Transcatheter Repair for Patients with Tricuspid Regurgitation.

BACKGROUND: Severe tricuspid regurgitation is a debilitating condition that is associated with substantial morbidity and often with poor quality of life. Decreasing tricuspid regurgitation may reduce symptoms and improve clinical outcomes in patients with this disease. METHODS: We conducted a prospective randomized trial of percutaneous tricuspid transcatheter edge-to-edge repair (TEER) for severe tricuspid regurgitation. Patients with symptomatic severe tricuspid regurgitation were enrolled at 65 centers in the United States, Canada, and Europe and were randomly assigned in a 1:1 ratio to receive either TEER or medical therapy (control). The primary end point was a hierarchical composite that included death from any cause or tricuspid-valve surgery; hospitalization for heart failure; and an improvement in quality of life as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), with an improvement defined as an increase of at least 15 points in the KCCQ score (range, 0 to 100, with higher scores indicating better quality of life) at the 1-year follow-up. The severity of tricuspid regurgitation and safety were also assessed. RESULTS: A total of 350 patients were enrolled; 175 were assigned to each group. The mean age of the patients was 78 years, and 54.9% were women. The results for the primary end point favored the TEER group (win ratio, 1.48; 95% confidence interval, 1.06 to 2.13; P = 0.02). The incidence of death or tricuspid-valve surgery and the rate of hospitalization for heart failure did not appear to differ between the groups. The KCCQ quality-of-life score changed by a mean (±SD) of 12.3±1.8 points in the TEER group, as compared with 0.6±1.8 points in the control group (P<0.001). At 30 days, 87.0% of the patients in the TEER group and 4.8% of those in the control group had tricuspid regurgitation of no greater than moderate severity (P<0.001). TEER was found to be safe; 98.3% of the patients who underwent the procedure were free from major adverse events at 30 days. CONCLUSIONS: Tricuspid TEER was safe for patients with severe tricuspid regurgitation, reduced the severity of tricuspid regurgitation, and was associated with an improvement in quality of life. (Funded by Abbott; TRILUMINATE Pivotal ClinicalTrials.gov number, NCT03904147.).

Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts.

Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.

Mitral valve surgery after failed transcatheter edge-to-edge repair: a review and word of caution.

PURPOSE OF REVIEW: As transcatheter edge-to-edge mitral valve repair (TEER) evolves and indications broaden to include younger and lower surgical risk patients, it is essential to understand TEER failure trends and potential impact on subsequent mitral valve surgery, especially when pertaining to feasibility of durable valve reconstruction as opposed to de-novo repair. RECENT FINDINGS: Results of the two largest series analysing mitral valve surgery following TEER have demonstrated remarkably low repairability rates with consequent need for valve replacement. Post TEER surgery was associated with high early and late mortalities, likely as a reflection of patient baseline characteristics and acuity of surgery. Presence and correction of concomitant cardiac pathologies were a frequent finding. Centre and surgeon volumes were important factors in optimizing the likelihood of salvage repair and reducing perioperative risks. SUMMARY: Surgical mitral valve repair in reference centres remain the gold standard and the most durable treatment for degenerative mitral disease with excellent perioperative safety outcomes. Given the high likelihood of needing high-risk mitral valve replacement when TEER fails, consideration for potentially less durable transcatheter alternatives should be taken with caution in younger or lower surgical risk patients.

The use of transesophageal echocardiography to predict surgical complexity scoring system for degenerative mitral valve repair.

BACKGROUND: For severe mitral valve (MV) degenerative disease, repair is recommended. Prediction of repair complexity and referral to high volume centers can increase rates of successful repair. This study sought to demonstrate that TEE is a feasible imaging modality to predict the complexity of surgical MV repair. METHODS: Two hundred TEE examinations of patients who underwent MV repair (2009-2011) were retrospectively reviewed and scored by two cardiac anesthesiologists. TEE scores were compared to surgical complexity scores, which were previously assigned based on published methods. Kappa values were reported for the agreement of TEE and surgical scores. McNemar's tests were used to test the homogeneity of the marginal probabilities of different scoring categories. RESULTS: TEE scores were slightly lower (2[1,3]) than surgical scores (3[1,4]). The agreement was 66% between the scoring methods, with a moderate kappa (.46). Using surgical scores as the gold standard, 70%, 71%, and 46% of simple, intermediate and complex surgical scores, respectively, were correctly scored by TEE. P1, P2, P3, and A2 prolapse were easiest to identify with TEE and had the highest agreement with surgical scoring (P1 agreement 79% with kappa .55, P2 96% [kappa .8], P3 77% [kappa .51], A2 88% [kappa .6]). The lowest agreement between the two scores occurred with A1 prolapse (kappa .05) and posteromedial commissure prolapse (kappa .14). In the presence of significant disagreement, TEE scores were more likely to be of higher complexity than surgical. McNemar's test was significant for prolapse of P1 (p = .005), A1 (p = .025), A2 (p = .041), and the posteromedial commissure (p < .0001). CONCLUSION: TEE-based scoring is feasible for prediction of the complexity of MV surgical repair, thus allowing for preoperative stratification.

Plasma Renin Activity Increases With Cardiopulmonary Bypass and is Associated With Vasoplegia After Cardiac Surgery.

OBJECTIVES: To describe the trend in plasma renin activity over time in patients undergoing cardiac surgery on cardiopulmonary bypass, and to investigate if increased plasma renin activity is associated with postcardiopulmonary bypass vasoplegia. DESIGN: A prospective cohort study. SETTING: Patients were enrolled from June 2020 to May 2021 at a tertiary cardiac surgical institution. PATIENTS: A cohort of 100 adult patients undergoing cardiac surgery on cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma renin activity was measured at 5 time points: baseline, postoperatively, and at midnight on postoperative days 1, 2, and 3. Plasma renin activity and delta plasma renin activity were correlated with the incidence of vasoplegia and clinical outcomes. The median plasma renin activity increased approximately 3 times from baseline immediately after cardiac surgery, remained elevated on postoperative days 0, 1, and 2, and began to downtrend on postoperative day 3. Plasma renin activity was approximately 3 times higher at all measured time points in patients who developed vasoplegia versus those who did not. CONCLUSIONS: In patients undergoing cardiac surgery on cardiopulmonary bypass, plasma renin activity increased postoperatively and remained elevated through postoperative day 2. Additionally, patients with vasoplegic syndrome after cardiac surgery on cardiopulmonary bypass had more robust elevations in plasma renin activity than nonvasoplegic patients. These findings support the need for randomized controlled trials to determine if patients undergoing cardiac surgery with high plasma renin activity may benefit from targeted treatment with therapies such as synthetic angiotensin II.

Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients.

BACKGROUND: Transcatheter aortic-valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis who are at increased risk for death from surgery; less is known about TAVR in low-risk patients. METHODS: We performed a randomized noninferiority trial in which TAVR with a self-expanding supraannular bioprosthesis was compared with surgical aortic-valve replacement in patients who had severe aortic stenosis and were at low surgical risk. When 850 patients had reached 12-month follow-up, we analyzed data regarding the primary end point, a composite of death or disabling stroke at 24 months, using Bayesian methods. RESULTS: Of the 1468 patients who underwent randomization, an attempted TAVR or surgical procedure was performed in 1403. The patients' mean age was 74 years. The 24-month estimated incidence of the primary end point was 5.3% in the TAVR group and 6.7% in the surgery group (difference, -1.4 percentage points; 95% Bayesian credible interval for difference, -4.9 to 2.1; posterior probability of noninferiority >0.999). At 30 days, patients who had undergone TAVR, as compared with surgery, had a lower incidence of disabling stroke (0.5% vs. 1.7%), bleeding complications (2.4% vs. 7.5%), acute kidney injury (0.9% vs. 2.8%), and atrial fibrillation (7.7% vs. 35.4%) and a higher incidence of moderate or severe aortic regurgitation (3.5% vs. 0.5%) and pacemaker implantation (17.4% vs. 6.1%). At 12 months, patients in the TAVR group had lower aortic-valve gradients than those in the surgery group (8.6 mm Hg vs. 11.2 mm Hg) and larger effective orifice areas (2.3 cm2 vs. 2.0 cm2). CONCLUSIONS: In patients with severe aortic stenosis who were at low surgical risk, TAVR with a self-expanding supraannular bioprosthesis was noninferior to surgery with respect to the composite end point of death or disabling stroke at 24 months. (Funded by Medtronic; ClinicalTrials.gov number, NCT02701283.).

Conventional versus modified delivery system technique in commissural alignment from the Evolut low-risk CT substudy.

OBJECTIVES: We assessed the impact of conventional delivery system (DS) insertion technique on "Hat-marker" orientation/commissural alignment in patients who underwent transcatheter aortic valve replacement (TAVR) in the Evolut Low Risk Trial CT substudy versus a modified technique. BACKGROUND: Unlike surgical aortic valve replacement, where alignment of the surgical valve commissures with native commissures can be achieved virtually 100% of the time, commissural alignment during TAVR is not achieved consistently. This may subsequently impact the feasibility of both coronary access and reintervention after TAVR. METHODS: "Hat-marker" orientations during deployment were characterized as outer curve (OC), center front (CF), inner curve, and center back. Severe commissure-to-CA overlap was 0-20°. "Hat-marker" orientations and CA overlap were compared to 240 patients from a single center using the modified 3-o'clock flush port DS technique. RESULTS: In the CT substudy in which conventional DS insertion was performed (flush port at 12 o'clock); 154/249 had both analyzable CT and procedural fluoroscopy to validate "Hat-marker" to C-tab/commissural orientation. On post-TAVR CT, Evolut valve commissural orientation and coronary artery (CA) ostia were identified. Compared to conventional DS technique in the CT substudy, the modified technique had higher rates of "Hat-marker" at OC/CF orientation, improved commissural alignment and reduced severe CA overlap; (left main, 14.2 vs. 27.9%; right coronary artery, 11.7 vs. 27.3% both, 5.0 vs. 13.6%; 1 or both CA, 20.8 vs. 41.6%, all p < 0.01). CONCLUSIONS: The modified technique improved initial "Hat-marker" orientation during Evolut deployment and resulted in better commissural alignment and reduced CA overlap.

Bidirectional Cross-Talk between Biliary Epithelium and Th17 Cells Promotes Local Th17 Expansion and Bile Duct Proliferation in Biliary Liver Diseases.

There is no effective treatment for autoimmune biliary diseases. Therefore, understanding their immunopathology is crucial. The biliary epithelial cells (BEC), expressing TLR-4, are constantly exposed to gut microbes and bacterial wall LPS, and in settings of inflammation, the immune infiltrate is dense within the peribiliary region of human liver. By dual immunohistochemistry, we affirm human intrahepatic T cell infiltrate includes CCR6+CD4+ and AhR+CD4+ T cells with potential for plasticity to Th17 phenotype. Mechanistically, we demonstrate that Th1 and Th17 inflammatory cytokines and LPS enhance human primary BEC release of the CCR6 ligand CCL20 and BEC secretion of Th17-polarizing cytokines IL-6 and IL-1ß. Cell culture assays with human BEC secretome showed that secretome polarizes CD4 T cells toward a Th17 phenotype and supports the survival of Th17 cells. BEC secretome did not promote Th1 cell generation. Additionally, we give evidence for a mutually beneficial feedback of the type 17 cell infiltrate on BEC, showing that treatment with type 17 cytokines increases BEC proliferation, as monitored by Ki67 and activation of JAK2-STAT3 signaling. This study identifies human BEC as active players in determining the nature of the intrahepatic immune microenvironment. In settings of inflammation and/or infection, biliary epithelium establishes a prominent peribiliary type 17 infiltrate via recruitment and retention and enhances polarization of intrahepatic CD4 cells toward Th17 cells via type 17 cytokines, and, reciprocally, Th17 cells promote BEC proliferation for biliary regeneration. Altogether, we provide new insight into cross-talk between Th17 lymphocytes and human primary biliary epithelium in biliary regenerative pathologies.

Anatomic classification of mitral annular calcification for surgical and transcatheter mitral valve replacement.

BACKGROUND AND AIM OF THE STUDY: A systematic approach to quantify mitral annular calcification (MAC) in all-comers by multidetector computed tomography (MDCT) is essential to guide treatment, but lacking. METHODS: From September 2015 to July 2019, 82 patients with MAC underwent MDCT at two institutions to evaluate for surgical mitral valve replacement (SMVR), transcatheter mitral valve replacement (TMVR), or medical management. Type 1 MAC was defined as <270° annular calcium and Type 2 as ≥270°. Absence/presence of predicted left ventricular outflow tract (LVOT) obstruction with virtual valve placement was used to further define Type 2 MAC into 2A/B for our treatment algorithm. RESULTS: Type 1 MAC was present in 51.2%, Type 2A in 18.3%, and Type 2B in 30.5%. Operable Type 1 patients (50.0%) underwent hybrid transatrial TMVR or SMVR. Type 2A underwent a variety of treatments, and Type 2B surgical candidates (40.0%) underwent hybrid transatrial TMVR secondary to difficult suture anchoring with significant MAC and predicted LVOT obstruction. At a follow-up of 29.6 ± 12.0 months, mortality was 42.7% with 46.3% in the intervention group and 39.0% in the medical group (p = 0.47). All percutaneous TMVR patients expired. This translated to a disproportionate number of Type 2A deaths (80.0% with intervention), but all were high/extreme surgical risk. The hybrid TMVR group consisted of 95.0% Type 1/2B patients and had a lower Society of Thoracic Surgeons predicted risk of operative mortality (7.4% vs. 9.2%, p = 0.43)/mortality. CONCLUSIONS: The highest mortality was seen in percutaneous TMVR Type 2A MAC patients, but they were at the greatest risk. Here we provide an objective MAC treatment algorithm for all-comers based on operability/anatomy.

Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients.

BACKGROUND: Although transcatheter aortic-valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk. METHODS: We evaluated the clinical outcomes in intermediate-risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self-expanding prosthesis) with surgical aortic-valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic-valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement. RESULTS: A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, -5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic-valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group. CONCLUSIONS: TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910 .).

Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials.

OBJECTIVES: The aim of this integrated analysis is to evaluate the long-term safety and tolerability of ixekizumab in adults with psoriasis, PsA and axial SpA. METHODS: Integrated safety data from 21 clinical trials are presented by indication in patients who received at least one dose of ixekizumab. Adverse events (AEs) and treatment-emergent adverse events (TEAEs) adjusted incidence rates (IRs) per 100 patient-years (PY) up to 5 years' exposure are reported. RESULTS: A total of 8228 patients with an ixekizumab exposure of 20 895.9 PY were included in this analysis. The most common TEAEs were nasopharyngitis, upper respiratory tract infection and injection-site reactions. Across populations, IRs were low for AEs leading to discontinuation (IRs ≤5.1 per 100 PY), serious AEs (IRs ≤6.0 per 100 PY) and death (IRs ≤0.3 per 100 PY). The most reported TEAEs of special interest were infections (IRs ≤35.8 per 100 PY). Patients rarely reported malignancies (IR ≤0.8), IBD including ulcerative colitis and Crohn's disease (IR ≤0.8) and major adverse cardiovascular events (IR ≤0.5). TEAEs were most commonly reported the first 2 years of exposure with ixekizumab and IR decreased over the years (infections, injection-site reactions and depression) or remained constant over the entire treatment period (serious infections, major adverse cardiovascular events, malignancies and IBD). CONCLUSION: This long-term analysis on the safety of ixekizumab was consistent with previously published reports and did not show any new safety signals. The safety profile and tolerability reported in this integrated analysis remained consistent with the known safety profile for ixekizumab.

Surgical management of mitral annular calcification.

PURPOSE OF REVIEW: The aim of the article is to discuss different therapeutic options for patients with severe mitral valve dysfunction because of mitral annular calcification (MAC), including mitral valve repair, conventional mitral valve replacement, percutaneous transcatheter mitral valve replacement (TMVR), and hybrid procedures. RECENT FINDINGS: Optimal management of severe mitral valve disease because of MAC remains challenging. Various 'resect' or 'respect' repair strategies have been standardized and are applicable in eligible patients. Mitral valve replacement with a standard surgical bioprosthesis is often possible in nonrepair candidates, especially with noncircumferential MAC. TMVR has evolved as a feasible option for anatomically and/or clinically prohibitive open-surgery cases, with the caveat of strict anatomic eligibility criteria. Hybrid TMVR provides the advantages of both open-surgery and TMVR and has emerged as a promising alternative in select patients. SUMMARY: Surgical management of MAC and severe mitral valve disease continues to evolve. The addition of transcatheter valve options may benefit many patients previously considered inoperable and are now candidates for intervention. This review will summarize state-of-the-art management options for patients with MAC.

Association of Anesthesiologist Handovers With Short-term Outcomes for Patients Undergoing Cardiac Surgery.

BACKGROUND: Complete handover of anesthesia care to a second anesthesiologist has been demonstrated to be associated with worse short-term adverse outcomes among cardiac surgery patients, but little information from multi-institutional studies is available. METHODS: New York's cardiac surgery registry was used to identify patients who underwent cardiac surgery in New York between 2010 and 2016 with and without complete handovers of anesthesia care. A retrospective observational study with inverse probability treatment weighting (IPTW) based on the propensity score was used to adjust for differences in preoperative patient characteristics while comparing differences in the primary outcome (in-hospital/30 day mortality), major complications in the index admission or within 30 days of the index surgery, readmissions within 30 days, and length of stay. RESULTS: A total of 8.5% of the 103,102 cardiac surgery procedures involved complete handovers. After adjustment, there was a difference between patients with and without handovers in the primary outcome (2.86% vs 2.48%, adjusted risk ratio [ARR] = 1.15 [1.01-1.31]). There was no difference in readmissions within 30 days (13.7% vs 14.4%, ARR = 0.95 [0.90-1.00]), and the differences in complications and length of stay were not clinically meaningful (adjusted differences of <10%). CONCLUSIONS: Cardiac surgery patients in New York who had complete anesthesia handovers experienced higher short-term mortality rates, but there were no meaningful differences in other outcomes. Unnecessary handovers should be carefully monitored.

Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial.

BACKGROUND: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis, otherwise known as ankylosing spondylitis, when conventional therapies are not effective. We report efficacy and safety data on ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A), in patients with radiographic axial spondyloarthritis who have not previously been treated with bDMARDs. METHODS: In this phase 3, randomised, double-blind, placebo-controlled superiority study of ixekizumab, adult patients with inadequate response or intolerance to non-steroidal anti-inflammatory drugs, an established diagnosis of radiographic axial spondyloarthritis, radiographic sacroiliitis centrally defined by modified New York criteria, and at least one spondyloarthritis feature according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, were recruited from 84 sites (12 countries) in Europe, Asia, and North America. By use of a computer-generated random sequence, patients were randomly assigned (1:1:1:1) to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference group), or placebo. The primary objective was to compare the proportion of patients achieving an ASAS40 response, a composite measure of clinical improvement in axial spondyloarthritis, at week 16 for both ixekizumab treatment groups versus the placebo group. The adalimumab reference group was included as an in-study active reference for comparison with placebo to provide additional context to interpretation of the ixekizumab study results. FINDINGS: Between June 20, 2016, and Aug 22, 2017, 341 patients were randomly assigned to either the placebo group (n=87), adalimumab group (n=90), ixekizumab Q2W (n=83), or ixekizumab Q4W (n=81). At week 16, compared with placebo (16 [18%] of 87), more patients achieved ASAS40 with ixekizumab Q2W (43 [52%] of 83; p<0·0001), ixekizumab Q4W (39 [48%] of 81; p<0·0001), and adalimumab (32 [36%] of 90; p=0·0053). One serious infection occurred in each of the ixekizumab Q2W (1%), ixekizumab Q4W (1%), and adalimumab (1%) groups; none were reported with placebo. One (1%) Candida infection occurred in the adalimumab group and one (1%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No treatment-emergent opportunistic infections, malignancies, or deaths occurred. INTERPRETATION: Each dosing regimen of ixekizumab was superior to placebo for improving radiographic axial spondyloarthritis signs and symptoms in patients not previously treated with bDMARDs; the safety profile was consistent with previous indications of ixekizumab. FUNDING: Eli Lilly and Company.

Ixekizumab improves patient-reported outcomes in patients with active psoriatic arthritis and inadequate response to tumour necrosis factor inhibitors: SPIRIT-P2 results to 52 weeks.

OBJECTIVES: To report patient-reported outcomes (PROs) of ixekizumab-treated patients with psoriatic arthritis (PsA) and an inadequate response (IR) or intolerance to tumour necrosis factor inhibitors (TNFi) to 52 weeks. METHODS: In SPIRIT-P2, patients with active PsA and an IR or intolerance to TNFi were randomised to ixekizumab 80 mg every 4 weeks (IXEQ4W; N=122) or every 2 weeks (IXEQ2W; N=123), or placebo (PBO; N=118) during the initial 24-week double-blind treatment period. At Week 16, background therapy was modified for IRs; additionally, IRs in the placebo group were re-randomised (1:1) to IXEQ2W or IXEQ4W. Patients receiving ixekizumab at Week 24 received the same dose during the study remainder. Patients completed several PROs for PsA disease activity, skin, health-related quality of life (HRQOL, and work through Week 52. RESULTS: Ixekizumab-treated patients reported significant improvements versus PBO in 36-Item Short Form Health Survey version 2, European Quality of Life 5 Dimensions visual analogue scale, Bath Ankylosing Spondylitis Disease Activity Index (total score and question 2), and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (3 of 4 domains) through Week 24. At Week 24, 9% (PBO), 52% (IXEQ4W), and 50% (IXEQ2W) of patients reported Dermatology Life Quality Index scores of 0 or 1; 0% (PBO) and 24% (IXEQ4W and IXEQ2W) reported Itch Numeric Rating Scale score of 0. Where data were collected, improvements persisted through Week 52. CONCLUSIONS: In patients with PsA and an IR or intolerance to TNFi, ixekizumab significantly improved disease activity, skin symptoms, HRQOL, and work productivity to 52 weeks.

Impaired Transmigration of Myeloid-Derived Suppressor Cells across Human Sinusoidal Endothelium Is Associated with Decreased Expression of CD13.

Human monocytic myeloid-derived suppressor cells (MO-MDSCs) within the hepatic compartment suppress inflammation and impair immune surveillance in liver cancer. It is currently not known whether recruitment of MO-MDSCs from blood via hepatic sinusoidal endothelium (HSEC) contributes to their enrichment within the hepatic compartment. We compared the transmigratory potential of MO-MDSCs and monocytes after adhesion to hepatic endothelial monolayers in flow-based assays that mimic in vivo shear stress in the sinusoids. Despite comparable binding to HSEC monolayers, proportionally fewer MO-MDSCs underwent transendothelial migration, indicating that the final steps of extravasation, where actin polymerization plays an important role, are impaired in MO-MDSCs. In this article, we found reduced levels of CD13 on MO-MDSCs, which has recently been reported to control cell motility in monocytes, alongside reduced VLA-4 expression, an integrin predominantly involved in adherence to the apical side of the endothelium. CD13 and VLA-4 blocking and activating Abs were used in flow-based adhesion assays, live-cell imaging of motility, and actin polymerization studies to confirm a role for CD13 in impaired MO-MDSC transmigration. These findings indicate that CD13 significantly contributes to tissue infiltration by MO-MDSCs and monocytes, thereby contributing to the pathogenesis of hepatic inflammation.

Correlation of 2-Dimensional and 3-Dimensional Echocardiographic Analysis to Surgical Measurements of the Tricuspid Valve Annular Diameter.

OBJECTIVE: This study sought to determine if 3-dimensional (3D) echocardiography would more closely correspond to direct surgical measurements of the maximal tricuspid valve (TV) annular diameter than 2-dimensional (2D) measurements. DESIGN: Prospective study. SETTING: The cardiothoracic operating rooms (ORs) at Mount Sinai Medical Center in New York, NY. PARTICIPANTS: Fifty-nine patients over 18 years of age underwent elective mitral valve surgery for severe mitral regurgitation from 2014 to 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-dimensional and 3D data sets and surgical TV annular dimensions were measured. Bland-Altman analysis was conducted and absolute differences were compared using paired t tests and the McNemar test. The observed mean difference between the 2D measurements by transgastric right ventricular diastolic view and the surgical measurements was 0.21 cm (standard deviation [SD] = 0.36 cm); the mean difference between the 3D measurements and surgical measures was -0.03 cm (SD = 0.19 cm). The McNemar test showed that the rate of highly successful measurements, defined as those within 0.2 cm of the true surgical score, using the 3D technique (66%) was significantly better than the rate of highly successful measurements using the 2D technique (25%), p< 0.01, 2-sided. CONCLUSION: Three-dimensional imaging and measurement of the TV annular diameter is feasible in the OR setting. The superiority of the 3D measurements versus 2D measurements allows for greater precision and accuracy and may guide better intraoperative surgical decision-making.

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury.

Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1(+) macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP(+) fibrogenic cells. Stabilin-1(-/-) macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6C(lo) monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1(+) monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage-specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1(+) macrophages shape the tissue microenvironment during liver injury and healing.

CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.

OBJECTIVE: Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. DESIGN: Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. RESULTS: Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. CONCLUSION: Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.