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Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment.

ABSTRACT: OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of ?-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of ?-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

SUBMITTER: Orban T

PROVIDER: S-EPMC3964491 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment.

Orban Tihamer T Bundy Brian B Becker Dorothy J DJ Dimeglio Linda A LA Gitelman Stephen E SE Goland Robin R Gottlieb Peter A PA Greenbaum Carla J CJ Marks Jennifer B JB Monzavi Roshanak R Moran Antoinette A Peakman Mark M Raskin Philip P Russell William E WE Schatz Desmond D Wherrett Diane K DK Wilson Darrell M DM Krischer Jeffrey P JP Skyler Jay S JS

Diabetes care 20131202 4

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geome ...[more]

PMID: 24296850

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Project description:BackgroundThe immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes.MethodsIn this multicentre, double-blind, randomised controlled trial, patients aged 6-45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375.Findings112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1-112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47-15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]).InterpretationCo-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions.FundingUS National Institutes of Health.

Project description:ObjectiveTo evaluate the rate of radiographic structural progression in the sacroiliac (SI) joints in patients with radiographic or nonradiographic axial spondyloarthritis (SpA), and to determine factors predisposing to such progression, over 2 years.MethodsPatients with recent-onset axial SpA (from the Devenir des Spondyloarthropathies Indifferérenciées Récentes cohort) were assigned a radiographic SI joint score according to the modified New York criteria. Demographic characteristics, smoking status, HLA-B27 positivity, inflammation on magnetic resonance imaging (MRI) of the SI joints, disease activity, and treatment were investigated as potential predisposing factors. The main analysis consisted of the evaluation of the switch from nonradiographic to radiographic axial SpA, but other definitions of radiographic progression were also evaluated.ResultsOf the 708 patients enrolled, 449 had baseline and 2-year pelvic radiographs. Of these patients, 47% were men. Their mean?±?SD age was 34?±?9 years, 61% were B27 positive, and 37% had inflammation of the SI joints on MRI. The percentages of patients who switched from nonradiographic to radiographic axial SpA (4.9% [16 of 326]) and from radiographic to nonradiographic axial SpA (5.7% [7 of 123]) were low. The mean?±?SD change in the total SI joint score (range 0-8) was small (0.1?±?0.8) but highly significant (P?<?0.001). The potential baseline predisposing factors for meeting the modified New York criteria in the multivariate analysis were current smoking, HLA-B27 positivity, and inflammation of the SI joints on MRI, with odds ratios of 3.3 (95% confidence interval [95% CI] 1.0-11.5], 12.6 (95% CI 2.3-274), and 48.8 (95% CI 9.3-904), respectively.ConclusionOur findings suggest that structural progression does exist in early SpA, but it is quite small and observed in a small number of patients, and that environmental (smoking status), genetic (HLA-B27 positivity), and inflammation (inflammation of the SI joints on MRI) markers might be independent predisposing factors for progression.

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Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment.

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Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment.

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