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In a 24-week trial involving patients with rheumatoid arthritis that was refractory to biologic agents, the JAK1 inhibitor upadacitinib was superior to the T-cell costimulation modulator abatacept in reducing disease activity as assessed by a composite measure of joint changes and C-reactive protein level.

This study evaluated 7-year efficacy and safety outcomes in transplant recipients assigned to a more-intensive or less-intensive belatacept regimen or cyclosporine for immunosuppression. Both belatacept regimens were associated with significantly superior patient and graft survival. The use of prolonged maintenance immunosuppressive therapy after kidney transplantation has improved the short-term outcomes, 1 but the effect on long-term allograft survival is not known. 2 Prospective, phase 3, randomized studies examining the outcomes of immunosuppressive regimens beyond 5 years or showing a survival advantage of newer immunosuppressive regimens over that afforded by regimens containing the calcineurin inhibitor cyclosporine are lacking. 3 – 5 Belatacept is a selective costimulation blocker that has been developed to improve long-term outcomes in kidney-transplant recipients by providing effective immunosuppression without the toxic effects of calcineurin inhibitors. Current standard-of-care immunosuppressive regimens combine calcineurin inhibitors with antiproliferative drugs, with . . .

Background Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections. We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011–2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs). Methods Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of ≥3 months’ SC abatacept. All patients received fixed-dose abatacept 125 mg/week with background DMARDs. A pre-vaccination blood sample was taken, and after 28 ± 3 days a final post-vaccination sample was collected. The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as ≥2-fold increase in post-vaccination titers to ≥3 of 5 antigens and protective antibody level of ≥1.6 μg/mL to ≥3 of 5 antigens; influenza: defined as ≥4-fold increase in post-vaccination titers to ≥2 of 3 antigens and protective antibody level of ≥1:40 to ≥2 of 3 antigens). Safety and tolerability were evaluated throughout the sub-studies. Results Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively. Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline. Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively. In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer ≥1.6 μg/mL to ≥3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer ≥1:40 to ≥2 of 3 antigens) at Day 28 post-vaccination. Vaccines were well tolerated with SC abatacept with background DMARDs. Conclusions In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines. Trial registration NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008).

Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013–003413–18). Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan–Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28–78; p<0·0001) at 12 months and 99 days (95% CI 38–161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Bristol Myers Squibb.

Background Patients with rheumatoid arthritis (RA) are at an increased risk of developing certain cancers and infections compared with the general population. Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are effective treatment options for RA, but limited evidence is available on the comparative risks among b/tsDMARDs. We assessed the risk of malignancies and infections in patients with RA who initiated abatacept versus other b/tsDMARDs in a real-world setting. Methods This retrospective, observational study used administrative data from three large US healthcare databases (MarketScan, PharMetrics, and Optum) to identify patients treated with abatacept or other b/tsDMARDs. In both groups, age-stratified incidence rates (IRs) with 95% confidence intervals (CIs) were calculated for total malignancy and hospitalized infections; propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs for total malignancy, lung cancer, lymphoma, breast cancer, non-melanoma skin cancer (NMSC), hospitalized infections, opportunistic infections, and tuberculosis (TB), both within individual databases and in meta-analyses across the three databases. Results A rounded total of 19.2, 13.6, and 4.2 thousand patients initiating abatacept and 55.3, 40.8, and 13.8 thousand initiating other b/tsDMARDs were identified in the MarketScan, PharMetrics, and Optum databases, respectively. The IRs for total malignancy and hospitalized infections were similar between the two groups in each age stratum. In meta-analyses, total malignancy risk (HR [95% CI] 1.09 [1.02–1.16]) of abatacept versus other b/tsDMARDs was slightly but statistically significantly increased; small, but not statistically significant, increases were seen for lung cancer (1.10 [0.62–1.96]), lymphoma (1.27 [0.94–1.72]), breast cancer (1.15 [0.92–1.45]), and NMSC (1.10 [0.93–1.30]). No significant increase in hospitalized infections (0.96 [0.84–1.09]) or opportunistic infections (1.06 [0.96–1.17]) was seen. For TB, low event counts precluded meta-analysis. Conclusions In this real-world multi-database study, the risks for specific cancers and infections did not differ significantly between patients in the abatacept and other b/tsDMARDs groups. The slight increase in total malignancy risk associated with abatacept needs further investigation. These results are consistent with the established safety profile of abatacept.

Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014–000555–93). Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9–45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04–0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04–0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. Innovative Medicine Initiative.

Background In rheumatoid arthritis (RA), macrophages play an important role in modulating the immunoinflammatory response through their polarisation into “classically” (M1) or “alternatively activated” (M2) phenotypes. In RA, CTLA4-Ig (abatacept) reduces the inflammatory activity of macrophages by interacting with the costimulatory molecule CD86. The study aimed to investigate the efficacy of CTLA4-Ig treatment to induce an M2 phenotype both in M1-polarised monocyte-derived macrophages (MDMs) obtained from healthy subjects (HS) and in cultured MDMs obtained from active RA patients. Methods Cultured MDMs were obtained from peripheral blood mononuclear cells of 7 active RA patients and from 10 HS after stimulation with phorbol myristate acetate (5 ng/mL) for 24 h. HS-MDMs were then stimulated with lipopolysaccharide (LPS, 1 mg/mL) for 4 h to induce M1-MDMs. M1-MDMs and RA-MDMs were treated with CTLA4-Ig (100 μM and 500 μM) for 3, 12, 24, and 48 h. The gene expression of CD80, CD86, and TLR4 (M1 markers); CD163, CD204, and CD206 (surface M2 markers); and MerTK (functional M2 marker) was evaluated by qRT-PCR. The protein synthesis of surface M2 markers was investigated by Western blotting. The statistical analysis was performed by the Wilcoxon t -test. Results In LPS-induced HS-M1-MDMs, CTLA4-Ig 100 μM and 500 μM significantly downregulated the gene expression of M1 markers (3 h p <0.01 for all molecules; 12 h p <0.05 for TLR4 and CD86) and significantly upregulated that of M2 markers, primarily after 12 h of treatment (CD163: p < 0.01 and p < 0.05; CD206: p < 0.05 and p < 0.01; CD204: p < 0.05 by 100 mg/mL). Moreover, in these cells, CTLA4-Ig 500 μM increased the protein synthesis of surface M2 markers ( p < 0.05). Similarly, in RA-MDMs, the CTLA4-Ig treatment significantly downregulated the gene expression of M1 markers at both concentrations primarily after 12 h ( p < 0.05). Furthermore, both concentrations of CTLA4-Ig significantly upregulated the gene expression of CD206 (after 3 h of treatment; p < 0.05), CD163, and MerTK (after 12 h of treatment, p < 0.05), whereas CD204 gene expression was significantly upregulated by the high concentration of CTLA4-Ig ( p < 0.05). The protein synthesis of all surface markers was increased primarily by CTLA4-Ig 500 μM, significantly for CD204 and CD206 after 24 h of treatment ( p < 0.05). Conclusions CTLA4-Ig treatment seems to induce the in vitro shift from M1 to M2 macrophages, of both HS-M1-MDMs and RA-MDMs, as observed by the significant downregulation exerted on selected M1 markers and the upregulation of selected M2 markers suggesting an additional mechanism for its modulation of the RA inflammatory process.

Trial design We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study. Conclusions There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration Current Controlled Trials, ID: ISRCTN46017566 . Registered on 4 July 2014.

ObjectivesTo evaluate efficacy and safety of abatacept in adults with active primary Sjögren’s syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.MethodsEligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.ResultsOf 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI −3.2 abatacept vs −3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.ConclusionsAbatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

Background AVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy. Methods During the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP]) < 2.6, were assessed. For patients achieving early sustained SDAI remission at weeks 24/40/52, flow between disease activity categories and individual trajectories was evaluated; flow was also evaluated for later remitters (weeks 40/52 but not week 24). Results Among patients treated with abatacept + methotrexate ( n / N  = 451/752) at IP week 24, 22% achieved SDAI remission, 17% achieved Boolean remission, and 42% achieved DAS28 (CRP) < 2.6; of these, 56%, 58%, and 74%, respectively, sustained a response throughout IP weeks 40/52. Among patients with a sustained response at IP weeks 24/40/52, 82% (14/17) on weekly abatacept + methotrexate, 81% (13/16) on abatacept monotherapy, 63% (12/19) who de-escalated/withdrew abatacept, and 65% (11/17) on abatacept placebo + methotrexate were in SDAI remission at end of the DE period; rates were higher than for later remitters in all arms except abatacept placebo + methotrexate. Conclusions A high proportion of individual patients achieving clinical endpoints at IP week 24 with abatacept + methotrexate sustained their responses through week 52. Of patients achieving early and sustained SDAI remission through 52 weeks, numerically more maintained remission during the DE period if weekly abatacept treatment continued. Trial registration NCT02504268 (ClinicalTrials.gov), registered July 21, 2015.