowest number of participants (n = 54). Concerning etanercept, children with extended oligoarticular JIA were more likely to achieve inactive disease than other subtypes, with rheumatoid factor (RF) negative patients achieving inactive disease more frequently than RF positive children. Prospective data showed similar responses to etanercept in persistent oligoarticular groups compared to other subtypes. Etanercept was also shown to be efficacious in ERA and PsA, although the drug was not successfully discontinued in any of these patients without recurrence of the disease. In a study of abatacept, no differences were seen across subtypes. Systemic JIA appeared to be less responsive to etanercept when compared to tocilizumab over 12 weeks (etanercept: ACR30 58-78% and tocilizumab: ACR30 85%). However, longer term response over 12 months was more similar (etanercept: ACR30 83-100% and tocilizumab: ACR30 87-98%). This review has provided some evidence of a differing response to individual biologics according to JIA subtype and highlighted the under-representation of certain subtypes in published studies. Comparison of efficacy of individual biologics within subtypes is limited as published studies use variable methodology and head-to-head trials of biologics are lacking. Future trial design should consider differences in treatment response across and within ILAR subtypes to enable clinicians to make more relevant treatment decisions and achieve better patient outcomes.

AB0318 Abatacept (abt) equivalent to anti-tumor necrosis factor a (tnfa) in terms of joint destruction inhibition: multicenter study of 107 patients treated for 52 weeks

BackgroundAlthough two years have passed since the launch of abatacept (ABT) in Japan, little data are available on its efficacy in reducing structural joint damage. We performed a clinical assessment...

Phase II dose–response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

Objective The objective of this study was to assess the response to abatacept at doses of 2 mg/kg and 10 mg/kg compared to placebo in patients with active rheumatoid arthritis (RA) with an inadequate clinical response to methotrexate (MTX).Methods In this multicenter, placebo-controlled, double-blind, parallel-group, dose–response study, 195 Japanese patients with active RA with an inadequate response to MTX were randomized 1:1:1 to receive 10 mg/kg or 2 mg/kg abatacept plus MTX, or placebo plus MTX, for 24 weeks.Results Abatacept demonstrated a dose–response relationship when given at 2 and 10 mg/kg. Based on the American College of Rheumatology criteria (20, 50, and 70 %), the responses to 10 mg/kg abatacept were significantly greater than those to placebo at week 24 (p < 0.001). Smaller yet statistically significant responses were also seen in the 2 mg/kg abatacept group. Overall rates of adverse events, serious adverse events, and treatment discontinuations because of adverse events were comparable in all three groups.Conclusions Abatacept (2 mg/kg and 10 mg/kg) showed a dose–response relationship in Japanese patients with active RA with an inadequate clinical response to MTX. Administration of abatacept in combination with MTX for 24 weeks was well tolerated.

Erratum to: Phase II dose–response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

Erratum to: Phase II dose–response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

Abatacept for lupus nephritis: Alternative definitions of complete response support conflicting conclusions

Recent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis. Patients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology. According to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups). The choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis.

Abatacept in the treatment of lupus

Introduction: In contrast to other areas in rheumatology, the therapeutic armamentarium in systemic lupus erythematosus (SLE) has lagged behind due to a number of reasons. While SLE is the prototypical multi-system autoimmune disease, its low incidence and the heterogeneity in its clinical manifestations have made it difficult to study. Despite advances in the understanding and application of immunology, the emergence of new targets has not been successfully validated largely due to the difficult-to-use outcome measures. Among the many targets studied, co-stimulation blockade that prevents activation of T cells by antigen-presenting cells, poses an interesting concept that is plausible based on basic science, animal and early human studies.Areas covered: The authors hereby review the development of abatacept in the treatment of SLE and possible future directions.Expert opinion: Despite failure to achieve primary efficacy end points, the studies of abatacept in lupus provided tantalising evidence that co-stimulatory blockade is a feasible option worthy of further exploration.

Long term follow-up after sudden withdrawal from a multicentric study of abatacept in juvenile idiopathic arthritis – data from the Portuguese cohort

Results Eight patients (7M/1F) with mean age of 16.5 years (range 13-19years) and disease duration of 8,6years (range 1,5-13years) were followed. All patients had polyarticular involvement only partially responsive to methotrexate (extended oligoarticular (OE)-3, polyarticular Rheumatoid factor IgM negative (Poly)-2, systemic onset (SoJIA)-3). Concurrent therapies, maintained after the abatacept trial included NSAIDS, Methotrexate (8/8) and low dose steroids (3/8). All patients met the ACRpedi30 criteria, 5 of which (OE and Poly) were either in remission (2/8) or had marked improvement (1or 2 active joints). After 12 months of follow-up, all OE patients had inactive disease, as well as one Poly (4/8). Subsequently, 1of the OE and the other Poly flared, with etanercept being introduced at 27 and 29months of follow-up, respectively; 3 patients currently remain in full remission after 4 years (2 OE, 1 poly). SoJIA patients maintained active disease, requiring biologic therapy (mean 18months).