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The CD86 occupancy assay has been developed to measure the number of CD86 molecules unbound to belatacept, but its association with clinical outcomes has not been assessed yet. All kidney transplant patients switched to belatacept in our center between 2016 and 2018 were included. Blood samples were collected before each infusion for 1 year to assess CD86 occupancy by CD86 antibody cytometry staining on the surface of CD14

We reported a patient with autoimmunity (multiple sclerosis), immunodeficiency (hypogammaglobulinemia with severe infections), enteropathy (diarrhea with intestinal inflammation), splenomegaly, lymphadenopathy and lymphocytic infiltration of non-lymphoid organs (lung, gut and brain). The patient was found to have a heterozygous mutation in cytotoxic T lymphocyte antigen-4, and had excellent response to abatacept.

Background Off-label (OL) drug use is the prescription of a drug for indications other than those authorised in its technical datasheet. The objective of this study was to identify drugs recommended in rheumatology but considered for off-label use in Argentina. Methods A list of medications for certain selected rheumatic conditions was compiled. A drug was considered recommended if it was endorsed by a) at least one Argentine or Pan-American treatment guideline or consensus, or b) two international treatment guidelines, or c) one international treatment guideline and one selected textbook. Approval of these drugs for any condition in Argentina until December 31st, 2018 was explored, and medicines were divided into those with on-label indications and those considered for OL use. Results One hundred and thirty-six medications were analysed in 13 clinical conditions. Sixty-seven OL recommendations (49%) were found, and several drugs had more than one. All the conditions included the recommendation of at least 1 OL drug except osteoporosis and rheumatoid arthritis. The frequency of OL recommendations for the following conditions was 100%: calcium pyrophosphate dihydrate crystal deposition disease, polymyalgia rheumatica, Sjogren syndrome, and systemic sclerosis. The drugs with the highest number of OL recommendations were methotrexate (in 7 conditions), and glucocorticoids and mycophenolate (in 4). There were 2 OL recommendations for rituximab and 1 for abatacept. Conclusions Almost all the rheumatic disorders analysed involved the recommendation of at least 1 OL medication, and in 4 conditions all the recommendations were OL. Most OL drugs recommended in rheumatology are neither biological nor small-molecule therapies.

Belatacept was developed to replace calcineurin inhibitors in kidney transplantation. Its use is associated with better kidney transplant function, a lower incidence of anti-donor antibodies and higher graft survival. However, it is also associated with a higher risk of cellular rejection. We studied the activation and proliferation mechanisms of belatacept-resistant T lymphocytes (TLs), to identify new pathways for control. We performed a transcriptomic analysis on CD4+ CD57+ PD1- memory TLs, which are responsible for a higher incidence of graft rejection, after allogeneic stimulation with activated dendritic cells (aDCs) in the presence or absence of belatacept. After six hours of contact with aDCs, the (CD4+ CD57+ PD1- ) (CD4+ CD57+ PD1+ ) and (CD4+ CD57- ) lymphocytes had different transcriptional profiles with or without belatacept. In the CD4+ CD57+ PD1- population, the IFNα-dependent activation pathway was positively overrepresented, and IRF7 transcript levels were high. IRF7 was associated with IFNα/β and IL-6 regulation. The inhibition of both these cytokines in a context of belatacept treatment inhibited the proliferation of CD4+ CD57+ PD1- T cells. Our results show that IRF7 is rapidly upregulated in belatacept-resistant CD4+ CD57+ PD1- TLs. The inhibition of type I IFN or IL-6 in association with belatacept treatment reduces the proliferation of belatacept-resistant TLs, paving the way for new treatments for use in organ transplantation.

The potential of adoptive cell therapy with regulatory T cells (Tregs) to promote transplant tolerance is under active exploration. However, the impact of specific transplant settings and protocols on Treg manufacturing is not well-delineated. Here, we compared the use of peripheral blood mononuclear cells (PBMCs) from patients before or after liver transplantation to the use of healthy control PBMCs to determine their suitability for Treg manufacture using ex vivo costimulatory blockade with belatacept. Despite liver failure or immunosuppressive therapy, the capacity for Treg expansion during the manufacturing process was preserved. These experiments did not identify performance or quality issues that disqualified the use of posttransplant PBMCs-the currently favored protocol design. However, as Treg input correlated with output, significant CD4-lymphopenia in both pre- and posttransplant patients limited Treg yield. We therefore turned to leukapheresis posttransplant to improve absolute yield. To make deceased donor use feasible, we also developed protocols to substitute splenocytes for PBMCs as allostimulators. In addition to demonstrating that this Treg expansion strategy works in a liver transplant context, this preclinical study illustrates how characterizing cellular input populations and their performance can both inform and respond to clinical trial design and Treg manufacturing requirements.

Poor responses to mRNA COVID-19 vaccine have been reported after 2 vaccine injections in kidney transplant recipients (KTRs) treated with belatacept. We analyzed the humoral response in belatacept-treated KTRs without a history of SARS-CoV-2 infection who received three injections of BNT162b2-mRNA COVID-19 vaccine. We also investigated vaccine immunogenicity in belatacept-treated KTRs with prior COVID-19 and characterized symptomatic COVID-19 infections after the vaccine in belatacept-treated KTRs. Among the 62 belatacept-treated KTRs (36 [58%] males), the median age (63.5 years IQR [51-72]), without COVID-19 history, only four patients (6.4%) developed anti-SARS-CoV-2 IgG with low antibody titers (median 209, IQR [20-409] AU/ml). 71% were treated with mycophenolic acid and 100% with steroids in association with belatacept. In contrast, in all the 5 KTRs with prior COVID-19 history, mRNA vaccine induced a strong antibody response with high antibody titers (median 10 769 AU/ml, IQR [6410-20 069]) after two injections. Seroprevalence after three-vaccine doses in 35 non-belatacept-treated KTRs was 37.1%. Twelve KTRs developed symptomatic COVID-19 after vaccination, including severe forms (50% of mortality). Breakthrough COVID-19 occurred in 5% of fully vaccinated patients. Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Other strategies aiming to improve patient protection are needed.

OBJECTIVE: To review the available evidence on the impact of rheumatoid arthritis (RA) treatments in associated diffuse interstitial lung disease (ILD). METHODS: Systematic review of studies evaluating the impact of pharmacological treatment in patients with RA and ILD. A bibliographic search in MEDLINE, EMBASE and Cochrane, a selection of articles and the methodological quality assessment (FLC 3.0 OSTEBA) and grading of the level of evidence (SING) of the selected articles were performed. RESULTS: 1,720 references were identified in primary search and 7 in manual or indirect. Forty-three articles were included: 7 systematic reviews, 2 randomized clinical trials, 5 cohort studies, 8 case-control studies and 21 case series. Methotrexate (MTX) and leflunomide (LEF) do not increase incidence, complications or mortality due to ILD. Although the results are not uniform, anti-TNF have often had worse outcomes in incidence, progression and mortality due to ILD than MTX, LEF, abatacept (ABA) and rituximab (RTX). The evidence found is scarce for JAK kinase and antifibrotic inhibitors, and controversial for IL-6 inhibitors. CONCLUSIONS: There is no evidence that MTX or LEF worsens the prognosis of patients with AR-EPID. RTX and ABA seem to have better results than other biologicals, such as anti-TNF, often achieving stabilization and, in some cases, the improvement of ILD in patients with RA.

Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pre-transplant T cell phenotypes of patients who reject vs. those that remain stable on belatacept identified three potential “risky” memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4(+) CD28(+) T(EM), CD8(+) CD28(null) and CD4(+) CD57(+) PD1(−) subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Co-culture of human memory CD4(+) and CD8(+) T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3(+) Treg, suggesting that agonism of the TIGIT pathway increases FOXP3(+) Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.

CTLA4 deficiency and LRBA deficiency are a group disorders of immune dysregulation that affect CTLA4 pathway. The patients mainly present with autoimmunity, antibody deficiency and recurrent infections. Here we reported three Chinese patients with LRBA and CTLA4 mutations. They all presented with chronic diarrhea, hypokalemia, organomegaly, recurrent infections, and hypogammaglobulinemia. Reduced Treg cells and increased percentage of circulating follicular helper T (cTfh) cells were revealed in these patients. Although steroid and immunoglobulin therapy were given, the enteropathy was persistent. Therefore, abatacept treatment was provided to these patients. They showed a marked improvement of enteropathy and gastrointestinal endoscopy showed alleviated inflammatory lesion and follicular hyperplasia. Furthermore, the frequency of cTfh cells was reduced after abatacept therapy. Taken together, targeted therapy with abatacept is a promising treatment modality for patients with LRBA and CTLA4 deficiency. The findings also suggest that the frequency of cTfh cells could serve as a marker for tracking disease activity and the response to abatacept therapy.

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naive T (TNaive ) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaive cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+ CD31+ ) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+ CD31+ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57- cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction. Trial Registration: ClinicalTrials.gov - NCT00565773.

Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.

Objectives To determine the association of first, second, and third-line biologic disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib with drug survival among seropositive rheumatoid arthritis (RA) patients. Methods The study population was composed of 8,018 seropositive RA patients who were prescribed bDMARDs or tofacitinib between January 2014 and January 2019 from the Korean Health Insurance Review and Assessment Service database. First, second, and third-line choice of tumor necrosis factor inhibitors (TNFi) including etanercept, infliximab, adalimumab, and golimumab, as well as non-TNFi including tocilizumab, rituximab, tofacitinib, and abatacept were assessed. Multivariate Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for drug failure according to bDMARD or tofacitinib choice starting from the initial prescription date. Results Compared to first etanercept users, patients with first tocilizumab (aHR 0.56, 95% CI 0.46–0.68), tofacitinib (aHR 0.27, 95% CI 0.18–0.42), or abatacept (aHR 0.83, 95% CI 0.69–0.99) had lower risk of drug failure. Second choice of tocilizumab (aHR 0.38, 95% CI 0.25–0.55), tofacitinib (aHR 0.23, 95% CI 0.15–0.37), or abatacept (aHR 0.54, 95% CI 0.35–0.84) was associated with lower drug failure risk compared to second etanercept users. Finally, third choice of tocilizumab (aHR 0.32, 95% CI 0.16–0.62) or tofacitinib (aHR 0.35, 95% CI 0.19–0.63) was associated with lower drug failure risk compared to third TNFi users. Conclusion First and second-line tocilizumab, tofacitinib, or abatacept may lead to improved drug survival. Third-line use of tocilizumab or tofacitinib may be beneficiary in reducing drug failure risk among seropositive RA patients.

Summary Background Recent randomised controlled trials (RCTs) in primary Sjogren's syndrome used the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjogren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjogren's syndrome: the Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS). Methods A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders. Findings Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjogren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p Interpretation The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjogren's syndrome. As a next step, the CRESS will require validation in a prospective RCT. Funding None. Translation For the Dutch translation of the abstract see Supplementary Materials section.

Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4-68.5]) were converted to belatacept (median of 11.5 months [2.5-37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R- CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR

Kidney transplant recipients administered belatacept‐based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor‐specific antibodies (DSAs), and improved renal function and long‐term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)‐based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept‐based regimen than with CNI‐based immunosuppression. Although these early co‐stimulation blockade‐resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept‐based maintenance regimens. Steroid‐sparing, belatacept‐based immunosuppression (following T cell–depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI‐based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept‐based regimen for minimizing early cellular AR occurrence., Kirk et al. discuss available data on alternative de novo belatacept‐based immunosuppression regimens in place of the approved belatacept regimen to reduce acute rejection rates in kidney transplant recipients.

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.

To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc).Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests.Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p0.03 and p0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p0.05) and on morning stiffness at 6 and 12 months (p0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p0.05). No changes in lung or gastrointestinal involvement were found.ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

Background Tumour necrosis factor inhibitors (TNFis) improve joints outcomes and reduce cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). However, 20%-45% of RA patients are TNFi poor responders and have a significantly higher risk of CV events. In these TNFi nonresponders, the use of second-line biologic agents to improve synovial outcomes is supported by clinical trials and real-world experience. However, it remains unknown what kind of immune-mediated agent has the best CV prevention effect in this high-risk population. Methods A nationwide RA cohort obtained from Taiwan’s National Health Insurance claims database was constructed. RA patients first treated with TNFis who then received either rituximab, tocilizumab, or abatacept were enrolled and followed for 2 years. Results A total of 89,973 RA patients were screened and 1,584 patients ultimately included. The incidences of major adverse cardiac events (MACE) at 2 years in the rituximab, tocilizumab, and abatacept groups were 7.17%, 2.75% and 2.38%, respectively. Multivariate adjusted Cox analysis showed that tocilizumab had significantly lower risk than rituximab in myocardial infarction (hazard ratio [HR] 0.12, 95% confidence interval [CI] 0.02-0.56; P = 0.008), and MACE (HR 0.41, 95% CI 0.23-0.72; P = 0.002). In addition, abatacept also had significant lower adjusted risk than rituximab in stroke (HR 0.18, 95% CI 0.05-0.64; P = 0.008), heart failure (HR 0.20, 95% CI 0.05-0.83; P = 0.027), and MACE (HR 0.25, 95% CI 0.11-0.55; P Conclusions TNFi-nonresponder patients with RA who received second-line tocilizumab or abatacept had more benefit on CV events prevention compared with those who received rituximab.

Objectives To assess the risk of developing cancer in patients with rheumatoid arthritis (RA) exposed to non-TNF inhibitors (TNFi) biologics or tofacitinib therapy. Methods Systematical search of PubMed, EMBASE and Cochrane Library plus a hand search of conference proceedings were performed. Observational studies that reported cancer incidence in patients with RA treated with biologics or tofacitinib with active comparator of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or TNFi were eligible for inclusion. The pooled relative risk (RR) and 95% confidence interval (CI) were calculated with fix-effects or random-effects model. Results Of 2,819 identified articles, a total of 10 studies involving over 40,587 patients with more than 87,622 patient-years of exposure to non-TNF inhibitors (TNFi) biologics and 2,221 patients with more than 4,506 patient-years of exposure to tofacitinib were included. Pooled analysis showed there was no increased risk of developing cancer in general or specific cancer types in RA patients receiving treatment with rituximab (pooled RR 0.87, 95% CI 0.74-1.03), tocilizumab (pooled RR 0.92, 95% CI 0.79-1.06), or tofacitinib, compared with those receiving csDMARDs or TNFi. But abatacept was associated with a slightly increased overall cancer risk (pooled RR 1.13, 95% CI 1.02-1.24) and non-melanoma skin cancer (pooled RR 1.26, 95% CI 1.09-1.45), relative to csDMARDs or TNFi in RA patients. Conclusion Among RA patients, a small statistically significant increase in developing cancer was observed for abatacept exposure, while no increased cancer risk for rituximab, tocilizumab or tofacitinib, in comparison with csDMARDs or TNFi.

The major hindrances to the success of a haploidentical hematopoietic cell transplantation for hemoglobinopathies are graft failure, early post-transplant hemophagocytic syndrome (PTHPS), and graft-versus-host disease (GVHD). Following the successful incorporation of CTLA4Ig (abatacept) in post-transplantation cyclophosphamide-based haploidentical transplantation, we piloted this approach in 10 patients (aged 3 to 19 years), with thalassemia major (TM, n=5) and sickle cell disease (n = 5). Pretransplant immunosuppressive therapy (pTIST) was administered for 10 weeks. Conditioning was myeloablative. CTLA4Ig was administered every 2 weeks during pTIST and on days –1, +5, +20, and +35 and every 4 weeks thereafter for 6 months, along with sirolimus. A short course of low-dose dexamethasone was given from day +6 for 14 days. Nine patients engrafted at a median of 15 days, with 1 patient with TM dying of sepsis on day +19. None of the patients developed acute or chronic GVHD. All 9 patients are alive and disease free at a median follow-up of 28 months. Only 4 patients had cytomegalovirus reactivation. The pattern of immune reconstitution showed a prompt and sustained recovery of T cell subsets with memory phenotype, along with early and sustained increase of Tregs and NKG2C+ natural killer (NK) cells. This novel approach, targeting CD80 and CD86 on monocytes/macrophages, promoted engraftment and limited early-onset PTHPS and graft failure. The lack of GVHD and serious infections with this approach reflects an early recovery of Tregs, memory T cells, and persistence of NKG2C+ NK cells.

Background Biologic agents may pose a potential risk for exacerbations of pulmonary comorbidities in rheumatoid arthritis (RA) patients. Methods Using U.S. Medicare and Truven MarketScan databases, we identified three cohorts of RA patients with interstitial lung disease (ILD), chronic obstructive pulmonary disease (COPD), or asthma who initiated abatacept or a TNF inhibitor (TNFi). The primary outcome was a composite exacerbation of individual pulmonary comorbidities based on inpatient or emergency department (ED) visits due to exacerbation of the given pulmonary comorbidity. To adjust for >60 baseline confounders, we used propensity-score fine stratification (PSS) and weighting. Negative binomial regression model estimated a cohort-specific incidence rate ratio (IRR) and 95% confidence interval (CI) of the primary outcome per database, comparing abatacept versus TNFi. Database-specific IRRs were combined using a random-effects meta-analysis. Results We identified 3,295 ILD, 7,161 COPD, and 5,613 asthma patients with RA who initiated either abatacept or a TNFi. IR of composite exacerbation was high in all three pulmonary cohorts but highest in COPD cohort (3.59-11.80 per 100 person-years in ILD, 20.68-34.97 in COPD, and 4.66-13.78 in asthma). After PSS weighting, the combined IRR (95%CI) in abatacept initiators versus TNFi initiators was 0.44 (0.18-1.09) for ILD exacerbation, 0.91 (0.80-1.03) for COPD exacerbation, and 0.81 (0.54-1.22) for asthma exacerbation. Conclusion Among patients with RA and pulmonary comorbidities, exacerbations requiring inpatient or ED visits occurred frequently after initiating abatacept or TNFi. Overall, we found no significant difference in the risk of ILD, COPD or asthma exacerbation between abatacept and TNFi initiators, but precision of our estimates is limited.

Understanding the correlation between transplant symptoms, health-related quality of life (HRQoL), and graft outcomes is needed to support patient-focused drug development and posttransplant management. A post-hoc analysis of patient-reported outcomes from the Phase III belatacept trials was conducted in order to investigate the interrelationship between trajectories of HRQoL, symptom experience, and allograft outcomes. HRQoL and symptom experience were evaluated using Short-Form 36 Survey (SF-36) and Modified Transplant Symptom Occurrence and Distress Scale (MTSOSD-59R), respectively. HRQoL was captured in 831 eligible renal transplant patients at baseline, 12, 24, and 36 months posttransplant. Following transplantation, patients reported improvements in all SF-36 subscales compared to baseline. Latent class analysis revealed four trajectories in perceived general health, which were associated with graft failure after adjustment. Compared to patients with good perceived health, patients with fair and poor perceived health had 4.7 (95% confidence interval [CI] 1.5-14.8, P < .01) and 19.8 (95% CI 5.9-66.0, P < .01) times the risk of graft failure, respectively. Using multinomial logistic regression, different sets of symptoms were associated with perceived general health at baseline and 12 months posttransplant. The study supports monitoring HRQoL and symptom experience to capture each patient's health perspective, improve drug development, and optimize posttransplant management.

There is lack of research on the safety of medications used to treat rheumatic diseases in men wishing to conceive. When evaluating medication safety for potential fathers, two major reproductive issues are to be considered: first, whether a drug induces infertility, and second, whether a drug can cause adverse pregnancy outcomes. Cyclophosphamide is the only medication used in rheumatic disease management that causes irreversible infertility. All men prescribed cyclophosphamide should be counseled on fertility preservation including sperm banking. Sulfasalazine can cause reversible azoospermia; when conception is delayed, this medication should be held for three months and semen analysis should be performed. There are limited data on the teratogenic risk of paternal exposure to medications. Men wanting to conceive should avoid cyclophosphamide and thalidomide. Methotrexate; NSAIDs; glucocorticoids; sulfasalazine; the immunosuppressive agents azathioprine, 6-mercaptopurine, cyclosporine, tacrolimus, and mycophenolate mofetil; colchicine; TNF-alpha blockers; hydroxychloroquine; IVIG; rituximab; abatacept; and anakinra are compatible with paternal exposure. There are insufficient data to conclude the safety of other biologics and small molecules in men seeking to father a child.

Lymphocyte depletion has been shown to control costimulation blockade-resistant rejection but, in some settings, to exacerbate antibody-mediated rejection (AMR). We have used alemtuzumab, which depletes T and B cells, combined with belatacept and rapamycin and previously reported control of both costimulation blockade-resistant rejection and AMR. To evaluate this regimen's effect on B cell signatures, we investigated 40 patients undergoing this therapy. B cell counts and phenotypes were interrogated using flow cytometry, and serum was analyzed for total IgG, IgM, and donor-specific alloantibody (DSA). Alemtuzumab induction produced pan-lymphocyte depletion; B cells repopulated faster and more completely than T cells. Reconstituting B cells were predominantly naive, and memory B cells were significantly reduced (P = .001) post repopulation. Two B cell populations with potential immunomodulatory effects-regulatory (CD38hi CD24hi IgMhi CD20hi ) and transitional B cells (CD19+ CD27- IgD+ CD38hi )-were enriched posttransplant (P = .001). Total serum IgG decreased from baseline (P = .016) while IgM levels remained stable. Five patients developed DSAs within 36 months posttransplant, but none developed AMR. Baseline IgG levels in these patients were significantly higher than those in patients without DSAs. These findings suggest that belatacept and rapamycin together limit homeostatic B cell activation following B cell depletion and may lessen the risk of AMR. This regimen warrants prospective, comparative study. ClinicalTrials.gov NCT00565773.

Adolescent transplant recipients are at risk for nonadherence, development of de novo donor-specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor-based regimens in adults; however, its use in children is scant. Three adolescents were initiated on belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid-free belatacept and sirolimus for two patients. One patient was initially maintained steroid-free on belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy-proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m2 at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid-responsive acute cellular rejection. Belatacept-based regimens can be tailored for adolescent recipients with good short-term clinical outcomes.

Summary Strides have been made in the treatment of pulmonary arterial hypertension and interstitial lung disease in patients with systemic sclerosis, with successful trials of combination therapies in pulmonary arterial hypertension and of new drugs that slow the decline of lung function in interstitial lung disease. However, many trials in patients with early diffuse cutaneous systemic sclerosis have been negative, including trials of tocilizumab, abatacept, and riociguat, despite improvements in skin scores and other endpoints that approached statistical significance. Trials of macitentan for digital ulcers in these patients have also been disappointing. Trials that do not meet their primary endpoint do not necessarily signify ineffective therapies, as there are many other possible reasons for negative trial results, including features of trial design, insufficient trial duration, or insufficient power to detect differences between groups. In this Series paper, I discuss some of these reasons and what the research community can learn from negative trials to inform future trial design going forward.

Summary Background The risk of serious infection is a major concern when prescribing a disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. Little evidence exists with regard to serious infection risk associated with tofacitinib, a targeted synthetic (ts)DMARD, compared with biologic DMARDs (bDMARDs) among patients with rheumatoid arthritis. We compared the risk of serious infection in patients with rheumatoid arthritis initiating tofacitinib versus one of the seven bDMARDs. Methods In this multidatabase cohort study, we identified eight mutually exclusive groups of patients with rheumatoid arthritis initiating tofacitinib or one of the seven bDMARDs using US public (Medicare 20012–15) and private (Optum Clinformatics 2012–18 and IBM MarketScan 2012–17) health insurance programmes. Eligible patients were aged 18 years or older, and had one inpatient visit or two or more outpatient visits (7–365 days apart) for rheumatoid arthritis using International Classification of Diseases 9th and 10th revision codes. The primary outcome was a composite endpoint of admission to hospital for serious infection including bacterial, viral, or opportunistic infection based on the inpatient principal diagnosis code. Secondary outcomes were individual types of serious infections and herpes zoster. We adjusted for more than 60 potential confounders through propensity score-based inverse probability treatment weighting in each database. Database-specific adjusted hazard ratios (aHRs) were combined using a fixed-effects meta-analysis. Findings We identified 130 718 patients with rheumatoid arthritis across the three databases. During 100 790 person-years of follow-up, 3140 serious infections occurred (crude incidence rate per 100 person-years 3·12, 95% CI 3·01–3·23). The aHR for serious infection associated with tofacitinib was 1·41 (95% CI 1·15–1·73) versus etanercept, 1·20 (0·97–1·49) versus abatacept, 1·23 (0·94–1·62) versus golimumab, and 1·17 (0·89–1·53) versus tocilizumab. The serious infection risk with tofacitinib was similar to adalimumab (1·06, 0·87–1·30) and certolizumab (1·02, 0·80–1·29), and was lower than infliximab (0·81, 0·65–1·00). Tofacitinib was associated with a 2-fold higher risk of herpes zoster versus all bDMARDs. Interpretation This study found potential differences between tofacitinib and several bDMARDs in the risk of admission to hospital for serious infection, as well as herpes zoster, in patients with rheumatoid arthritis. These results contribute to the evolving understanding of the overall risk-benefit profile of tofacitinib. Funding Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, Harvard University, MA, USA.

Objectives To assess factors influencing the choice and effectiveness of biological disease-modifying antirheumatic drugs (DMARDs) following failure of rituximab (RTX) in rheumatoid arthritis (RA), taking patient profile into account. Methods In a retrospective, multicenter study, data about RA patients starting a new biologic during the year after RTX discontinuation were collected at baseline (when the biologic was introduced after RTX), and during follow-up (3, 6, and 12 months). Characteristics of patients receiving tocilizumab (TCZ), abatacept (ABA), or a TNFα inhibitor (TNFi), EULAR response, and retention rate were compared using multidimensional factorial analysis for patient profiles and multivariate analysis including propensity score built on the patient profile. Results Among 152 patients analyzed (37.5% TCZ, 31.6% ABA, 30.9% TNFi), sex, disease characteristics and activity, concomitant DMARDs or glucocorticoids, and previous use of RTX and TNFi were similar at baseline. Patients receiving ABA were slightly older. Multimorbidity index was higher but not significantly different. Multidimensional factorial analysis showed a distinct profile of patients receiving ABA, characterized by older age, more men, more smokers, more comorbidities, and higher anti-cyclic citrullinated peptide antibody. At 1 year, drug retention was higher for ABA than TNFi after adjustment for disease duration, concomitant DMARDs, glucocorticoids, and propensity score (P = 0.04). Tolerance and serious infections were similar among groups. Conclusions The profile of patients receiving ABA following failure of RTX differed from TNFi and TCZ using multidimensional factorial analysis. After adjustment for propensity score, drug retention rate remained higher with ABA than TNFi.

Summary Background Patients with rheumatoid arthritis have increased risk of seasonal influenza and influenza-related complications but have reduced vaccine immunogenicity. It is unknown whether patients with rheumatoid arthritis would benefit from more immunogenic vaccine formulations. This study investigated the immunogenicity and safety of a high-dose trivalent inactivated influenza vaccine (HD-TIV) in patients with rheumatoid arthritis compared to a standard-dose quadrivalent influenza vaccine (SD-QIV). Methods This study was a treatment-stratified, randomised, double-blind trial to compare the immunogenicity and safety of SD-QIV (15 μg of haemagglutinin [HA] per strain) versus HD-TIV (60 μg of HA per strain) in adults with rheumatoid arthritis who are positive for rheumatoid factor or anti-cyclic citrullinated peptide, or both, recruited during the 2016–17 and 2017–18 influenza seasons at three hospitals affiliated with McGill University (Montreal, QC, Canada). Participants had received treatment for rheumatoid arthritis with conventional or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) or biological DMARDs, or combinations of them, were still on treatment at the time of enrolment, and their treatment had not been modified during the 3 months before enrolment. They were stratified into one of three groups according to treatment. Patients who, at enrolment, were taking conventional or targeted synthetic DMARDs (methotrexate, hydroxychloroquine, and sulfasalazine) as monotherapy or in combination were stratified to group 1; those who were taking a biological DMARD (anti-tumour necrosis factor or anti-interleukin 6), with or without methotrexate, hydroxychloroquine, or sulfasalazine (or a combination thereof) were stratified to group 2; and those who were taking abatacept, tofacitinib, or rituximab, with or without methotrexate, hydroxychloroquine, or sulfasalazine (or a combination thereof) were stratified to group 3. Participants were randomly allocated (1:1) to receive the SD-QIV or HD-TIV vaccine. Randomisation was based on a computer-generated allocation sequence, and participants, investigators, and research nurses responsible for safety assessments were masked to vaccine assignment. The primary outcome was the seroconversion rate (as measured by haemagglutination-inhibition assay) per strain at day 28. Analysis was done in the modified intention-to-treat population, which included all randomly assigned participants for whom seroconversion status was available. Safety was assessed throughout the surveillance period (day 0–186). This trial is registered at ClinicalTrials.gov , number NCT02936180 . Findings Between Oct 24, 2016, and Dec 6, 2017, 696 patients with rheumatoid arthritis were invited to participate in the study and 279 were randomly assigned and vaccinated (140 [50%] received SD-QIV and 139 [50%] HD-TIV). 136 patients who received SD-QIV and 138 who received HD-TIV were included in the modified intention-to-treat anaysis. Patients who received HD-TIV were more likely to seroconvert than those who received SD-QIV: the odds ratio was 2·99 (95% CI 1·46–6·11) for seroconversion to strain A/H3N2, 1·95 (1·19–3·22) for seroconversion to strain B/Bris, 3·21 (1·57–6·56) for seroconversion to strain A/H1N1 (in 2016–2017), and 2·44 (1·18–5·06) for seroconversion to strain A/H1N1 (in 2017–2018). Similar results were observed in patients from groups 1 and 2; the number of individuals in group 3 was insufficient to draw conclusions. Local and systemic adverse events were similar in both vaccine groups, no serious adverse events were reported between days 0 and 28 in any group, and neither vaccine increased rheumatoid arthritis disease activity. Interpretation Our data suggest that in patients with seropositive rheumatoid arthritis, HD-TIV is safe and more immunogenic than SD-QIV. These results are the first evidence to support the use of the HD-TIV in these patients. Funding The Arthritis Society-Canada.

Background: Immune dysregulation as a result of an inborn error of immunity (IEI) leads to the complicated symptoms of refractory multi-organ immune dysregulation. B lymphocytes with immune regulatory capacity (Breg) are activated by environmental triggers and act as regulators of the immune response as observed in several autoimmune diseases.Objective: We sought to investigate the Breg profile and the CD21low expressing B cells of patients with LRBA deficiency (N symbolscript 6) and non-LRBA deficiency IEI (N symbolscript 13) with overlapping clinical symptoms of immune dys-regulation. Normal values for Breg subpopulations were obtained from patients age-matched healthy cohorts (N symbolscript 48). Furthermore, we investigated the impact of abatacept treatment in LRBA deficient patients receiving biweekly abatacept (N symbolscript 5).Methods: Using a flow cytometric approach with a pre-formulated antibody panel in peripheral blood samples, Breg subsets including plasmablasts symbolscript transitional B cells (CD24hiCD38hi), and B10 cells symbolscript and additionally the CD21low B cells (CD21lowCD38low) were analyzed. Breg function was assessed by the interleukin-10 expression within the symbolscript population. Additionally, B cell cytokines were measured in cell culture supernatants. Results: We observe significant alterations of B cell/Breg subpopulations in the LRBA deficient cohort including a severe lack of memory B cells (P symbolscript 0.031) and B10 cells (P symbolscript 0.031) as well as a tendency towards higher CD21low B cells (P symbolscript 0.063). Within the non-LRBA deficient cohort, we observe a significant expansion of the plasmablasts (P symbolscript 0.012), and a tendency towards elevated levels of CD21low expressing B cells (P symbolscript 0.063). The treatment with abatacept ameliorated disease symptoms in the LRBA deficient cohort and led to an effective decrease in CD21low B cells over time (P symbolscript 0.021). Furthermore, there was a significantly increased level of B cell-activating factor (BAFF; P symbolscript 0.02) and lower IL-12p70 secretion upon stimulation (P symbolscript 0.020) in the LRBA cohort.Conclusion: Aberrant maturation of Breg subsets and the pathological expansion of CD21low B cells in patients with IEI may have therapeutic implications. Patients suffering from LRBA deficiency show a lack of memory B cells, insufficient expansion of B10 cells, increased BAFF levels as well as an increase in circulating CD21low B cells. Abatacept treatment results in a steady decrease in CD21low B cells., University Hospital Frankfurt, Germany, This work was funded by the University Hospital Frankfurt, Germany. Authors have no conflict of interest.

Objectives To examine the rate of incident malignancies excluding non-melanoma skin cancer (NMSC) in patients with rheumatoid arthritis (RA) newly treated with tocilizumab versus other biologic drugs. Methods We conducted a cohort study using data from 3 U.S. insurance claims databases – Medicare (2010–2015), ‘IMS’ PharMetrics Plus (2011–2015) and Truven ‘MarketScan’ (2011–2015). Adults with RA who newly started tocilizumab or a TNF inhibitor (TNFi) after failing a different TNFi, abatacept or tofacitinib were included. The primary outcome was development of any malignancies excluding NMSC. For confounding control, tocilizumab starters were propensity score (PS)-matched to TNFi starters with a variable ratio of 1:3 within each database. Hazard ratios (HR) from the 3 PS-matched cohorts were combined by an inverse variance-weighted, fixed-effects model. We conducted a secondary analysis where we compared tocilizumab initiators with abatacept initiators. Results We included 13,102 tocilizumab initiators PS-matched to 26,727 TNFi initiators in all three databases. The incidence rate of malignancies per 1,000 person-years ranged from 8.27 (IMS) to 23.18 (Medicare) in the tocilizumab group and from 9.64 (MarketScan) to 21.46 (Medicare) in the TNFi group. The risk of incident malignancies was similar between tocilizumab and TNFi initiators across all three databases, with a combined HR of 0.98 (95%CI 0.80–1.19) in tocilizumab versus TNFi. The secondary analysis comparing tocilizumab versus abatacept showed similar results (combined HR 0.97, 95%CI 0.74–1.27). Conclusions This large multi-database cohort study found no difference in the risk of malignancies excluding NMSC in RA patients who newly started tocilizumab compared with TNFi or abatacept.

CTLA-4Ig (belatacept) blocks the CD80/CD86 ligands for both CD28 and CTLA-4; thus, in addition to the intended effect of blocking CD28-mediated costimulation, belatacept also has the unintended effect of blocking CTLA-4-mediated coinhibition. Recently, anti-CD28 domain antibodies (dAb) that selectively target CD28 while leaving CTLA-4 intact were shown to more effectively inhibit alloimmune responses and prolong graft survival. However, the impact of selective CD28 blockade on protective immunity has not been extensively investigated. Here, we sought to compare the impact of CTLA-4Ig vs. anti-CD28dAb on CD8(+) T cell immunity to a transplant-relevant pathogen, a murine homolog of Epstein-Barr virus. Mice were infected with murine gammaherpesvirus-68 (MHV) and treated with PBS, CTLA-4Ig, or anti-CD28dAb. While anti-CD28dAb resulted in a decrease in virus-specific CD8(+) T cell numbers as compared to CTLA-4Ig, cytolytic function and the expression of markers of high-quality effectors was not different from CTLA-4Ig treated animals. Importantly, MHV-68 viral load was not different between the treatment groups. These results suggest that preserved CTLA-4 co-inhibition limits MHV-specific CD8(+) T cell accumulation, but the population that remains retains cytolytic function and migratory capacity and is not inferior in its ability to control viral burden relative to T cell responses in CTLA-4Ig-treated animals.

Background Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. Methods Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents’ group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). Results Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of ≥ 2 years of uveitis inactivity. Conclusions An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (−90.9–96.6) and −0.28% (−21.1–15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4+ but not CD8+ T cell populations, including decreases in CD4+ CCR5+ (p = 0.02) and CD4+ PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4+ CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes.

Objective To assess whether abatacept as initial biologic disease-modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis is associated with an increased risk of serious infections, including bone and joint, gastrointestinal, respiratory tract, skin and soft tissue, and urinary tract, when compared with other biologic DMARDs. Methods We performed a population-based cohort study among patients newly-treated with biologic DMARDs within the US-based Truven MarketScan® population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious infections requiring hospitalisation associated with initiation of abatacept, compared with initiation of other bDMARDs, after controlling for age and deciles of the propensity score. Results The cohort included 5,752 patients who initiated abatacept and 78,556 who initiated another biologic DMARD, of whom 193 and 1531 had a serious infection during follow-up (crude incidence rate 4.45 per 100 person-years and 3.62 per 100 person-years, respectively). Compared with other biologic DMARDs, the use of abatacept was not associated with an increased incidence of serious infections overall (HR 1.04, 95% CI 0.89–1.21). The risk did not vary by duration of use ( 1 year: HR 1.08, 95% CI 0.77–1.52). In addition, the risk was not increased for the site-specific infections. Conclusion The use of abatacept as first biologic DMARD in the treatment of rheumatoid arthritis was not associated with different risks of serious infections compared with other biologic DMARDs.

Tuberculosis (TB) mortality is high among kidney transplant (KT) recipients. Although local epidemiology is an important factor, diagnostic/therapeutic challenges and immunosuppressive therapy (ISS) may influence outcomes. We analyzed the cumulative incidence (CumI) of TB in KT recipients receiving a variety of ISS with long-term follow-up. Our retrospective single-center cohort study included all KT procedures performed between January 1, 1998, and August 31, 2014, with follow-up until August 31, 2014. Induction therapy was based on perceived immunological risk; maintenance ISS included prednisone and calcineurin inhibitor (CNI) plus azathioprine (AZA), and mycophenolic acid (MPA) or mechanistic target of rapamycin inhibitor (mTORi). Thirty-four patients received belatacept/MPA. KT was performed on 11 453 patients and followed for 1989 (IQR 932 to 3632) days. Among these, 152 patients were diagnosed with TB (CumI 1.32%). Median time from KT to TB was 18.8 (IQR 7.2 to 60) months, with 59% of patients diagnosed after the first year. Unadjusted analysis revealed an increasing confidence interval (CI) of TB (0.94% CNI/AZA vs 1.6% CNI/MPA [HR = 1.62, 95% CI = 1.13 to 2.34, P = .009] vs 2.85% CNI/mTORi [HR = 2.45, 95% CI = 1.49 to 4.32, P

OBJECTIVE: To analyse and report the incidence of side effects of biological agents in paediatric patients with inflammatory diseases using of real-life follow-up cohort. METHODS: In this international, observational, retrospective, multicentre study of children treated by biological agents and followed in the Juvenile Inflammatory Rheumatism (JIR) cohort (JIRcohorte) network, a Kaplan-Meier method was used to estimate the occurrence of adverse events. A Cox model was constructed to identify independent predictors of adverse events. RESULTS: Overall 813 patients totalling 3439 patients-year (PY) of biological agents were included. The main diagnosis was juvenile idiopathic arthritis (84%). A total of 222 patients (27.3%) had 419 adverse events, representing an incidence rate of 12.2 per 100 PY 95% CI [11.0; 13.4]. The overall incidence rate of serious adverse events was 3.9 per 100 PY 95% CI [3.2; 4.6]. Tocilizumab and infliximab were significantly associated with adverse events and canakinumab with serious adverse events. Univariate and multivariable analysis of adverse events and serious adverse events indicated that patients under biological agents with concomitant immunosuppressive drugs (excluding methotrexate) suffered from more of these events. CONCLUSION: This study suggests an overall an acceptable safety of biologic agents in children with inflammatory rheumatic diseases treated with biological agents. However, the concomitant prescription of immunosuppressive drugs with biological agents represents a substantial risk of adverse events. ispartof: JOINT BONE SPINE vol:86 issue:3 pages:343-350 ispartof: location:France status: published

Cytotoxic T-lymphocyte-associated protein 4-Ig (CTLA4-Ig) produced using Chinese hamster ovary (CHO) cell lines is a fusion protein of CTLA4 and the Fc region of antibody. In the present study, we identified and overexpressed genes capable of increasing sialic acid levels in CTLA4-Ig to develop cell lines using glycoengineering technology. CTLA4-Ig was produced using CHO cells overexpressing N-acetylglucosaminyltransferase (GnT) and α2,6-sialyltransferase (α2,6-ST). The conditions were wild type (WT), overexpression (GnT-IV, GnT-V, and α2,6-ST), and co-overexpression (GnT-IV and α2,6-ST, and GnT-V and α2,6-ST). GnT-IV and GnT-V were transfected into CHO cells to determine tri-antennary structure formation in CTLA4-Ig. CHO

Objectives While tocilizumab may increase serum lipid levels, recent studies do not suggest a link between tocilizumab use and clinical cardiovascular risk in patients with rheumatoid arthritis (RA). Methods To compare cardiovascular safety of tocilizumab with abatacept, we conducted a cohort study using data from Medicare (2010–2013), IMS PharMetrics (2011–2014) and MarketScan (2011-6/2015). RA patients aged ≥18 years who newly started tocilizumab or abatacept entered the cohort on the day of their first use of tocilizumab or abatacept after a continuous enrollment period for ≥365 days. The primary outcome was a composite cardiovascular endpoint of hospitalization for myocardial infarction or stroke. To control for more than 60 confounders, tocilizumab starters were propensity score (PS)-matched to abatacept starters with a variable ratio of 1:3 within each database. A fixed-effects model combined database-specific hazard ratios (HR). Results We included 6237 tocilizumab starters PS-matched to 14,685 abatacept starters in all three databases. Mean age was 72 years in Medicare, 51 in PharMetrics and 53 in MarketScan. The incidence rate of the composite cardiovascular events per 100 person-years ranged from 0.37 (PharMetrics) to 1.64 (Medicare) in the tocilizumab group and from 0.59 (PharMetrics) to 1.69 (Medicare) in the abatacept group. The risk of the composite cardiovascular events was similar between the two groups across all three databases, with a combined HR of 0.82 (95% CI: 0.55–1.22) in tocilizumab versus abatacept starters. Conclusions This multi-database cohort study found no difference in the risk of cardiovascular events in RA patients who newly started tocilizumab versus abatacept.

Rheumatoid arthritis is an autoimmune disease that primarily affects the joints. The emergence of highly effective anti-rheumatic drugs such as biologic agents and janus kinase inhibitors has dramatically improved the management of the disease by preventing irreversible joint destruction and disability. This disease can manifest the serious extra-articular involvements including interstitial lung disease, which has the significant impact on the patients' morbidity and mortality. However, treatment strategy specific for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has not been yet established. Therefore, understanding the pathogenesis and clinical features of RA-ILD is critical to provide the better management and improve the prognosis of the patients. Accumulation of evidence suggest that it is essentially important to achieve remission or at least low disease activity of arthritis to prevent new emergence, progression, or acute exacerbation of RA-ILD. RA-ILD patients frequently show high titers of autoantibodies including rheumatoid factor and anti-CCP antibody, and the excessive formation of tertiary lymphoid organs is found in the local affected lungs, indicating the adaptive immune response as a key pathogenic inducer. In this regard, non-TNF inhibitors targeting adaptive immune responses such as abatacept and rituximab were reported to be promising for the stabilization and improvement of RA-ILD. Nintedanib, an anti-fibrotic agent, was shown to be effective for reducing the decline of forced vital capacity in RA-ILD. In this review, we summarized the current evidence in the pathogenesis, clinical features, and treatments for RA-ILD and provide future prospects.

Objective: To investigate treatment efficacy of long-term abatacept treatment in pSS patients.Methods: The single-centre ASAP-III trial consisted of two phases: the randomised, double-blind, placebo-controlled phase (1:1 randomisation) from baseline to week 24, of which results have been published previously, and the open-label extension phase from week 24 to 48, in which all patients received abatacept. Main inclusion criteria were fulfilment of the AECG criteria, positive gland biopsy, disease duration = 5. Long-term treatment effects of abatacept on clinical, patient-reported, glandular and laboratory outcome measures were assessed in patients treated with abatacept from baseline to week 48. Furthermore, Composite of Relevant Endpoints for Sj_ogren's Syndrome (CRESS) response (response on >= 3 of 5 items) was analysed.Results: In patients on abatacept treatment for 48 weeks (n = 40), median ESSDAI improved from baseline 14.0 (IQR 9.0 - 16.8) to 4.0 (2.0 - 8.0) at week 48 (p < 0.001), with 50% of patients reaching low disease activity (ESSDAI < 5) at week 48. Median ESSPRI improved from 7.0 (IQR 5.4-7.7) to 5.0 (3.7-6.7) (p < 0.001). Significant improvement was also seen in dry eye and laboratory tests. Combining response at multiple clinically relevant items, 73% of patients were CRESS responders at week 48. Additional improvement was seen between week 24 and week 48 of abatacept treatment.Conclusion: In the open-label extension phase of the ASAP-III trial, improvement was seen up to 48 weeks of abatacept treatment in clinical, patient-reported, dry eye and laboratory outcomes. The majority of patients were CRESS responders at week 48. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)-based. As such, most recipients have experienced CNI-related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI-based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI-based regimen to a belatacept-based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept-based regimen, transitioned to a CNI-free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI-associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA.

Resumen: El síndrome hemolítico urémico atípico es una enfermedad relacionada con alteración en la regulación del complemento que generalmente evoluciona a enfermedad renal crónica terminal, con alta tasa de recaída en el trasplante renal y elevado riesgo de pérdida del injerto. La terapia anticomplemento ha mejorado el pronóstico de estos pacientes, logrando tener remisión de la enfermedad en la mayoría de los casos, aumentando la posibilidad de un trasplante renal exitoso e incrementando la supervivencia del paciente y del injerto; igualmente el uso de medicamentos con bajo riesgo de inducción de microangiopatías trombóticas como el belatacept y micofenolato se han utilizado con resultados satisfactorios. Presentamos el caso de una paciente joven de alto riesgo inmunológico, con síndrome hemolítico urémico atípico por mutación del factor H, a quien se realizó trasplante renal exitoso con eculizumab, timoglobulina, belatacept, micofenolato y esteroides conservando excelente función del injerto y sin recaídas de su enfermedad. Abstract: Atypical haemolytic uremic syndrome is a disease caused by complement regulation abnormalities that generally progresses to chronic end-stage renal disease with a high rate of recurrence in kidney transplantation and a high risk of graft loss. Anti-complement therapy has improved the prognosis of these patients, achieving disease remission in most cases, increasing the likelihood of a successful kidney transplant and increasing patient and graft survival. Drugs with low risk of induction of thrombotic microangiopathies such as belatacept and mycophenolate have also been used with satisfactory results. We present the case of a young patient at high immunological risk, with atypical haemolytic uraemic syndrome due to factor H mutation, who underwent a successful kidney transplantation with eculizumab, thymoglobulin, belatacept, mycophenolate and steroids, to date preserving excellent graft function without disease recurrence. Palabras clave: Síndrome hemolítico urémico atípico, Microangiopatías trombóticas, Trasplante de riñón, Eculizumab, Belatacept, Keywords: Atypical haemolytic uraemic syndrome, Thrombotic microangiopathies, Kidney transplantation, Eculizumab, Belatacept

The aim of this study was to compare the clinical outcome of patients with rheumatoid arthritis seen in routine clinical practice treated with either TNF inhibitors or abatacept. To overcome potential bias, both propensity score matching and Inverse Probability of Treatment Weighting were used for patient selection. The propensity score matching procedure selected 315 matched pairs of patients who were treated with TNF inhibitors or abatacept. At week 52, SDAI in TNF inhibitors was lower than abatacept. In contrast, analysis of biologics-naive patients using the propensity-score matching (n = 150; in each group) showed comparable clinical efficacy. Consistent results were obtained by the use of Inverse Probability of Treatment Weighting (581 patients treated with TNF inhibitors and 353 patients treated with abatacept). The predictors of response to each treatment were different; abatacept appeared to benefit patients with high baseline RF titers while TNF inhibitors appeared to benefit patients with low baseline HAQ-DI.

We analyzed the transcriptome of detailed CD4+ T cell subsets including them after abatacept treatment, and examined the difference among CD4+ T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4+ T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4+ T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4+ T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 × 10−9) and abatacept administration (Spearman's rho = −0.91, p = 5 × 10−57). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept.

Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants.