Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation.

Solid organ transplant donor-recipient eplet mismatch has been correlated with donor-specific antibody (DSA) formation, antibody-mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens and have not fully explored differences in ethnically and racially diverse populations. Evidence indicates that patients on belatacept have lower rates of DSA formation, suggesting mediation of the immunogenicity of mismatched human leukocyte antigen polymorphisms. We performed a retrospective, single-center analysis of class II eplet disparity in a cohort of kidney transplant recipients treated using belatacept with tacrolimus induction (Bela/TacTL) or tacrolimus regimens between 2016 and 2019. Bela/TacTL (n = 294) and tacrolimus (n = 294) cohorts were propensity score-matched with standardized difference <0.15. Single-molecule eplet risk level was associated with immune event rates for both groups. In Cox regression analysis stratified by eplet risk level, Bela/TacTL immunosuppression was associated with a decreased rate of DSA (hazard ratio [HR] = 0.4), antibody-mediated rejection (HR = 0.2), and rejection (HR = 0.45). In the low-risk group, cumulative graft failure was lower for patients on Bela/TacTL (P < .02). Analysis of eplet mismatch burden may be a useful adjunct in identifying high-risk populations with increased immunosuppression requirements and should encourage the design of allocation rules to incentivize lower-risk pairings without negatively impacting equity in access.

[18F]FDG PET/CT for therapeutic assessment of Abatacept in early-onset polymyalgia rheumatica.

PURPOSE: Evaluate the benefit of 2-deoxy-2-[18F]-fluoro-D-glucose ([18F] FDG) positron emission tomography/computed tomography (PET/CT) for the therapeutic assessment of Abatacept (ABA) as first-line therapy in early-onset polymyalgia rheumatica (PMR) patients. METHODS: This was an ancillary study of ALORS trial (Abatacept in earLy Onset polymyalgia Rheumatica Study) assessing the ability of ABA versus placebo to achieve low disease activity (C-Reactive Protein PMR activity score (CRP PMR-AS) ≤ to 10) without glucocorticoid (GC) at week 12 in patients with early-onset PMR. The patients underwent [18F] FDG PET/CT at baseline and after 12 weeks of treatment. Responses to treatments were evaluated according to CRP PMR-AS, Erythrocyte Sedimentation Rate (ESR) PMR-AS, Clin PMR-AS, and CRP-Imputed (Imput-CRP) PMR-AS. Quantitative score by maximal standardized uptake value (SUVmax) and combined qualitative scores according to liver uptake (Leuven, Leuven/Groningen, and Besançon Scores) were used for assessment of [18F] FDG uptake in regions of interest (ROI) usually affected in PMR. Student's t-test was applied to evaluate the clinical, biological, and [18F] FDG uptake variation difference in ABA and placebo groups between W0 and W12. Subgroup analysis by GC rescue was performed. RESULTS: At W12, there was no significant difference according to SUVmax between the ABA and the placebo groups in all ROI. Subgroup analysis according to GC administration demonstrated a significant (p 0.047) decrease in SUVmax within the left sternoclavicular joint ROI in the ABA group (- 0.8) compared to the placebo group (+ 0.6) without GC rescue. Other results did not reveal any significant difference between the ABA and placebo groups. According to combined qualitative scores, there was no significant difference between ABA and placebo groups for the direct comparison analysis and subgroup analysis according to GC rescue. CONCLUSION: [18F] FDG PET/CT uptake did not decrease significantly after ABA compared to placebo in anatomical areas usually affected in PMR patients. These results are correlated with the clinical-biological therapeutic assessment. CLINICAL TRIAL REGISTRATION: The study was approved by the appropriate ethics committee (CPP Sud-Est II Ref CPP: 2018-33), and all patients gave their written informed consent before study enrollment. The protocol was registered on Clinicaltrials.gov (NCT03632187).

ADA_ETA_BIO2021: real-world evaluation of adherence, persistence, and cost-effectiveness of originator and biosimilar biologic drugs in the treatment of rheumatoid arthritis: a multicenter study in Italy.

OBJECTIVES: The objective was to assess the adherence, persistence, and costs of bDMARDs through a multicentre study of nine Italian hospital pharmacies. METHODS: The drugs analysed were Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab and Tocilizumab.Adult subjects with Rheumatoid Arthritis were considered in the analysis.In this study, we calculated the following metrics: Adherence to treatment was evaluated as dose-intensity, which is the ratio between the amount of medication received and probably taken by the patient at home (Received Daily Dose, RDD) and the amount prescribed by the clinician (Prescribed Daily Dose, PDD). Persistence was calculated as the number of days between the first and last dispensing of the same drug. Lastly, costs were assessed based on persistence to treatment and normalized for adherence. RESULTS: Adherence to treatment was found to be above 0.8 for all drugs studied. The median persistence for a 5-year treatment period was 1.4 years for Abatacept, 1.7 years for Adalimumab, 1.8 years for Certolizumab, 1.4 years for Etanercept, 1.3 years for Golimumab, and 1.6 years for Tocilizumab. CONCLUSIONS: This multicentre retrospective observational study of bDMARDs used in the treatment of RA showed that, for all the drugs studied, there was no problem with adherence to treatment but rather a difficulty in maintaining treatment with the same drug over time.

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

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: ABA-1L demonstrated a favourable cost-effectiveness profile in RA patients, accruing savings for the Japanese healthcare payers.

Comparative Risk of Alzheimer Disease and Related Dementia Among Medicare Beneficiaries With Rheumatoid Arthritis Treated With Targeted Disease-Modifying Antirheumatic Agents.

Importance: Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping. Objective: To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD. Design, Setting, and Participants: This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021. Main Outcomes and Measures: The main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching. Results: After 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score-matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%] women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]). Conclusions and Relevance: This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.

Risk and cost of infection-related hospitalizations in medicare beneficiaries with comorbid rheumatoid arthritis treated with abatacept versus other targeted disease-modifying anti-rheumatic drugs.

OBJECTIVE: This study evaluated infection-related hospitalization risk and cost in tumor necrosis factor inhibitor (TNFi)-experienced and targeted DMARD (tDMARD) naïve rheumatoid arthritis (RA) patients that were treated with abatacept, TNFi, or other non-TNFi. METHODS: This retrospective study used 100% Medicare Fee-for-Service claims to identify patients ≥65 age, diagnosed with RA, and were either 1) TNFi-experienced, who switched from a TNFi to another tDMARD (subsequent tDMARD claim served as index), or 2) tDMARD naïve (first therapy claim served as index), who initiated either abatacept, TNFi, or non-TNFi as their first tDMARD, between 2010 and 2017. Follow-up ended at the date of disenrollment, death, end of study period, or end of index treatment, whichever occurred first. Infection-related hospitalizations included pneumonia, bacterial respiratory, sepsis, skin and soft tissue, joint or genitourinary infections. A Cox proportional hazard model and two part generalized linear model were developed to estimate adjusted infection-related hospitalization risk and costs. Costs were normalized to per-patient-per-month (PPPM) and inflated to 2019 US$. RESULTS: The infection-related hospitalizations rate was lower during follow-up than during baseline periods for abatacept users, but was reversed for both TNFi and other non-TNFi users in both TNFi-experience and tDMARD naïve (p value < .001 based on Breslow-Day test for homogeneity of odds ratios). Infection-related hospitalization PPPM cost was significantly lower in abatacept treated patients compared to TNFi (TNFi-experienced: by $74; tDMARD naïve: $42) and other non-TNFi (TNFi-experienced: by $68; tDMARD naïve: $60). The adjusted infection-related hospitalization risk was significantly higher for RA patients treated with TNFi (TNFi-experienced HR: 1.48; 95% CI: 1.26-1.75, p < .0001; tDMARD naïve HR:1.59; 95% CI: 1.43-1.77, p < .0001) and other non-TNFi (TNFi-experienced HR:1.46; CI:1.28-1.66; tDMARD naïve HR:1.63; 95% CI: 1.44-1.83) than with abatacept. CONCLUSION: RA Medicare Fee-For-Service beneficiaries who either switched or initiated abatacept have a lower infection-related hospitalization risk and cost compared to patients who switched to or initiated other tDMARDs.

Cost-utility analysis of treatment options after initial tumor necrosis factor inhibitor therapy discontinuation in patients with rheumatoid arthritis.

BACKGROUND: For patients with rheumatoid arthritis (RA) who discontinued initial treatment with tumor necrosis factor inhibitor (TNFi), 2 approaches are commonly used: cycling to another TNFi or switching to a drug with another mechanism of action. Currently, there is no consensus on which approach to use first. A report from the IBM MarketScan Research administrative claims database showed adalimumab (cycling strategy) and abatacept (switching strategy) were more commonly prescribed after the first TNFi discontinuation. OBJECTIVE: To evaluate the cost-utility of adalimumab versus abatacept in patients with RA whose initial TNFi therapy failed. METHODS: A probabilistic cost-utility microsimulation state-transition model was used. Our target population was commercially insured adults with RA, the time horizon was 10 years, and we used a payer perspective. Patients not responding to adalimumab or abatacept were moved to the next drug in a sequence of 3 and, finally, to conventional synthetic therapy. Incremental cost-utility ratios (2016 USD per quality-adjusted-life-year gained [QALY)] were calculated. Utilities were derived from a formula based on the Health Assessment Questionnaire Disability Index and age-adjusted comorbidity score. RESULTS: Switching to abatacept after the first TNFi showed an incremental cost of just more than $11,300 over 10 years and achieved a QALY benefit of 0.16 compared with adalimumab. The incremental cost-effectiveness ratio was $68,950 per QALY. Scenario analysis produced an incremental cost-effectiveness ratio range of $44,573 per QALY to $148,558 per QALY. Probabilistic sensitivity analysis showed that switching to abatacept after TNFi therapy failure had an 80.6% likelihood of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. CONCLUSIONS: Switching to abatacept is a cost-effective strategy for patients with RA whose discontinue initial therapy with TNFi. DISCLOSURES: Funding for this project was provided by a Rheumatology Research Foundation Investigator Award (principal investigator: Maria A. Lopez-Olivo). Karpes Matusevich's work was supported by a Doctoral Dissertation Research Award from the University of Texas, School of Public Health Office of Research. Lal reports competing interests outside of the submitted work (employed by Optum). Suarez-Almazor reports competing interests outside of the submitted work (consulting fees from Pfizer, AbbVie, Eli Lilly, Agile Therapeutics, Amag Pharmaceuticals, and Gilead). Chan, Swint, and Cantor have nothing to disclose.

Informe diário de evidências COVID-19: busca realizada em 17 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 17, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 13 protocolos.

Informe diário de evidências COVID-19: busca realizada em 2 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 2, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 17 artigos e 9 protocolos.

Comparison of infection-related hospitalization risk and costs in tumor necrosis factor inhibitor-experienced patients with rheumatoid arthritis (RA) treated with abatacept or other targeted disease-modifying anti-rheumatic drugs (tDMARDs).

Background: Evidence on the cost and risk of infection-related hospitalizations associated with targeted disease-modifying anti-rheumatic drugs (tDMARDs) in patients with RA previously treated with a tumor necrosis factor inhibitor (TNFi) is limited. This study compared the risk and cost of infection-related hospitalizations in commercially insured TNFi-experienced RA patients receiving abatacept, TNFi, or another non-TNFi.Methods: A retrospective observational study was conducted using 2 large insurance claims databases (1 January 2009-30 June 2017). Adult TNFi-experienced RA patients initiating a subsequent tDMARD (initiation date of tDMARD = index date) with 12 months of continuous enrollment pre-index date, and who had ≥1 inpatient or ≥2 outpatient medical RA claims on 2 different dates were included. Abatacept was compared to TNFis (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) and other non-TNFis (tocilizumab, rituximab, and tofacitinib). Cox proportional hazards models estimated the adjusted risk for infection-related hospitalization; costs were calculated on a per-member-per-month (PMPM) and per-patient-per-month (PPPM) basis using generalized linear models.Results: More patients in the abatacept cohort had an infection-related hospitalization at baseline (4.5%) vs TNFis (2.0%, p < .0001) and other non-TNFis (3.6%, p = .2619). However, during follow-up abatacept patients had fewer infection-related hospitalizations (abatacept: 2.8%, TNFi: 3.7% and other non-TNFis: 5.2%; p < .05). Regression results indicated that compared to patients on abatacept, patients receiving a TNFi [HR: 1.6 (95% CI: 1.1, 2.2)] and other non-TNFis [HR: 1.9 (95% CI: 1.3, 2.8)] had a significantly higher risk of infection-related hospitalization. Abatacept PMPM costs were lowest ($0.25 vs $0.39 and $0.43 for TNFi and other non-TNFi respectively). Mean PPPM (95% CI) cost in the follow-up was lower for abatacept compared to TNFi ($73 vs. $115; p = .042), and other non-TNFi ($73 vs. $125; p = .039).Conclusions: There were significantly lower infection-related hospitalizations and associated costs in TNF-experienced RA patients treated with abatacept than TNFis and other non-TNFis.

A budget impact analysis for making treatment decisions based on anti-cyclic citrullinated peptide (anti-CCP) testing in rheumatoid arthritis.

Aim: Given that rheumatoid arthritis (RA) patients with high anti-citrullinated protein antibodies (ACPA) titer values respond well to abatacept, the aim of this study was to estimate the annual budget impact of anti-cyclic citrullinated peptide (anti-CCP) testing and treatment selection based on anti-CCP test results.Materials and methods: Budget impact analysis was conducted for patients with moderate-to-severe RA on biologic or Janus kinase inhibitor (JAKi) treatment from a hypothetical US commercial payer perspective. The following market scenarios were compared: (1) 90% of target patients receive anti-CCP testing and the results of anti-CCP testing do not impact the treatment selection; (2) 100% of target patients receive anti-CCP testing and the results of anti-CCP testing have an impact on treatment selection such that an increased proportion of patients with high titer of ACPA receive abatacept. A hypothetical assumption was made that the use of abatacept would be increased by 2% in Scenario 2 versus 1. Scenario analyses were conducted by varying the target population and rebate rates.Results: In a hypothetical health plan with one million insured adults, 2,181 patients would be on a biologic or JAKi treatment for moderate-to-severe RA. In Scenario 1, the anti-CCP test cost was $186,155 and annual treatment cost was $101,854,295, totaling to $102,040,450. In Scenario 2, the anti-CCP test cost increased by $20,684 and treatment cost increased by $160,467, totaling an overall budget increase of $181,151. This was equivalent to a per member per month (PMPM) increase of $0.015. The budget impact results were consistently negligible across the scenario analyses.Limitations: The analysis only considered testing and medication costs. Some parameters used in the analysis, such as the rebate rates, are not generalizable and health plan-specific.Conclusions: Testing RA patients to learn their ACPA status and increasing use of abatacept among high-titer ACPA patients result in a small increase in the total budget (<2 cents PMPM).

Real-world outcomes among patients with early rapidly progressive rheumatoid arthritis.

OBJECTIVES: To characterize treatment patterns, healthcare resource utilization (HRU), and disease activity among patients with early rapidly progressive rheumatoid arthritis (eRPRA) in the United States when treated with a first-line biologic disease-modifying antirheumatic drug (bDMARD) tumor necrosis factor-α (TNF) inhibitor or first-line abatacept. STUDY DESIGN: Observational, multicenter, retrospective, longitudinal, medical records-based, cohort study. METHODS: Patients with eRPRA were identified by anti-citrullinated protein antibody positivity, 28-joint Disease Activity Score-C-reactive protein of 3.2 or greater, symptomatic synovitis in 2 or more joints for at least 8 weeks prior to the index date, and onset of symptoms within 2 years or less of the index date. Patients received abatacept or a TNF inhibitor as first-line treatment. Patient characteristics, treatment patterns, HRU, and disease activity following bDMARD initiation were compared across the 2 groups. Odds ratios (ORs) of HRU in the first 6 months of bDMARD treatment were estimated using multivariable logistic regression to adjust for patient mix. RESULTS: There were 60 patients treated with abatacept and 192 treated with a TNF inhibitor in the first line. Those treated with first-line abatacept had lower adjusted odds of hospitalization (OR, 0.42; 95% CI, 0.18-0.95), emergency department (ED) visits (OR, 0.39; 95% CI, 0.16-0.93), and magnetic resonance imaging (MRI) (OR, 0.45; 95% CI, 0.21-0.97) than those treated with a first-line TNF inhibitor (all P <.05). Adjusted odds of achieving low disease activity as measured by clinical disease activity index within 100 days of bDMARD initiation favored first-line abatacept versus a first-line TNF inhibitor (OR, 4.37; 95% CI, 1.34-13.94; P = .01). CONCLUSIONS: Adjusting for disease severity, patients with eRPRA who were treated with first-line abatacept were less likely to have hospitalizations, ED visits, and MRI use during the first 6 months of bDMARD treatment and more likely to achieve low disease activity within 100 days of bDMARD start compared with those who received a first-line TNF inhibitor.

Cost-effectiveness of abatacept, tocilizumab and TNF-inhibitors compared with rituximab as second-line biologic drug in rheumatoid arthritis.

OBJECTIVES: The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. METHODS: A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. RESULTS: Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. CONCLUSIONS: TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.

Preliminary assessment of the feasibility of autologous myeloid-derived suppressor cell infusion in non-human primate kidney transplantation.

Myeloid-derived suppressor cells (MDSC) are a heterogenous population of immunosuppressive myeloid cells now considered important immune regulatory cells in diverse clinical conditions, including cancer, chronic inflammatory disorders and transplantation. In rodents, MDSC administration can inhibit graft-versus-host disease lethality and enhance organ or pancreatic islet allograft survival. There is also evidence, however, that under systemic inflammatory conditions, adoptively-transferred MDSC can rapidly lose their suppressive function. To our knowledge, there are no reports of autologous MDSC administration to either human or clinically-relevant non-human primate (NHP) transplant recipients. Monocytic (m) MDSC have been shown to be more potent suppressors of T cell responses than other subsets of MDSC. Following their characterization in rhesus macaques, we have conducted a preliminary analysis of the feasibility and preliminary efficacy of purified mMDSC infusion into MHC-mismatched rhesus kidney allograft recipients. The graft recipients were treated with rapamycin and the high affinity variant of the T cell co-stimulation blocking agent cytotoxic T lymphocyte antigen 4 Ig (Belatacept) that targets the B7-CD28 pathway. Graft survival and histology were not affected by infusions of autologous, leukapheresis product-derived mMDSC on days 7 and 14 post-transplant (cumulative totals of 3.19 and 1.98 × 106 cells/kg in n = 2 recipients) compared with control monkeys that did not receive MDSC (n = 2). Sequential analyses of effector T cell populations revealed no differences between the groups. While these initial findings do not provide evidence of efficacy under the conditions adopted, further studies in NHP, designed to ascertain the appropriate mMDSC source and dose, timing and anti-inflammatory/immunosuppressive agent support are likely to prove instructive regarding the therapeutic potential of MDSC in organ transplantation.

Cost per response for abatacept versus adalimumab in patients with seropositive, erosive early rheumatoid arthritis in the US, Germany, Spain, and Canada.

BACKGROUND: Effective treatment of rheumatoid arthritis (RA) with biologic DMARDs poses a significant economic burden. The AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE RA subjects with background methotrexate) trial was a head-to-head, randomized study comparing abatacept with adalimumab. A post hoc analysis showed improved efficacy for abatacept in patients with versus without seropositive, erosive early RA. OBJECTIVE: The aim of the current study was to evaluate the cost per response (ACR20/50/70/90 and HAQ-DI) and patient in remission (DAS28-CRP, CDAI, and SDAI) for abatacept relative to adalimumab, in patients with seropositive, erosive early RA in the US, Germany, Spain, and Canada. METHODS: A previously published model was used to compare abatacept and adalimumab in a cohort of 1000 patients over 2 years. Clinical inputs were updated based on two subpopulations from the AMPLE trial. Cohort 1 included patients with early RA (disease duration ≤ 6 months), RF and/or ACPA seropositivity, and > 1 radiographic erosion. Cohort 2 included patients with RA in whom at least one of these criteria was absent. RESULTS: For cohort 1, all incremental costs per additional health gain (patient response or patient in remission) favoured abatacept in all countries, except for DAS28-CRP remission in Canada. Cost savings versus adalimumab were greater when more stringent response criteria were applied and also in cohort 1 patient (versus cohort 2 patients). CONCLUSION: The cost per responder and patient in remission favoured abatacept in patients with seropositive, erosive early RA across all the countries. In this patient population, the use of abatacept instead of adalimumab can lead to lower costs in the US, Germany, Spain, and Canada.

Timing of Abatacept Before Elective Arthroplasty and Risk of Postoperative Outcomes.

OBJECTIVE: Guidelines recommend withholding biologic therapies before hip and knee arthroplasty, yet evidence to inform optimal timing is limited. The aim of this study was to determine whether withholding abatacept infusions is associated with lower risk of adverse postoperative outcomes. METHODS: This retrospective cohort study, which used US Medicare and Truven MarketScan administrative data from January 2006 to September 2015, evaluated adults with rheumatoid arthritis who received intravenous abatacept (precisely dated in claims data) within 6 months of elective primary or revision hip or knee arthroplasty. Propensity weighted analyses using inverse probability weights compared the risk of 30-day hospitalized infection and 1-year prosthetic joint infection (PJI) between patients with different abatacept stop timing (time between last infusion and surgery). Secondary analyses evaluated nonurinary hospitalized infections and 30-day readmissions. RESULTS: After 1,939 surgeries among 1,780 patients, there were 175 hospitalized infections (9.0%), 115 nonurinary hospitalized infections (5.9%), 39 PJIs (2.4/100 person-years), and 114/1,815 30-day readmissions (6.3%). There were no significant differences in outcomes with abatacept stop timing <4 weeks (1 dosing interval) versus 4-8 weeks (hospitalized infection odds ratio [OR] 0.93 [95% confidence interval (95% CI) 0.65-1.34]; nonurinary hospitalized infection OR 0.93 [95% CI 0.60-1.44]; PJI hazard ratio 1.29 [95% CI 0.62-2.69]; 30-day readmission OR 1.00 [95% CI 0.65-1.54]). Similarly, there were no significant differences in outcomes with abatacept stop timing <4 weeks versus ≥8 weeks. Glucocorticoid use >7.5 mg/day was associated with greater risk of hospitalized infection (OR 2.19 [95% CI 1.28-3.77]) and nonurinary hospitalized infection (OR 2.38 [95% CI 1.22-4.64]). CONCLUSION: Compared to continuing intravenous abatacept, withholding abatacept for ≥4 weeks (one dosing interval) before surgery was not associated with a lower risk of hospitalized infection, nonurinary hospitalized infection, PJI, or 30-day readmission.

The economic burden of switching targeted disease-modifying anti-rheumatic drugs among rheumatoid arthritis patients.

AIMS: To estimate real world healthcare costs and resource utilization of rheumatoid arthritis (RA) patients associated with targeted disease modifying anti-rheumatic drugs (tDMARD) switching in general and switching to abatacept specifically. MATERIALS AND METHODS: RA patients initiating a tDMARD were identified in IMS PharMetrics Plus health insurance claims data (2010-2016), and outcomes measured included monthly healthcare costs per patient (all-cause, RA-related) and resource utilization (inpatient stays, outpatient visits, emergency department [ED] visits). Generalized linear models were used to assess (i) average monthly costs per patient associated with tDMARD switching, and (ii) among switchers only, costs of switching to abatacept vs tumor necrosis factor inhibitors (TNFi) or other non-TNFi. Negative binomial regressions were used to determine incident rate ratios of resource utilization associated with switching to abatacept. RESULTS: Among 11,856 RA patients who initiated a tDMARD, 2,708 switched tDMARDs once and 814 switched twice (to a third tDMARD). Adjusted average monthly costs were higher among patients who switched to a second tDMARD vs non-switchers (all-cause: $4,785 vs $3,491, p < .001; RA-related: $3,364 vs $2,297, p < .001). Monthly RA-related costs were higher for patients switching to a third tDMARD compared to non-switchers remaining on their second tDMARD ($3,835 vs $3,383, p < .001). Switchers to abatacept had significantly lower RA-related monthly costs vs switchers to TNFi ($3,129 vs $3,436, p = .021), and numerically lower all-cause costs ($4,444 vs $4,741, p = 0.188). Switchers to TNFi relative to abatacept had more frequent inpatient stays after switch (incidence rate ratio (IRR) = 1.85, p = .031), and numerically higher ED visits (IRR = 1.32, p = .093). Outpatient visits were less frequent for TNFi switchers (IRR = 0.83, p < .001) compared to switchers to abatacept. LIMITATIONS AND CONCLUSIONS: Switching to another tDMARD was associated with higher healthcare costs. Switching to abatacept, however, was associated with lower RA-related costs, fewer inpatient stays, but more frequent outpatient visits compared to switching to a TNFi.

Abatacept initiation in rheumatoid arthritis and the risk of cancer: a population-based comparative cohort study.

OBJECTIVE: To assess whether abatacept as initial biological DMARD (bDMARD) in the treatment of RA, when compared with other bDMARDs, is associated with an increased risk of cancer overall and by specific cancer sites (breast, lung, lymphoma, melanoma and non-melanoma skin cancer). METHODS: We performed a population-based cohort study among patients newly treated with bDMARDs within the US-based Truven MarketScan population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs of any cancer (and specific cancers) associated with initiation of abatacept, compared with initiation of other bDMARDs, adjusted for age and deciles of the propensity score. RESULTS: The cohort included 4328 patients on abatacept and 59 860 on other bDMARDs, of whom 409 and 4197 were diagnosed with any cancer during follow-up (incidence rates 4.76 per 100 per year and 3.41 per 100 per year, respectively). Compared with other bDMARDs, the use of abatacept was associated with an increased incidence of cancer overall (hazard ratioadjusted 1.17; 95% CI 1.06, 1.30). Analyses by specific cancer sites showed a significantly increased incidence of non-melanoma skin cancer (hazard ratioadjusted 1.20; 95% CI 1.03, 1.39), but no significant difference for other specific cancer sites. CONCLUSION: The use of abatacept as first bDMARD in the treatment of RA was associated with a slight increased risk of cancer overall and particularly non-melanoma skin cancer, compared with other bDMARDs. This potential signal needs to be replicated in other settings.

Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT.

BACKGROUND: Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. OBJECTIVES: To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. DESIGN: Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. SETTING: UK outpatient rheumatology departments. PARTICIPANTS: Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi. INTERVENTIONS: Alternative TNFi, abatacept or rituximab (and continued background MTX). MAIN OUTCOME MEASURES: The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity. LIMITATIONS: Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early. RESULTS: Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity. FUTURE WORK: The results will add to the randomised evidence base and could be included in future meta-analyses. CONCLUSIONS: How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 34. See the NIHR Journals Library website for further project information.