Abatacept Research Articles

Abatacept versus tumor necrosis factor inhibitors on mortality and medical utilizations in the treatment of rheumatoid arthritis associated interstitial lung disease: a large-scale real-world retrospective cohort study

Rheumatoid arthritis is a chronic inflammatory disease, and interstitial lung disease is one of the important extra-articular manifestations. There is limited evidence comparing abatacept (ABA) and tumor necrosis factor inhibitors (TNFi) regarding the risk of mortality among patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD). The aim of this study is to investigate the risk of mortality in patients with RA-ILD treated with ABA compared to TNFi. This retrospective cohort study utilized TriNetX electronic health record database. We enrolled patients who were diagnosed with RA-ILD and had received a new prescription for either ABA or TNFi. Patients were categorized into two cohorts based on their initial prescription. The primary outcome was all-cause mortality, and secondary outcomes were healthcare utilizations, including hospitalization, critical care services, and mechanical ventilation. Subgroup analyses were performed on age, presence of anti-citrullinated peptide antibodies (ACPA), and cardiovascular risk. Among 34,388 RA-ILD patients, 895 were selected for each group (ABA and TNFi) following propensity score matching. The ABA group exhibited a higher all-cause mortality risk. (HR 1.296, 95% CI 1.006–1.671). Subgroup analysis showed a heightened risk of receiving mechanical ventilation in ABA-treated patients aged 18–64 years old (HR 1.853, 95% CI 1.002–3.426), and those with cardiovascular risk factors (HR 2.015, 95% CI 1.118–3.630). Another subgroup analysis indicated a higher risk of mortality among ABA-treated patients with positive-ACPA. (HR 4.138 95% CI 1.343–12.75). This real-world data research demonstrated a higher risk of all-cause mortality in RA-ILD patients treated with ABA compared to TNFi, particularly those aged 18–64 years, lacking cardiovascular risk factors, and positive-ACPA. ABA was associated with an increased risk of mechanical ventilation in patients aged 18–64 years and those with cardiovascular risk factors.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

Thesafety and efficacy of upadacitinib 15mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. Thesafety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n =277/309) that initially received ABA. Of patients on UPA15 in the LTE (n =547), 28.3% (n =155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in theAmerican College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in theHealth Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n =263/303, 86.8%; ABA to UPA15: n =273/309, 88.3%) showed similar responses to the total population. The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

Subcutaneous vs intravenous abatacept in rheumatoid arthritis-interstitial lung disease. National multicentre study of 397 patients

BackgroundEvidence on abatacept (ABA) utility for rheumatoid arthritis (RA) – associated interstitial lung disease (ILD) is growing. Clinical trials have shown equivalence in subcutaneous (SC) and intravenous (IV) administration of ABA for articular manifestations. However, this has not been studied in respiratory outcomes. ObjectiveTo compare the effectiveness of ABA in RA-ILD patients according to the route of administration. MethodsNational retrospective multicentre study of RA-ILD patients on treatment with ABA. They were divided into 2 groups: a) IV, and b) SC. The following outcomes were analysed from baseline to final follow-up using linear mixed models: a) forced vital capacity (FVC), b) diffusing capacity of the lungs for carbon monoxide (DLCO), c) chest high resolution computed tomography (HRCT), d) dyspnoea, e) RA activity, and f) sparing corticosteroids effect. ResultsA total of 397 patients were included (94 IV-ABA and 303 SC-ABA), median follow-up of 24 [10–48] months. After adjustment for possible confounders, FVC and DLCO remained stable during the first 24 months without differences between IV-ABA and SC-ABA (p = 0.6304 and 0.5337). Improvement/ stability of lung lesions in HRCT was observed in 67 % of patients (75 % IV-ABA, 64 % SC-ABA; p = 0.07). Dyspnoea stabilized/ improved in 84 % of patients (90 % IV-ABA, 82 % SC-ABA; p = 0.09). RA - disease activity improved in both groups. No statistically significant differences regarding any of the variables studied between the two groups were found. ABA was withdrawn in 87 patients (21.9 %), 45 % IV-ABA and 37 % SC-ABA (p = 0.29). ILD worsening and articular inefficacy were the most common reasons for ABA discontinuation. ConclusionIn patients with RA-ILD, ABA seems to be equally effective regardless of the route of administration.

Retention rate of abatacept in rheumatoid arthritis patients in a real-life setting: results from a monocentric cohort.

Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis. This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate. This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3). Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.

Long-term effects of abatacept on atherosclerosis and arthritis in older vs. younger patients with rheumatoid arthritis: 3-year results of a prospective, multicenter, observational study

BackgroundWe aimed to reveal the effect of abatacept (ABT) on atherosclerosis in rheumatoid arthritis (RA) patients, 3-year efficacy for arthritis, and safety in a population of older vs. younger patients.MethodsIn this open-label, prospective, observational study, patients were stratified into four groups: younger (20–64 years old) and older (≥ 65 years) patients taking ABT (AY and AO) and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (CY and CO). Primary endpoints were change from baseline in mean intima-media thickness (IMT) of the common carotid artery, IMT max (bulbus, bifurcation, and internal and common carotid artery), and plaque score at Week 156. Disease activity, retention rate, and adverse effects were also evaluated.ResultsThe ABT group (AY + AO) tended to have smaller increases in mean IMT, max IMT, and plaque score than the csDMARD group (CY + CO) at Week 156, although the differences between groups were not statistically significant. Multivariate analysis showed significantly lower increases in plaque score with ABT than with csDMARDs, only when considering disease activity at 156 weeks (p = 0.0303). Proportions of patients with good or good/moderate European League Against Rheumatism response were higher in the ABT group, without significant difference between older and younger patients. No significant differences were observed in ABT retention rates between older and younger patients. Serious adverse effects, especially infection, tended to be more frequent with ABT than with csDMARDs, although no significant differences were found.ConclusionsABT may decelerate atherosclerosis progression and may be useful for patients with high risk of cardiovascular disease, such as older patients.Trial registration number:UMIN000014913.

Abatacept: A Promising Repurposed Solution for Myocardial Infarction-Induced Inflammation in Rat Models.

Myocardial infarction (MI) is irreversible damage to the myocardial tissue caused by prolonged ischemia/hypoxia, subsequently leading to loss of contractile function and myocardial damage. However, after a perilous period, ischemia-reperfusion (IR) itself causes the generation of oxygen free radicals, disturbance in cation homeostasis, depletion of cellular energy stores, and activation of innate and adaptive immune responses. The present study employed Abatacept (ABT), which is an anti-inflammatory drug, originally used as an antirheumatic response agent. To investigate the cardioprotective potential of ABT, primarily, the dose was optimized in a chemically induced model of myocardial necrosis. Thereafter, ABT optimized the dose of 5 mg/kg s.c. OD was investigated for its cardioprotective potential in a surgical model of myocardial IR injury, where animals (n = 30) were randomized into five groups: Sham, IR-C, Telmi10 + IR (Telmisartan, 10 mg/kg oral OD), ABT5 + IR, ABT perse. ABT and telmisartan were administered for 21 days. On the 21st day, animals were subjected to LAD coronary artery occlusion for 60 min, followed by reperfusion for 45 min. Further, the cardioprotective potential was assessed through hemodynamic parameters, oxidant-antioxidant biochemical enzymatic parameters, cardiac injury, inflammatory markers, histopathological analysis, TUNEL assay, and immunohistochemical evaluation, followed by immunoblotting to explore signaling pathways. The statistics were performed by one-way analysis of variance, followed by the Tukey comparison post hoc tests. Noteworthy, 21 days of ABT pretreatment amended the hemodynamic and ventricular functions in the rat models of MI. The cardioprotective potential of ABT is accompanied by inhibiting MAP kinase signaling and modulating Nrf-2/HO-1 proteins downstream signaling cascade. Overall, the present work bolsters the previously known anti-inflammatory role of ABT in MI and contributes a mechanistic insight and application of clinically approved drugs in averting the activation of inflammatory response.

Disease-modifying antirheumatic drug selection in Japanese patients with rheumatoid arthritis treated with biologics or JAK inhibitors without methotrexate: A retrospective hospital-based administrative claims database study.

We evaluated the medication selection and clinical characteristics of rheumatoid arthritis patients who started treatment with/without methotrexate (MTX) (using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors instead) in Japan. Using a Japanese hospital-based administrative claims database, rheumatoid arthritis patients who received treatment [abatacept (ABA), interleukin-6 receptor inhibitor, tumor necrosis factor inhibitor, or Janus kinase inhibitor] between 1 January 2015 and 31 December 2019 were enrolled. Overall, 19,301 patients were included (10,530 receiving MTX; 8771 not receiving MTX within 60 days of the first treatment). Mean ages at diagnosis were 60.7 and 65.9 years in the MTX and non-MTX groups, respectively (P < .0001). The non-MTX group had higher proportions of patients with Charlson Comorbidity Index ≥1 (P < .0001) and higher comorbidity rates. ABA was the most frequently used drug among patients with infectious/parasitic, circulatory, and respiratory diseases at baseline. Interleukin-6 receptor inhibitor had the highest use rate among patients with neoplasms; blood, gastrointestinal, and genitourinary diseases; and abnormal clinical/laboratory findings. ABA had the highest persistence probability from 6 months onward. MTX is used less frequently among older Japanese rheumatoid arthritis patients or those with comorbidities. In such patients, ABA is the most frequently used drug, followed by interleukin-6 receptor inhibitor, when MTX is not used at treatment start.

Retinal microvascular alterations in patients with active rheumatoid arthritis without cardiovascular risk factors: the potential effects of T cell co-stimulation blockade.

The evaluation of microvascular alterations might provide clinically useful information for patients with an increased cardiovascular (CV) risk, such as those with rheumatoid arthritis (RA), being the small artery remodeling the earliest form of target organ damage in primary CV diseases, such as arterial hypertension. The evaluation of retinal arterioles is a non-invasive technique aimed to identify an early microvascular damage, represented by the increase of the wall-to-lumen ratio (WLR) index. Abatacept (ABA), a T-cell co-stimulator blocker, is used to treat RA. A CV protective action was hypothesized for its peculiar mechanism of action in the modulation of T-cells, potentially involved in the pathogenesis of CV comorbidity. The study aimed to non-invasively investigate morphological characteristics of retinal arterioles in a cohort of RA patients treated with ABA. Seventeen RA patients [median (25th-75thpercentile) age = 58 (48-64) years, baseline 28-joint Disease Activity Score DAS28-C-reactive protein (DAS28-CRP) = 4.4 (3.9-4.6), body mass index (BMI) = 24.2 (23.4-26) kg/m2, rheumatoid factor positive:52.9%, anti-citrullinated peptide autoantibodies positive:76.5%] without known CV risk factors (arterial hypertension, diabetes, hypercholesterolemia, previous CV events, smoking) were evaluated by the adaptive optics imaging system of retinal arterioles before and every 6 months of therapy with ABA (T0, T6 and T12). Office blood pressure evaluation, 24-h ambulatory blood pressure monitoring and tissue-doppler echocardiography were also performed. A progressive significant reduction of the WLR of retinal arterioles was observed [T0 = 0.28 (0.25-0.30), T6 = 0.27 (0.24-0.31), T12 = 0.23 (0.23-0.26); p T0 vs. T6 = 0.414; p T6 vs. T12 = 0.02; p T0 vs. T12 = 0.009], without significant variations in other parameters. The T0-T12 reduction of WLR was correlated with that of DAS28-CRP (r:0.789; p = 0.005). Moreover, a significant reduction of diastolic office blood pressure and a trend for reduction of daily pressure measured by ambulatory monitoring were observed. In a cohort of RA patients without known CV risk factors, a reduction of retinal microvascular alterations was demonstrated after treatment for 12 months with ABA, in parallel with the reduction of disease activity. These results might suggest the possibility of microvascular abnormalities regression induced by the immune system modulation.

Circulating Tfh cells are differentially modified by abatacept or TNF blockers, and predict treatment response in Rheumatoid Arthritis.

CD4+CXCR5+PD-1hi follicular helper T (Tfh) cells dwell in the germinal centers (GCs) of lymphoid organs and participate in Rheumatoid Arthritis (RA) pathogenesis; the frequency of their circulating counterparts (cTfh-frequency) is expanded in RA and correlates with the pool of GC Tfh cells. Our objective was to study the effect of abatacept (ABT) or TNF blockers (TNFb) on the cTfh-frequency in RA. Peripheral blood was drawn from seropositive-longstanding RA patients chronically receiving csDMARDS (n = 45), TNFb (n = 59), or ABT (n = 34), and healthy controls (HC) (n = 137). Also, patients with an incomplete response to csDMARDS (n = 41) who initiated TNFb (n = 19) or ABT (n = 22), were studied at 0 and 12 months. The cTfh-frequency was examined by cytometry. As compared with HC, an increased cTfh-frequency was seen in seropositive-longstanding RA chronically receiving csDMARDs or TNFb but not ABT. After escalating from csDMARDs, the cTfh-frequency did not vary in patients who were given TNFb but decreased to HC levels in those given ABT. In the ABT group, the baseline cTfh-frequency was higher for patients who attained 12M remission (12Mr), vs those who remained active (12Ma): 0m cutoff for remission >0.38% (Sens. 92%, Sp. 90%), OR 25.3. Conversely, in the TNFb group, the baseline cTfh-frequency was lower for 12Mr vs 12Ma: 0m cutoff for non-remission >0.44% (Sens. 67%, Sp. 90%), OR 8.5. ABT but not TNFb, is able to curtail the cTfh-frequency in RA. A higher baseline cTfh-frequency predicts a good response to ABT but a poor response to TNFb.

Janus kinase inhibitors vs. abatacept about safety and efficacy for patients with rheumatoid arthritis-associated interstitial lung disease: a retrospective nested case-control study

BackgroundInterstitial lung disease (ILD) related to rheumatoid arthritis (RA) is among the leading causes of death and an essential prognostic factor. There is only limited evidence for the safety of anti-rheumatic drugs for patients with RA-ILD. The aim of this study is to investigate the safety and efficacy of Janus kinase inhibitors (JAKis) by comparing it with abatacept (ABT) in patients with RA-ILD.MethodsThis single centre, retrospective nested case–control study enrolled patients with RA-ILD treated with JAKi or ABT. To determine the safety of the two drugs for existing ILD, we compared their drug persistency, incidence rates of pulmonary complications, and change of chest computed tomography (CT) image. For their efficacy as RA treatment, disease activity scores and prednisolone (PSL)-sparing effect were compared. We performed propensity score matching to match the groups’ patient characteristics.ResultsWe studied 71 patients with RA-ILD (ABT, n = 45; JAKi, n = 26). At baseline, the JAKi group had longer disease duration, longer duration of past bDMARD or JAKi use and higher usual interstitial pneumonia rate. After propensity score matching, no significant differences in patient characteristics were found between the two groups. No significant difference in the drug persistency rate for the first 2 years (ABT, 61.9%; JAKi, 42.8%; P = 0.256) was observed between the two matched groups. The incidence rate of pulmonary complications did not differ significantly between the two groups (P = 0.683). The CT score did not change after the treatment for the ABT group (Ground-glass opacities (GGO): P = 0.87; fibrosis: P = 0.78), while the GGO score significantly improved for the JAKi group (P = 0.03), although the number was limited (ABT: n = 7; JAKi: n = 8). The fibrosis score of the JAKi group did not change significantly.(P = 0.82). Regarding the efficacy for RA, a significant decrease in disease activity scores after the 1-year treatment was observed in both groups, and PSL dose was successfully tapered, although no significant differences were observed between the two drugs.ConclusionsJAKi is as safe and effective as ABT for patients with RA-ILD. JAKi can be a good treatment option for such patients.

Real-world retention rates of biologics in patients with rheumatoid arthritis

Although biologics have their own characteristics, there are no clear criteria for selecting them to treat the patients with rheumatoid arthritis. To assist in selecting biologics, we investigated the retention rates of biologics at our institution. We examined retention rates, and reasons for dropout for biologics in 393 cases and 605 prescriptions (of which 378 prescriptions were as naive) at our hospital since October 2003. Throughout the entire course of the study, etanercept (ETN) was the most frequently used biologic, followed by adalimumab (ADA) and tocilizumab (TCZ). When narrowed down to the later period from 2010, ETN was still the most used, followed by TCZ and abatacept (ABT). When the retention rates were compared in biologic naive patients, the retention rates were TCZ, ABT, ETN, certolizumab pegol (CZP), golimumab (GLM), infliximab (IFX), and ADA, in that order. The retention rates were better with the first use of each biologic. The main reasons for dropout were primary ineffectiveness, secondary ineffectiveness, and infection. ETN was the most used biologic in our hospital, with an increasing trend toward the use of non-TNF inhibitors. Retention rates were higher in non-TNF inhibitors.

Predictive value of baseline concomitant glucocorticoid for abatacept-mediated long-term inhibition of radiographic progression: insights from the KURAMA cohort

Abatacept (ABT) is a biological disease-modifying antirheumatic drug (bDMARDs) for rheumatoid arthritis (RA) when conventional synthetic DMARDs are ineffective. We aimed to evaluate the long-term effects of ABT on joint destruction in patients treated for over 2 years. Radiographic progression was evaluated using the van der Heijde-modified Total Sharp Score (mTSS) by two rheumatologists at ABT initiation and after 2 years. Multivariate logistic regression analysis was used to identify factors associated with structural remission, defined as the mean annual change in mTSS ≤0.5. Among the 111 patients included, 48 discontinued, and 63 continued ABT treatment until radiographic evaluation was performed. The rate of patients who achieved estimated TSS REM (yearly progression of van der Heijde modified total Sharp scores ≤0.5) was significantly lower in ABT-dropouts than in the ABT-continued group (69% vs. 48%, p = .0336 by Fisher’s exact test). Among the continued ABT cases, concomitant glucocorticoid treatment at ABT initiation was the strongest negative predictive factor of estimated TSS REM in univariate and multivariate logistic regression analyses. Radiographic progression after ABT administration should be evaluated separately for dropout and non-dropout cases. Glucocorticoids at the initiation of ABT may serve as a predictive factor for joint destruction in long-term ABT use.

Abatacept in usual and in non-specific interstitial pneumonia associated with rheumatoid arthritis

ObjectiveTo compare the effectiveness of abatacept (ABA) in Rheumatoid Arthritis-associated Interstitial Lung Disease (RA-ILD) according to the radiological patterns of usual (UIP) or non-specific interstitial pneumonia (NSIP). MethodsFrom an observational longitudinal multicentre study of 263 RA-ILD patients treated with ABA, those with UIP or NSIP were selected. Lung function, chest high resolution computerised tomography (HRCT) and dyspnoea were recorded and compared in both groups from baseline to the end of follow-up (progression definitions: improvement or worsening >10% of FVC or DLCO, changes in HRCT extension and 1-point change in the mMRC scale, respectively). Differences between final and baseline visits were calculated as the average difference (95% CI) through mixed effects models regression. ResultsWe studied 190 patients with UIP (n=106) and NSIP (n=84). General features were similar in both groups except for older age, positive rheumatoid factor, and previous sulfasalazine therapy, which were more frequent in patients with UIP. ILD duration up to ABA initiation was relatively short: median 16 [4-50] and 11 [2-36] months (p=0.36) in UIP and NSIP, respectively. Mean baseline FVC and DLCO were 82% and 63% in UIP and 89% and 65% in NSIP, respectively. Both parameters remained stable during 24 months with ABA. HRCT lesions and dyspnoea improved/stabilized in 73.1% and 90.5% and 72.9% and 94.6% of UIP and NSIP patterns, respectively. ConclusionABA seems equally effective in stabilizing dyspnoea, lung function and radiological impairment in both UIP and NSIP patterns of RA-ILD. Early administration of ABA may prevent RA-ILD progression, regardless of the radiological pattern.

Difficult-to-treat rheumatoid arthritis treated with Abatacept combined with Baricitinib: A case report

Sporadic cases of rheumatoid arthritis (RA) due to unsatisfactory responses to Abatacept (ABT) have been reported; however, the rescue therapy has not been finalized. Here, we present a case with difficult-to-treat RA (D2T RA) that was resistant to either a single ABT or a Janus kinase (JAK) inhibitor (Tofacitinib), but improved with a combination of ABT and JAK inhibitor (Baricitinib, BAT). A 46-year-old Chinese woman who had RA for ten years that was resistant to Tocilizumab, Etanercept, Adalimumab, and ABT. According to the European League Against Rheumatism definition, the patient was diagnosed with D2T RA. It was then improved with a combination of ABT and a JAK inhibitor BAT. ABT combined with BAT may be an acceptable strategy for treating D2T RA.

Radiological evaluation of interstitial lung disease in patients with rheumatoid arthritis treated with abatacept or JAK inhibitors for 1 year

BackgroundWe evaluated the radiological deterioration of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) treated with abatacept (ABT) or Janus-kinase inhibitors (JAKi) for 1 year. MethodsThis study enrolled 84 patients with RA who had started treatment with ABT (48 patients) or JAKi (36 patients) between 2017 and 2020. All patients underwent chest CT before administration and at 1 year post-treatment. ResultsIn all patients, the rate of deterioration of ILD in ABT and JAKi was 4.2% and 5.6%, respectively (p = 0.847). In the patients with pre-existing ILD, the rates of deterioration of ILD in the ABT and JAKi groups were 10.5% and 18.2%, respectively (p = 0.611). Meanwhile, newly developed ILD did not occur in the two groups without pre-existing ILD. ConclusionThe present study demonstrated that the safety of pulmonary toxicity with ABT and JAKi treatments was similar in patients with RA. JAKi may be a potentially acceptable treatment option for patients with RA.

Efficacy and safety of abatacept in patients with rheumatoid arthritis with previous malignancy.

Abatacept (ABT) is known to lower infection risk than other biologics and is effective and safe in elderly patients with rheumatoid arthritis (RA). However, there were inconsistent reports on the impact of ABT on malignancies which are more common in the elderly and strongly related to prognosis. This study aimed to evaluate the efficacy and safety of ABT in patients with RA with previous malignancy in clinical practice. A multicenter, retrospective study. Patients who received ABT for RA in two hospitals in Yokohama until May 2022 were included in this study. The patients were divided into two groups according to the presence or absence of a history of malignancy (no previous malignancy: NP group, previous malignancy: PM group). The collected parameters were compared between the groups using propensity score matching. In this study, 312 patients were included, of whom 73 had previous malignancies when starting ABT. The age at ABT initiation was significantly higher in the PM group, the rate of methotrexate use was significantly lower in the PM group, and the Steinbrocker stage was significantly higher in the PM group. After matching these 3 factors, 68 patients were selected from each group. No significant differences in the ABT continuation rate, and malignancy incidence were observed between the two groups after ABT initiation. In addition to these factors, when matched for smoking history, interstitial lung disease, disease duration, sex, and inflammatory status, which are known risk factors for malignancy in RA, 40 patients were selected from each group. No significant differences in the ABT continuation rate, and malignancy incidence were observed between the two groups after ABT initiation. In our clinical practice, ABT was as effective and safe in patients with a history of malignancy as in those without.

Cost-consequence of abatacept as first-line therapy in Japanese rheumatoid arthritis patients using IORRA real-world data.

To investigate the cost-effectiveness of abatacept (ABA) as first-line (1L) therapy in Japanese rheumatoid arthritis (RA) patients using data from the Institute of Rheumatology, Rheumatoid Arthritis database. A decision-analytic model was used to estimate the cost per American College of Rheumatology response of at least 50% improvement (ACR50) responder and per patient in Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) remission from a Japanese healthcare payers' perspective over a 2-year time horizon. Clinical characteristics of patients on ABA-1L were matched with those of patients on ABA second or later line (2L+) or tumour necrosis factor inhibitor (TNFi)-1L directly or using propensity scores. Resource utilisation and medical costs were calculated from the Japan Medical Data Center claims database. Parameter uncertainty was addressed by sensitivity and subgroup analyses (age, treatment duration, Japanese version of Health Assessment Questionnaire [J-HAQ] score). Incremental costs per member per month (ΔPMPM) for ABA-1L versus TNFi-1L and ABA-2L+ were -1,571 Japanese Yen (JPY) and 81 JPY, respectively. For ABA-1L versus TNFi-1L, ΔPMPM by ACR50 response was -11,715 JPY and by CDAI and SDAI remission 11,602 JPY and 47,003 JPY, respectively. Corresponding costs for ABA-1L were lower for all outcome parameters versus those for ABA-2L+. Scenario analyses showed that ABA-1L was cost-effective over TNFi-1L in patients <65 years for any outcome. Furthermore, ABA-1L was cost-effective over ABA-2L+ for all outcomes in patients with age <65 years, disease duration <5 years and J-HAQ ≥1.5. ABA-1L demonstrated a favourable cost-effectiveness profile in RA patients, accruing savings for the Japanese healthcare payers.

A Real-World Evidence Comparison of 1-Year Overall Survival and Relapse-Free Survival between Patients Treated with Abatacept in Combination with a Calcineurin Inhibitor and Methotrexate Versus Antithymocyte Globulin or Post-Transplant Cyclophosphamide Following Allogeneic Hematopoietic Cell Transplantation

Introduction: Matched sibling or matched unrelated donor (MUD) availability remains a clinical challenge for hematopoietic cell transplant (HCT) recipients. Though HCTs with a mismatched unrelated donor (MMUD) may be an option, graft-versus-host disease (GVHD)-related mortality risk is elevated with MMUD HCTs. Abatacept (ABA), a selective T-cell costimulation modulator, when administered with calcineurin inhibitor/methotrexate (CNI/MTX), improved survival outcomes in 7/8 MMUD and 8/8 MUD recipients (Watkins B, et al. J Clin Oncol 2021) compared with CNI/MTX prophylaxis alone and was approved in the United States for acute GVHD prophylaxis (US FDA 2021). Alternative prophylactics, such as antithymocyte globulin (ATG) + CNI/MTX or post-transplant cyclophosphamide (PT-Cy) + tacrolimus (Tac) + mycophenolate mofetil (MMF) also show promise for improving post-HCT survival outcomes (Walker I, et al. Lancet Haematol 2020; Shaw B, et al. J Clin Oncol 2021; Luznik L, et al. J Clin Oncol 2022). This real-world analysis compared survival outcomes in 7/8 MMUD and 8/8 MUD recipients treated with ABA + CNI/MTX versus ATG + CNI/MTX and versus PT-Cy + Tac + MMF from the Center for International Blood and Marrow Transplant Research (CIBMTR) database of all allogeneic HCTs performed in the United States. Methods: This retrospective cohort study included CIBMTR database allogenic HCT recipients treated with ABA + CNI/MTX, ATG + CNI/MTX, and PT-Cy + Tac + MMF (PT-Cy). Recipients were aged ≥ 6 years; weighed ≥ 20 kg; had a Karnofsky/Lansky performance score ≥ 80%; were diagnosed with leukemia, lymphoma, or myelodysplastic syndrome; and underwent first allogeneic HCT from a 7/8 MMUD or 8/8 MUD in the United States between 2011 and 2018. Overall survival (OS; time between HCT date and documented date of death) and relapse-free survival (RFS; time between HCT date and date of death or relapse, whichever occurred first) were evaluated over 1 year post-HCT. A weighted log-rank test was used to compare outcomes using inverse probability of treatment weighting (IPTW), based on propensity score calculation to control for treatment bias. Marginal hazard ratios (HRs) and 95% CIs were estimated by a weighted Cox proportional hazards model with treatment as a covariate. Results: The 7/8 MMUD cohort included 378 recipients: 54 ABA + CNI/MTX, 162 ATG + CNI/MTX, and 162 PT-Cy. The 8/8 MUD cohort included 781 recipients: 71 ABA + CNI/MTX, 355 ATG + CNI/MTX, and 355 PT-Cy. For 7/8 MMUD recipients, OS (95% CI) was significantly higher with ABA + CNI/MTX (87% [67-95%]) versus ATG + CNI/MTX (58% [49-66%]); P = 0.0026; HR (95% CI): 0.24 (0.10-0.55). The OS comparison between ABA + CNI/MTX versus PT-Cy was 86% (66-94%) and 79% (70-85%), respectively; P = 0.3376; HR (95% CI): 0.61 (0.25-1.51). In 8/8 MUD recipients, OS (95% CI) was significantly higher with ABA + CNI/MTX versus ATG + CNI/MTX (86% [72-93%] versus 70% [65-75%], respectively); P = 0.0209; HR (95% CI): 0.43 (0.21-0.88). The OS comparison for ABA + CNI/MTX versus PT-Cy was 84% (66-93%) versus 78% (73-82%), respectively; P = 0.3616; HR (95% CI): 0.69 (0.30-1.54). In 7/8 MMUD recipients, the ABA + CNI/MTX subgroup had significantly higher RFS versus ATG + CNI/MTX (81% [60-92%] versus 48% [39-56%], respectively); P = 0.0015; HR (95% CI): 0.27 (0.13-0.55). The RFS comparison between ABA + CNI/MTX versus PT-Cy was 75% (56-87%) versus 62% (52-70%), respectively; P = 0.1636; HR (95% CI): 0.60 (0.26-1.39). For 8/8 MUD recipients, Figure 1 shows ABA + CNI/MTX had significantly higher RFS versus ATG + CNI/MTX (82% [69-90%] versus 61% [55-66%], respectively); P = 0.0032; HR (95% CI): 0.39 (0.21-0.73). Figure 2 shows the RFS comparison between ABA + CNI/MTX and PT-Cy (79% [61-90%] versus 65% [60-70%], respectively); P = 0.0944; HR (95% CI): 0.54 (0.26-1.11). Conclusions: ABA + CNI/MTX significantly improved OS and RFS over 1-year post-HCT compared with ATG + CNI/MTX prophylaxis. There was a trend toward improved OS and RFS 1-year post-HCT on ABA + CNI/MTX compared with PT-Cy, although this did not reach statistical significance. OS and RFS in 7/8 MMUD recipients receiving ABA + CNI/MTX was similar to those in 8/8 MUD recipients, suggesting that this treatment improved the risk/benefit ratio for MMUD HCTs. Study support: This study was sponsored by Bristol Myers Squibb. Medical writing: Efrah Yousuf and Ryan Miller (Caudex), funded by Bristol Myers Squibb. We acknowledge Brian Gavin, PhD, for his contributions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Breakthrough T Cell Proliferation Despite CNI/MTX Prophylaxis Is a Harbinger of Acute Gvhd (AGVHD) and Is Controlled By Abatacept: Mechanism of Success of the ABA2 Agvhd Prevention Trial

Background: Abatacept was recently FDA-approved for AGVHD prevention, based in part on the results of the ABA2 Phase 2 GVHD prevention trial. ABA2 demonstrated a significant decrease in Grade 2-4 AGVHD after both 8/8 and 7/8 URD HCT in patients prophylaxed with CNI/MTX + abatacept versus those receiving CNI/MTX alone. The randomized double-blind, placebo-controlled design of the 8/8 arm has enabled a rigorous determination of the immunologic drivers of the success of abatacept in preventing AGVHD. Methods: We studied hematopoietic and immune reconstitution in patients receiving 8/8 HLA-matched URD HCT enrolled on ABA2, who received either CNI/MTX + placebo (PBO) or CNI/MTX + abatacept (ABA) for GVHD prophylaxis. Flow cytometry using 16 ten-color panels evaluated T cell reconstitution, T cell naïve/effector cell balance, T cell proliferation and cytotoxicity. Comparisons were made between healthy controls (HC, n = 23), PBO (n = 69) and ABA (n = 73) patients, and between patients developing Gr 2-4 AGVHD (n=43 PBO and n = 31 ABA) versus Gr 0-1 AGVHD (n=26 PBO and n = 42 ABA). RNASeq was performed on CD4+ and CD8+ T cells purified by flow cytometry (within 3 hours of blood collection) at day 21 and 28 post-HCT at 2 central lab sites, from patients who developed Gr 2-4 AGVHD (PBO, n=87 total samples ; ABA, n=67 total samples) or Gr 0-1 AGVHD (PBO, n=45 total samples; ABA, n=89 total samples). RNASeq was performed using the Clontech SMART-Seq v4 kit, Illumina NexteraXT DNA library prep, and the Illumina HiSeq3000. Statistical modeling was performed using DESeq2, followed by differential expression and Gene Set Enrichment Analysis (GSEA). Results: Combined flow cytometric and transcriptomic analysis provided compelling evidence that T cell allo-proliferation was a harbinger of Gr 2-4 AGVHD onset in PBO patients, and that abatacept was able to control this proliferative escape. Thus, using flow cytometry, we detected early (Day +28) breakthrough CD4+ T cell proliferation (as measured by Ki67) in PBO patients who developed Grade 2-4 AGVHD compared with those who developed Gr 0-1 AGVHD (mean 20.4% vs 12.6% Ki67+ CD4 T cells) (p<0.05).In contrast, there was no increase in Ki67+ CD4 T cells in ABA patients with AGVHD (5.8% vs 6.7% Ki67+ CD4 T cells (p = ns). Concordant with flow cytometry results, RNA-Seq detected prominent Cell Cycle-associated transcriptomic signatures in PBO AGVHD samples via Gene Set Enrichment Analysis (GSEA) in both CD4+ and CD8+ T cells, with abatacept successfully controlling this proliferative escape (Fig.1). Importantly, despite the difference in Gr 2-4 AGVHD-associated breakthrough T cell proliferation between PBO and ABA patients, there was no difference in the longitudinal reconstitution of total T cells, total CD4+ T cells and CD8+ T cells in the two cohorts (Watkins et al, JCO 2021). Moreover, both PBO and ABA patients were able to mount homeostatic proliferative responses, with upregulated Ki67 compared to HC by flow cytometry (Day 28 Ki67+ CD4 and CD8 T cells higher in PBO vs HC and ABA vs HC, with p values <0.01 for all comparisons to HC). Notably, both PBO and ABA CD4 and CD8 T cells also demonstrated enrichment in RNASeq proliferation signatures compared to HC, as measured by GSEA (not shown). PBO and ABA patients also demonstrated equivalent T cell repertoire reconstitution as measured by longitudinal TCRSeq clonality measurements (Fig. 2), further substantiating intact T cell reconstitution in these patients. Unlike the proliferation-dominated breakthrough AGVHD profile in PBO patients, RNA-Seq revealed a unique AGVHD signature in ABA patients. Thus, patients who developed Gr 2-4 AGVHD despite abatacept exhibited a GSEA gene expression profile in both CD4+ and CD8+ T cells enriched for naïve T cell gene sets, prominently including IL6 signaling pathway transcripts. Conclusions: These data provide compelling evidence for early (Day 21-28) T cell allo-proliferative escape being a key mechanism driving breakthrough AGVHD after standard CNI/MTX prophylaxis, and control of this escape with abatacept. This analysis further documented retained overall T cell reconstitution with abatacept despite control of AGVHD-associated proliferation, consistent with the reassuring safety profile of abatacept observed in ABA2. Together, these results provide new insights into the central role that allo-proliferation has in breakthrough AGVHD, and its control with CD28:CD80/86 costimulation blockade. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and safety of abatacept for interstitial lung disease associated with antisynthetase syndrome: a case series.

This study investigated the efficacy and safety of abatacept (ABA) in interstitial lung disease (ILD) associated with antisynthetase syndrome (ASS). Eight patients were identified through retrospective analysis of the medical records of our centre. All patients fulfilled the Solomon criteria and had a disease complicated with ILD. Lung function, imaging, serum markers, clinical evaluation indicators of ILD, peripheral blood cell classification, cytokines, and prednisone doses were analysed. Seven of the eight patients were female. The mean age was 54.4 (standard deviation [SD] 6.0) years. Antibodies against Jo-1, PL-12, and PL-7 were present in three, three, and two patients respectively. At baseline, the mean diffusing lung capacity for carbon monoxide (DLCO) was 53.8% (SD 9.2%), the mean score of King's Brief Interstitial Lung Disease (KBILD) was 40.6 (SD 13.8), the median Krebs Von den Lungen-6 (KL-6) was 1612.5 (interquartile range [IQR] 1180.5-2431.5) U/ml. All patients experienced symptom alleviation after ABA therapy. The mean and median changes in DLCO percentage, KBILD, and KL-6 were 12.3% (p<0.05), 21.4 (p<0.01), and 174.5U/ml (p<0.01), respectively. No obvious adverse events related to ABA were observed during the treatment. Our study offers preliminary, but encouraging, clinical evidence in favour of ABA as a therapy for ASS-ILD. ABA demonstrated favourable effects on ILD and was well-tolerated. Well-designed randomised controlled studies are required to confirm the efficacy and safety of this strategy.