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RMD Open Aug 2023This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and...
OBJECTIVES
This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis.
METHODS
The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation.
RESULTS
TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55).
CONCLUSIONS
TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.
Topics: Humans; Abatacept; Cohort Studies; Janus Kinase Inhibitors; Retrospective Studies; Arthritis, Rheumatoid; Immunoglobulin G; Tumor Necrosis Factor Inhibitors; Biological Products
PubMed: 37597846
DOI: 10.1136/rmdopen-2023-003160 -
RMD Open Mar 2022Randomised controlled trials (RCTs) have compared biological and targeted systemic disease-modifying antirheumatic drugs (DMARDS) against placebo in psoriatic arthritis... (Meta-Analysis)
Meta-Analysis
Targeted systemic therapies for psoriatic arthritis: a systematic review and comparative synthesis of short-term articular, dermatological, enthesitis and dactylitis outcomes.
INTRODUCTION
Randomised controlled trials (RCTs) have compared biological and targeted systemic disease-modifying antirheumatic drugs (DMARDS) against placebo in psoriatic arthritis (PsA); few have compared them head to head.
OBJECTIVES
To compare the efficacy and safety of all evaluated DMARDs for active PsA, with a special focus on biological DMARDs (bDMARDs) licensed for PsA or psoriasis.
METHODS
A systematic review identified RCTs and Bayesian network meta-analysis (NMA) compared treatments on efficacy (American College of Rheumatology (ACR) response, Psoriasis Area and Severity Index (PASI) response, resolution of enthesitis and dactylitis) and safety (patients discontinuing due to adverse events (DAE)) outcomes. Subgroup analyses explored ACR response among patients with and without prior biological therapy exposure.
RESULTS
The NMA included 46 studies. Results indicate that some tumour necrosis factor inhibitors (anti-TNFs) may perform numerically, but not significantly, better than interleukin (IL) inhibitors on ACR response but perform worse on PASI response. Few significant differences between bDMARDs on ACR response were observed after subgrouping for prior bDMARD exposure. Guselkumab and IL-17A or IL-17RA inhibitors-brodalumab, ixekizumab, secukinumab-were best on PASI response. These IL-inhibitors and adalimumab were similarly efficacious on resolution of enthesitis and dactylitis. Infliximab with and without methotrexate, certolizumab 400 mg every 4 weeks and tildrakizumab showed the highest rates of DAE; abatacept, golimumab and the IL-inhibitors, the lowest.
CONCLUSIONS
Despite similar efficacy for ACR response, IL-17A and IL-17RA inhibitors and guselkumab offered preferential efficacy to anti-TNFs in skin manifestations, and for enthesitis and dactylitis, thereby supporting drug selection based on predominant clinical phenotype.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Psoriatic; Enthesopathy; Humans
PubMed: 35321874
DOI: 10.1136/rmdopen-2021-002074 -
JAMA Jul 2023Immune dysregulation contributes to poorer outcomes in COVID-19.
IMPORTANCE
Immune dysregulation contributes to poorer outcomes in COVID-19.
OBJECTIVE
To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.
INTERVENTIONS
Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).
MAIN OUTCOMES AND MEASURES
The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.
RESULTS
Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.
CONCLUSIONS AND RELEVANCE
Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04593940.
Topics: Male; Humans; Adult; Middle Aged; Female; COVID-19; Abatacept; Infliximab; SARS-CoV-2; Pandemics
PubMed: 37428480
DOI: 10.1001/jama.2023.11043 -
Journal of the American Society of... Dec 2021Calcineurin inhibitors (CNIs) are standard of care after kidney transplantation, but they are associated with nephrotoxicity and reduced long-term graft survival.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Calcineurin inhibitors (CNIs) are standard of care after kidney transplantation, but they are associated with nephrotoxicity and reduced long-term graft survival. Belatacept, a selective T cell costimulation blocker, is approved for the prophylaxis of kidney transplant rejection. This phase 3 trial evaluated the efficacy and safety of conversion from CNI-based to belatacept-based maintenance immunosuppression in kidney transplant recipients.
METHODS
Stable adult kidney transplant recipients 6-60 months post-transplantation under CNI-based immunosuppression were randomized (1:1) to switch to belatacept or continue treatment with their established CNI. The primary end point was the percentage of patients surviving with a functioning graft at 24 months.
RESULTS
Overall, 446 renal transplant recipients were randomized to belatacept conversion ( n =223) or CNI continuation ( n =223). The 24-month rates of survival with graft function were 98% and 97% in the belatacept and CNI groups, respectively (adjusted difference, 0.8; 95.1% CI, -2.1 to 3.7). In the belatacept conversion versus CNI continuation groups, 8% versus 4% of patients experienced biopsy-proven acute rejection (BPAR), respectively, and 1% versus 7% developed de novo donor-specific antibodies (dnDSAs), respectively. The 24-month eGFR was higher with belatacept (55.5 versus 48.5 ml/min per 1.73 m 2 with CNI). Both groups had similar rates of serious adverse events, infections, and discontinuations, with no unexpected adverse events. One patient in the belatacept group had post-transplant lymphoproliferative disorder.
CONCLUSIONS
Switching stable renal transplant recipients from CNI-based to belatacept-based immunosuppression was associated with a similar rate of death or graft loss, improved renal function, and a numerically higher BPAR rate but a lower incidence of dnDSA.Clinical Trial registry name and registration number: A Study in Maintenance Kidney Transplant Recipients Following Conversion to Nulojix® (Belatacept)-Based, NCT01820572.
Topics: Adult; Humans; Abatacept; Calcineurin Inhibitors; Kidney Transplantation; Immunosuppressive Agents; Kidney; Immunosuppression Therapy; Graft Rejection; Transplant Recipients; Graft Survival
PubMed: 34706967
DOI: 10.1681/ASN.2021050628 -
Nature Reviews. Clinical Oncology Jul 2023Immune-checkpoint-inhibitor-associated myocarditis has a high fatality rate, warranting the development of more-effective treatment strategies. Herein, we discuss a...
Immune-checkpoint-inhibitor-associated myocarditis has a high fatality rate, warranting the development of more-effective treatment strategies. Herein, we discuss a recent report of a series of patients who were managed using a novel approach that involved personalized abatacept dosing, ruxolitinib and close respiratory monitoring, which was associated with low mortality.
Topics: Humans; Immune Checkpoint Inhibitors; Myocarditis; Immunomodulation; Immunotherapy
PubMed: 37041273
DOI: 10.1038/s41571-023-00762-1 -
Lancet (London, England) Mar 2024Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
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.
METHODS
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).
FINDINGS
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.
INTERPRETATION
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.
FUNDING
Bristol Myers Squibb.
Topics: Adolescent; Adult; Humans; Abatacept; Arthralgia; Arthritis, Rheumatoid; Pain; Rheumatoid Factor; Synovitis
PubMed: 38364839
DOI: 10.1016/S0140-6736(23)02649-1 -
Journal of Clinical Medicine Oct 2023Rheumatoid arthritis (RA) is a chronic autoimmune multisystem inflammatory disease in which lung involvement is the most common extra-articular manifestation.... (Review)
Review
Rheumatoid arthritis (RA) is a chronic autoimmune multisystem inflammatory disease in which lung involvement is the most common extra-articular manifestation. Parenchymal lung involvement or interstitial lung disease (ILD) is a significant cause of morbidity and mortality and there is a paucity of evidence-based guidance on how to best treat RA-ILD. This review article aims to evaluate the evidence from cohort studies and best real word data from registries. Extensive discussion of the relative merits and drawbacks of glucocorticoids, various biologics, small molecules and anti-fibrotics is presented. The limited available guidelines in RA-ILD are also discussed and a rational treatment algorithm is offered.
PubMed: 37892795
DOI: 10.3390/jcm12206657 -
Inflammopharmacology Jun 2022To examine the effectiveness of Janus-kinase inhibitors (JAKis) or abatacept (ABA) in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD).
OBJECTIVES
To examine the effectiveness of Janus-kinase inhibitors (JAKis) or abatacept (ABA) in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD).
METHODS
Patients with RA-ILD receiving JAKis or ABA were retrospectively evaluated at baseline and after 18 months of treatment. A computer-aided method (CaM) was used to assess the extent of high-resolution computed tomography (HRCT) fibrosis percentage. According to HRCT fibrosis changes, patients were classified as "worsened" (progression of 15% or more), "stable" (changes within 15%) or "improved" (reduction of 15% or more). Correlations between RA characteristics and JAKis or ABA responses were studied using a multivariate regression model.
RESULTS
Seventy-five patients (69.3% women) were evaluated, 31 received a JAKi while 44 received ABA. In the JAKis group, five patients (16.1%) showed RA-ILD progression, 20 patients (64.5%) were considered stable, and six patients (19.4%) demonstrated RA-ILD improvement. In the ABA group, five patients (11.3%) showed RA-ILD progression, 32 patients (72.7%) were stable, and seven patients (16.0%) demonstrated RA-ILD improvement. In both groups, the percentage of current smokers was different between those classified as "worsened" and those classified as "improved/stable" (p = 0.01). In multivariate regression analysis, current smoking habit (p = 0.0051) and concomitant methotrexate treatment (p = 0.0078) were the two variables related to RA-ILD progression in ABA-treated patients, whereas in JAKis-treated patients, the only RA-ILD progression-related variable was disease duration of RA (p < 0.001).
CONCLUSIONS
Treatment with JAKis or ABA was related to stability or improvement of RA-ILD in 83.9% and 88.6% of patients, respectively. RA duration is the only variable associated with worsening RA-ILD in JAKis-treated patients.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Fibrosis; Humans; Janus Kinase Inhibitors; Lung Diseases, Interstitial; Male; Retrospective Studies
PubMed: 35462572
DOI: 10.1007/s10787-022-00936-w -
Frontiers in Pharmacology 2023Systemic Lupus Erythematosus (SLE) is a chronic autoimmune systemic disease with a wide range of clinical symptoms, complex development processes, and uncertain... (Review)
Review
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune systemic disease with a wide range of clinical symptoms, complex development processes, and uncertain prognosis. The clinical treatment of SLE is mainly based on hormones and immunosuppressants. Research on novel therapy strategies for SLE has flourished in recent years, especially the emergence of new targeted drugs and natural products that can modulate related symptoms. This review discusses the current experience including B-cell targeted drugs (belimumab, tabalumab, blisibimod, atacicept, rituximab, ofatumumab, ocrelizumab, obexelimab, and epratuzumab), T-cell targeted drugs (abatacept, dapirolizumab, and inhibitor of syk and CaMKIV), cytokines targeted drugs (anifrolumab and sifalimumab), and natural products (curcumin, oleuropein, punicalagin, sulforaphane, icariin, apigenin, and resveratrol). The aim of this paper is to combine the existing and models and clinical research results to summarize the efficacy and mechanism of natural drugs and targeted drugs in SLE for the reference and consideration of researchers.
PubMed: 37492083
DOI: 10.3389/fphar.2023.1235440